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1. Linoleate Isomerase Complex Contributes to Metabolism and Remission of DSS-Induced Colitis in Mice of Lactobacillus plantarum ZS2058

Author

Hui Qi, Catherine Stanton, Bo Yang, Jianxin Zhao, Hao Zhang, Haiqin Chen, Yang Chen, R. Paul Ross, He Gao, and Wei Chen

Subjects
Antioxidant, biology, Conjugated linoleic acid, Linoleic acid, medicine.medical_treatment, Lipid metabolism, General Chemistry, Metabolism, biology.organism_classification, Linoleate isomerase, chemistry.chemical_compound, chemistry, Biochemistry, Lactobacillus, medicine, General Agricultural and Biological Sciences, Lactobacillus plantarum
Abstract

A linoleate isomerase complex including myosin-cross-reactive antigen, short-chain dehydrogenase/oxidoreductase, and acetoacetate decarboxylase has been confirmed as the pivotal factor for conjugated linoleic acid (CLA) production in Lactobacillus plantarum. However, its role in the metabolism and health-associated benefits of Lactobacillus remain unclear. In the current study, the mild type, knockout, and complemented mutants of the linoleate isomerase complex of L. plantarum ZS2058 were used to investigate those putative effects. The metabonomic results showed that a linoleate isomerase complex could significantly influence the glycol-metabolism, lipid metabolism, and antioxidant compounds. Especially, with the stress of linoleic acid, linoleate isomerase complex knockout mutants induced the increase of several antioxidant compounds, such as glutamic acid, glycine, l-cysteine, glycerol, and l-sorbosone. Moreover, the linoleate isomerase complex played a pivotal role in ameliorating DSS-induced colitis. The knockout mutants showed effects similar to those in the DSS group, whereas complementation of the corresponding gene in the knockout mutants could restore the anti-inflammatory activity, wherein the integrity of a mucus layer was repaired, the level of pro-inflammatory cytokines decreased, and the amount of anti-inflammatory cytokines increased significantly. All the results indicated that the linoleate isomerase complex plays a key role in CLA production and metabolism as well as the health-associated benefits of L. plantarum ZS2058. These results are conducive to promote clinical trials and product development of probiotics for colitis.

Published
2021
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2. Exosomes derived from miR-1228 overexpressing bone marrow-mesenchymal stem cells promote growth of gastric cancer cells

Author

Ning Wang, Lili Chang, Xiaona Zhou, Shumei Zhang, He Gao, Huijun Yang, and Li Wang

Subjects
Male, Aging, Down-Regulation, exosomes, Biology, Exosome, Bone Marrow, Stomach Neoplasms, Cell Line, Tumor, Glioma, microRNA, Biomarkers, Tumor, Matrix Metalloproteinase 14, medicine, Humans, miR-1228, Aged, Cell Proliferation, Oligonucleotide Array Sequence Analysis, gastric cancer, Gene Expression Profiling, Mesenchymal stem cell, Cancer, Mesenchymal Stem Cells, Cell Biology, Transfection, Middle Aged, medicine.disease, Coculture Techniques, Healthy Volunteers, Microvesicles, Up-Regulation, Gene Expression Regulation, Neoplastic, MicroRNAs, Gastric Mucosa, Case-Control Studies, Cancer cell, MMP-14, Cancer research, Female, Research Paper, bone marrow-mesenchymal stem cells, Follow-Up Studies
Abstract

There has been increasing evidence that microRNAs (miRNAs) are related to glioma progression, and that genetically engineered mesenchymal stem cells (MSCs) can inhibit the growth of gliomas. However, the underlying mechanism of bone marrow-MSCs (BM--MSCs) and miRs in gastric cancer still remains unclear. Patients with gastric cancer treated in Shijiazhuang First Hospital as well as healthy individuals undergoing physical examinations were recruited to measure the expression of exosomal miR-1228. Receiver operating characteristic (ROC) curves were plotted and the patients were followed up. BM--MSCs from healthy subjects were collected and exosomes were extracted. The MSC cells were transfected with lentiviral vectors carrying miR-1228 and MMP-14 over-expression sequences and scramble sequence, followed by exosome extraction. The exosomes were co-cultured with SGC-7901 and MGC-823 cells to detect cell proliferation, invasion, apoptosis and migration. The correlation between miR-1228 and MMP-14 was determined by dual-luciferase reporter assay. miR-1228 was highly expressed in serum exosomes of patients with gastric cancer with a area under ROC curve (AUC) of 0.865. The exosomes derived from BM-MSCs are expected to be efficient nanocarriers. Up-regulation of miR-1228 can down-regulate the expression of MMP-14 and effectively hinders the development and progression of gastric cancer.

Published
2021
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3. CqsA/LuxS-HapR Quorum sensing circuit modulates type VI secretion system VflT6SS2 in Vibrio fluvialis

Author

He Gao, Anran Zhang, Yu Han, Xiaoshu Liu, Ping Liu, Biao Kan, Jingjing Pan, Weili Liang, and Yuanming Huang

Subjects
0301 basic medicine, Epidemiology, 030106 microbiology, Immunology, General Medicine, Enteric pathogen, Biology, biology.organism_classification, Microbiology, 03 medical and health sciences, Quorum sensing, 030104 developmental biology, Infectious Diseases, Vibrio fluvialis, Virology, Drug Discovery, Parasitology, Secretion, Type VI secretion system
Abstract

Vibrio fluvialis is an emerging enteric pathogen of increasing public health threat. Two quorum sensing (QS) systems, VfqI-VfqR and CqsA/LuxS-HapR, and two type VI secretion systems (T6SSs), VflT6S...

Published
2021
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4. Antioxidant Mechanism of Xiaojin Pill (小金丸) for Treatment of Peyronie’s Disease in Rats Based on Matrix Metalloproteinases

Author

Jun Guo, Bin Ouyang, Yu Zhao, Qing-He Gao, Qiang Han, Shao-Feng Chen, Qiang Geng, Zhong Li, Guo-Jin Yu, and Fu Wang

Subjects
medicine.medical_specialty, Antioxidant, medicine.medical_treatment, Rat model, 0211 other engineering and technologies, 02 engineering and technology, Matrix metalloproteinase, 030226 pharmacology & pharmacy, Superoxide dismutase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Internal medicine, 021105 building & construction, medicine, Pharmacology (medical), biology, business.industry, General Medicine, medicine.disease, Malondialdehyde, Endocrinology, Complementary and alternative medicine, chemistry, Pill, biology.protein, Peyronie's disease, business
Abstract

To evaluate the effects of Xiaojin Pill (小金丸) in the treatment of Peyronie’s disease (PD) in a rat model. Twenty-four male Sprague-Dawley rats were randomly divided into four groups with 6 in each: sham operation, PD model, vehicle control and Xiaojin Pill groups. The rats in the sham operation group received penile tunica albsginea (TA) injection with 50 μL vehicle, while the rats in the other 3 groups received 50 μL penile TA injection of 50 μg transforming growth factor (TGF)-β1. Forty-two days after the injection, rats in the vehicle control and Xiaojin Pill groups received 0.5 mL water and Xiaojin Pill solution (107 mg/kg of body weight), respectively by gavage for 28 days, while those in the sham operation and PD model groups did not receive any intervention. After intervention, the expressions of matrix metalloproteinase 2/9 (MMP2/9), nitric oxidesynthase (NOS), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured. Rats in the PD model and vehicle control groups presented obvious fibrosis in corpus cavernosum (CC) and demonstrated a significantly increased expressions of MMP2 and MMP9 in the CC compared with the sham operation group (all P

Published
2019
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5. Fermented Momordica charantia L. juice modulates hyperglycemia, lipid profile, and gut microbiota in type 2 diabetic rats

Author

Qixing Nie, Jielun Hu, He Gao, Shaoping Nie, Jia-Jia Wen, Tao Xiong, Haihong Chen, and Mingyong Xie

Subjects
Blood Glucose, Male, Momordica charantia, 030309 nutrition & dietetics, Gut flora, Diabetes Mellitus, Experimental, Prevotella melaninogenica, Butyric acid, 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, Lactobacillus, Animals, Food science, Rats, Wistar, 0303 health sciences, biology, Momordica, Chemistry, Prevotella oralis, food and beverages, 04 agricultural and veterinary sciences, biology.organism_classification, Lipids, 040401 food science, Gastrointestinal Microbiome, Rats, Fruit and Vegetable Juices, Hyperglycemia, Plant Preparations, Fermented Foods, Bacteroides thetaiotaomicron, Lactobacillus plantarum, Food Science
Abstract

The effect of Lactobacillus plantarum-fermentation on the anti-diabetic functionality of Momordica charantia was examined using a high-fat-diet and low-dose streptozocin-induced type 2 diabetic rat model. Fermented Momordica charantia juice (FMCJ) administration mitigated the hyperglycemia, hyperinsulinemia, hyperlipidemia, and oxidative stress in diabetic rats more favorably than the non-fermented counterpart. Treatments with FMCJ improved ergosterols and lysomonomethyl-phosphatidylethanolamines metabolisms more effectively. Supplement of FMCJ regulated the composition of the gut microbiota, such as increased the abundance of Bacteroides caecigallinarum, Oscillibacter ruminantium, Bacteroides thetaiotaomicron, Prevotella loescheii, Prevotella oralis, and Prevotella melaninogenica, in diabetic rats compared with untreated diabetic rats. Moreover, FMCJ-treated diabetic rats exhibited higher concentrations of acetic acid, propionic acid, butyric acid, total short-chain fatty acids and lower pH values in colonic contents than that in non-fermented juice-treated rats. These results demonstrated that Lactobacillus plantarum-fermentation enhanced the anti-diabetic property of MC juice by favoring the regulation of gut microbiota and the production of SCFAs.

Published
2019
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6. Momordica charantia juice with Lactobacillus plantarum fermentation: Chemical composition, antioxidant properties and aroma profile

Author

Shaoping Nie, Haihong Chen, Qixing Nie, Mingyong Xie, Tao Xiong, Jielun Hu, He Gao, and Jia-Jia Wen

Subjects
0303 health sciences, Antioxidant, biology, Momordica, 030309 nutrition & dietetics, medicine.medical_treatment, food and beverages, 04 agricultural and veterinary sciences, Sterilization (microbiology), biology.organism_classification, 040401 food science, Biochemistry, Lactic acid, carbohydrates (lipids), 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, chemistry, medicine, Fermentation, Food science, Aroma, Flavor, Lactobacillus plantarum, Food Science
Abstract

Momordica charantia L. has been consumed as a vegetable for thousands of years, and its fruit has various bioactive compounds. The aim of this study was to investigate the effect of fermentation with Lactobacillus plantarum (L. plantarum) NCU116 on the chemical composition, antioxidant activity, and volatile profile of M. charantia juice. Fermentation and sterilization increased the concentrations of short-chain fatty acids, while the total saponins in the juice was reduced. Fermentation increased lactic acid, total phenolics, and total flavonoids. Fermentation improved the phenolic composition of the juice, such as decreased caffeic and p-coumaric acids, and increased dihydrocaffeic and phloretic acids. Furthermore, the antioxidant properties of the juice and phenolic extracts increased after fermentation. Fermentation altered the aroma profile of the juice to confer a more desirable flavor by reducing aldehydes and ketones, while increasing alcohols and acids. Sterilization decreased lactic acid, total phenolic content, phenolic composition, antioxidant activities, and the aroma profile. These results suggested that L. plantarum fermentation had a beneficial effect on the physico-chemical properties, bioactive compounds, antioxidant property, as well as aroma composition of M. charantia.

Published
2019
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7. Overexpression and characterization of a thermostable β-agarase producing neoagarotetraose from a marine isolate Microbulbifer sp. AG1

Author

Hebin Li, Hui Ni, Lijun Li, Anfeng Xiao, Jiang Zedong, Yanbing Zhu, and He Gao

Subjects
chemistry.chemical_classification, 010504 meteorology & atmospheric sciences, biology, Agarase, Aquatic Science, 010502 geochemistry & geophysics, Oceanography, medicine.disease_cause, 01 natural sciences, Enzyme assay, law.invention, chemistry.chemical_compound, Enzyme, Biochemistry, chemistry, law, Enzymatic hydrolysis, biology.protein, Recombinant DNA, medicine, Agarose, Escherichia coli, 0105 earth and related environmental sciences, Thermostability
Abstract

An agarase gene containing 1 302 bp was cloned from Microbulbifer sp. AG1. It encoded a mature protein of 413 amino acids plus a 20-residue signal peptide. The recombinant enzyme without the signal peptide was expressed and purified from Escherichia coli BL21 (DE3). When agarose was used as a substrate, the optimal temperature and pH for the enzyme were 60°C and 7.5, respectively. The recombinant agarase showed excellent thermostability with 67% and 19% of residual activities after incubation at 50°C and 60°C for 1 h, respectively. Except SDS, the recombinant agarase had a relatively good resistance against the detected inhibitors, detergents and urea denaturant. Thin layer chromatography analysis and enzyme assay using p-nitrophenyl-α/β-Dgalactopyranoside revealed that the recombinant agarase was a β-agarase that degraded agarose into neoagarotetraose as the main end product. The enzymatic hydrolysis products with different degree of polymerization exhibited the antioxidant activities.

Published
2019
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8. Polysaccharide from Plantago asiatica L. attenuates hyperglycemia, hyperlipidemia and affects colon microbiota in type 2 diabetic rats

Author

Shaoping Nie, Qixing Nie, Jielun Hu, Haihong Chen, Linlin Fan, and He Gao

Subjects
0301 basic medicine, medicine.medical_specialty, General Chemical Engineering, medicine.medical_treatment, Plantago asiatica, Gut flora, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Diabetes mellitus, Hyperlipidemia, medicine, chemistry.chemical_classification, Triglyceride, biology, Insulin, food and beverages, Fatty acid, General Chemistry, biology.organism_classification, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, lipids (amino acids, peptides, and proteins), Bacteroides, Food Science
Abstract

Type 2 diabetes is a complex metabolic and endocrine disorder worldwide, which causes severe health and economic problems. The effects of polysaccharide from Plantago asiatica L. (PLP) on high-fat diet and streptozotocin-induced type 2 diabetic rats were examined. Administration of PLP caused significant decreases in the concentrations of blood glucose, insulin, total cholesterol, triglyceride, non-esterified fatty acid and maleic dialdehyde, and significant increases in the levels of high density lipoprotein-cholesterol and the activities of antioxidant enzymes compared with diabetic rats after 4 weeks’ treatment. The concentrations of short-chain fatty acids (SCFA) were significantly higher in the feces of diabetic rats after treatment with PLP. Moreover, colon bacterial diversity and abundance of bacteria, including Bacteroides vulgatus, Lactobacillus fermentum, Prevotella loescheii and Bacteroides vulgates were significantly increased by PLP treatment. These results indicated that the anti-diabetic effect of PLP in type 2 diabetic rats may be associated with regulation of gut microbiota and increased levels of SCFA.

Published
2019
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9. Acceptability, Usability, and Performance of Lateral Flow Immunoassay Tests for Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies: REACT-2 Study of Self-Testing in Nonhealthcare Key Workers

Author

Graham S Cooke, Wendy S. Barclay, Kimberly Bennet, Steven Riley, Helen Ward, He Gao, Deborah Ashby, Ara Darzi, Jordan Jenkins, Christina Atchison, Paul Elliott, Bethan Davies, Marzieh Araghi, Maya Moshe, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, Department of Health, and Abdul Latif Jameel Foundation

Subjects
medicine.medical_specialty, Population, antibody testing, COVID-19 diagnostic testing, Internal medicine, Epidemiology, Major Article, Medicine, Seroprevalence, education, education.field_of_study, biology, medicine.diagnostic_test, SARS-CoV-2, business.industry, Usability, Confidence interval, AcademicSubjects/MED00290, Infectious Diseases, Oncology, sensitivity and specificity, Immunoassay, Cohort, biology.protein, Antibody, business
Abstract

Background Seroprevalence studies are essential to understand the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Various technologies, including laboratory assays and point-of-care self-tests, are available for antibody testing. The interpretation of seroprevalence studies requires comparative data on the performance of antibody tests. Methods In June 2020, current and former members of the United Kingdom police forces and fire service performed a self-test lateral flow immunoassay (LFIA), had a nurse-performed LFIA, and provided a venous blood sample for enzyme-linked immunosorbent assay (ELISA). We present the prevalence of antibodies to SARS-CoV-2 and the acceptability and usability of self-test LFIAs, and we determine the sensitivity and specificity of LFIAs compared with laboratory ELISA. Results In this cohort of 5189 current and former members of the police service and 263 members of the fire service, 7.4% (396 of 5348; 95% confidence interval [CI], 6.7–8.1) were antibody positive. Seroprevalence was 8.9% (95% CI, 6.9–11.4) in those under 40 years, 11.5% (95% CI, 8.8–15.0) in those of nonwhite ethnicity, and 7.8% (95% CI, 7.1–8.7) in those currently working. Self-test LFIA had an acceptability of 97.7% and a usability of 90.0%. There was substantial agreement between within-participant LFIA results (kappa 0.80; 95% CI, 0.77–0.83). The LFIAs had a similar performance: compared with ELISA, sensitivity was 82.1% (95% CI, 77.7–86.0) self-test and 76.4% (95% CI, 71.9–80.5) nurse-performed with specificity of 97.8% (95% CI, 97.3–98.2) and 98.5% (95% CI, 98.1–98.8), respectively. Conclusions A greater proportion of this nonhealthcare key worker cohort showed evidence of previous infection with SARS-CoV-2 than the general population at 6.0% (95% CI, 5.8–6.1) after the first wave in England. The high acceptability and usability reported by participants and similar performance of self-test and nurse-performed LFIAs indicate that the self-test LFIA is fit for purpose for home testing in occupational and community prevalence studies.

Published
2021

10. Acceptability, usability and performance of lateral flow immunoassay tests for SARS-CoV-2 antibodies: REACT-2 study of self-testing in non-healthcare key workers

Author

Graham S Cooke, Steven Riley, Jordan Jenkins, Paul Elliott, Wendy S. Barclay, Christina Atchison, Helen Ward, Bethan Davies, Kimberly Bennet, Deborah Ashby, Maya Moshe, Ara Darzi, He Gao, and Marzieh Araghi

Subjects
education.field_of_study, medicine.medical_specialty, biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, Usability, Internal medicine, Cohort, Epidemiology, Health care, medicine, biology.protein, Seroprevalence, Antibody, education, business
Abstract

BackgroundSeroprevalence studies in key worker populations are essential to understand the epidemiology of SARS-CoV-2. Various technologies, including laboratory assays and point-of-care self-tests, are available for antibody testing. The interpretation of seroprevalence studies requires comparative data on the performance of antibody tests.MethodsIn June 2020, current and former members of the UK Police forces and Fire service performed a self-test lateral flow immunoassay (LFIA) and provided a saliva sample, nasopharyngeal swab, venous blood samples for Abbott ELISA and had a nurse performed LFIA. We present the prevalence of PCR positivity and antibodies to SARS-CoV-2 in this cohort following the first wave of infection in England; the acceptability and usability of self-test LFIAs (defined as use of the LFIA kit and provision of a valid result, respectively); and determine the sensitivity and specificity of LFIAs compared to laboratory ELISAs.ResultsIn this cohort of non-healthcare key workers, 7.4% (396/5,348; 95% CI, 6.7-8.1) were antibody positive. Seroprevalence was 8.9% (6.9-11.4) in those under 40 years, 11.5% (8.8-15.0) in those of non-white British ethnicity and 7.8% (7.1-8.7) in those currently working. The self-test LFIA had an acceptability of 97.7% and a usability of 90.0%. There was substantial agreement between within-participant LFIA results (kappa 0.80; 0.77-0.83). The LFIAs (self-test and nurse-performed) had a similar performance: compared to ELISA, sensitivity was 82.1% (77.7-86.0) self-test and 76.4% (71.9-80.5) nurse-performed with specificity of 97.8% (97.3-98.2) and 98.5% (98.1-98.8) respectively.ConclusionA greater proportion of the non-healthcare key worker cohort showed evidence of previous infection with SARS-CoV-2 than the general population at 6.0% (5.8-6.1) following the first wave in England. The high acceptability and usability reported by participants and the similar performance of self-test and nurse-performed LFIAs indicate that the self-test LFIA is fit for purpose for home-testing in occupational and community prevalence studies.

Published
2021
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11. Bioactive Dietary Fibers Selectively Promote Gut Microbiota to Exert Antidiabetic Effects

Author

Shaoping Nie, Qingying Fang, Xiaojun Huang, Qixing Nie, Jielun Hu, Jun-Yi Yin, Sheng Zuo, Mingzhi Li, He Gao, Haihong Chen, and Yonggan Sun

Subjects
0106 biological sciences, Dietary Fiber, Prevotella, Glucomannan, Gut flora, 01 natural sciences, Diabetes Mellitus, Experimental, Butyric acid, chemistry.chemical_compound, Arabinogalactan, Arabinoxylan, medicine, Animals, Hypoglycemic Agents, Food science, Guar gum, biology, Chemistry, 010401 analytical chemistry, Akkermansia, General Chemistry, biology.organism_classification, 0104 chemical sciences, Gastrointestinal Microbiome, Rats, General Agricultural and Biological Sciences, Xanthan gum, 010606 plant biology & botany, medicine.drug
Abstract

High intake of dietary fibers was found to be inversely associated with type-2 diabetes (T2D), whereas the difference among different dietary fibers on T2D remains unclear. Therefore, we have investigated the effects of different dietary fibers on T2D. Nine types of dietary fibers were used to investigate and evaluate their effects on type-2 diabetic rats via physiology, genomics, and metabolomics. We found that supplementation with β-glucan, arabinogalactan, guar gum, apple pectin, glucomannan, and arabinoxylan significantly reduced the fasting blood glucose, whereas carrageenan, xylan, and xanthan gum did not affect glycemic control in diabetic rats. Also, bioactive dietary fibers (β-glucan, arabinogalactan, guar gum, and apple pectin) associated with the increased butyric acid level and abundance of beneficial bacteria (Lachnobacterium, Parabacteroides, Faecalibacterium, Akkermansia, and some butyric acid-producing bacteria), as well as improved host metabolism by decreasing 12α-hydroxylated bile acids, acylcarnitines, and amino acids (leucine, phenylalanine, citrulline, etc.), thereby exert beneficial effects on T2D. It was also found that β-glucan might attenuate insulin resistance via downregulation of Prevotella copri-mediated biosynthesis of branched-chain amino acids in T2D. Together, our study uncovered the effects of different dietary fibers on T2D, along with their potential mechanism.

Published
2021

12. TTK predicts triple positive breast cancer prognosis and regulates tumor proliferation and invasion

Author

Shan-Shan Qu, Yun-He Gao, Lanqing Cao, and Min Yao

Subjects
Adult, Threonine, Cancer Research, Breast Neoplasms, Cell Cycle Proteins, Kaplan-Meier Estimate, Biology, Protein Serine-Threonine Kinases, Breast cancer, In vivo, Cell Line, Tumor, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, Cell Proliferation, Aged, 80 and over, Gene knockdown, Kinase, Cancer, Middle Aged, Protein-Tyrosine Kinases, medicine.disease, Prognosis, Oncology, Cell culture, Cancer research, Immunohistochemistry, Tyrosine, Female
Abstract

Background: This study was conducted to investigate the expression of the spindle assembly checkpoint kinase tyrosine/threonine kinase (TTK) in triple positive breast cancer (TPBC) and its effect on TPBC cells. Methods: We analyzed the status of TTK in 69 TPBC samples using immunohistochemistry. The correlation between TTK and clinicopathological parameters was analyzed using a chi-squared test. The prognostic value of TTK was evaluated using Kaplan–Meier survival curves. We analyzed the role of TTK in the invasion and proliferation of TPBC cells in vitro and in vivo. Results: The mean age of the 69 patients with TPBC enrolled in this study was 53 years (range: 29–86 years). TTK expression was positively correlated with tumor size (P = 0.034), p53 status (P = 0.023), TNM stage (P = 0.023), and Ki-67 index (P< 0.001). The Kaplan–Meier curves revealed that TTK expression was correlated with poor disease-free survival (P = 0.001) and overall survival (P = 0.050). Multivariate proportional hazard regression analyses showed that TTK and TNM staging were significant independent predictors of disease-free survival (P = 0.007 and P = 0.034, respectively). Additionally, TTK knockdown inhibited the invasion and proliferation of the BT474 TPBC cell line. Conclusions: The findings of the study indicate that TTK overexpression is associated with cancer progression and prognosis in patients with TPBC, whereas TTK knockdown inhibits the invasion and proliferation of TPBC cells. Thus, TTK may serve as a prognostic marker for TPBC.

Published
2021

13. Polysaccharides from fermented Momordica charantia L. with Lactobacillus plantarum NCU116 ameliorate metabolic disorders and gut microbiota change in obese rats

Author

Mingyong Xie, He Gao, Shaoping Nie, Haihong Chen, Qixing Nie, Jielun Hu, Yan-Li Zhang, Jia-Jia Wen, and Mingzhi Li

Subjects
0301 basic medicine, Male, food.ingredient, Momordica charantia, 030204 cardiovascular system & hematology, Gut flora, law.invention, Rats, Sprague-Dawley, 03 medical and health sciences, Probiotic, 0302 clinical medicine, food, Anaerostipes, Metabolic Diseases, law, Polysaccharides, Lactobacillus, Animals, Food science, Obesity, Bifidobacterium, biology, Plant Extracts, Probiotics, Body Weight, Lipid metabolism, General Medicine, biology.organism_classification, Lipids, Gastrointestinal Microbiome, Rats, 030104 developmental biology, Fermentation, Metabolome, Bacteria, Lactobacillus plantarum, Food Science
Abstract

Obesity is a chronic disease characterized by overweight resulting from fat accumulation, along with disturbance of metabolism and gut microbiota. Fermentation, as a green processing method, is beneficial for improving the nutrition capacity of food components. Polysaccharides are considered as one of the important components in food and are also potential supplements for anti-obesity treatment. This study aimed to investigate the anti-obesity effects of polysaccharides from fermented and non-fermented Momordica charantia L. with Lactobacillus plantarum NCU116 (FP and NFP) on obese rats by serum metabolomics and gut microbiota analysis. Metabolomics results revealed that abnormal lipid metabolism was formed due to obesity. The supplement of FP and NFP improved the glycerophospholipids, glycosphingolipids, and amino acid metabolism of the obese rats, which alleviated the hypercholesterolemia and overweight in rats. Furthermore, the disorder of gut microbiota was ameliorated by FP and NFP. FP promoted the growth of beneficial bacteria, such as phylum Firmicutes, Actinobacteria, and genera Anaerostipes, Coprococcus, Lactobacillus, and Bifidobacterium. FP also reduced several harmful bacteria belonging to the phylum Proteobacteria and genera Helicobacter. The positive correlation of the weight loss and lowering of serum lipids with the increased beneficial bacteria further elucidated that the anti-obesity effect of FP in obese rats is associated with the regulation of gut microbiota and serum metabolites. The results of this study could provide information for developing probiotic products in the future that may have beneficial effects on the prevention or treatment of obesity.

Published
2021

14. Development of a Rapid and Fully Automated Multiplex Real-Time PCR Assay for Identification and Differentiation of Vibrio cholerae and Vibrio parahaemolyticus on the BD MAX Platform

Author

Zhenpeng Li, Hongxia Guan, Wei Wang, He Gao, Weihong Feng, Jie Li, Baowei Diao, Hongqun Zhao, Biao Kan, and Jingyun Zhang

Subjects
0301 basic medicine, Microbiology (medical), 030106 microbiology, Immunology, lcsh:QR1-502, Biology, medicine.disease_cause, Microbiology, lcsh:Microbiology, 03 medical and health sciences, medicine, TaqMan, Multiplex, Vibrio cholerae, Toxin, Vibrio parahaemolyticus, Cholera toxin, BD MAX, biology.organism_classification, DNA extraction, multiplex, 030104 developmental biology, Infectious Diseases, Real-time polymerase chain reaction, real-time PCR
Abstract

Vibrio cholerae and Vibrio parahaemolyticus are common diarrheal pathogens of great public health concern. A multiplex TaqMan-based real-time PCR assay was developed on the BD MAX platform; this assay can simultaneously detect and differentiate V. cholerae and V. parahaemolyticus directly from human fecal specimens. The assay includes two reactions. One reaction, BDM-VC, targets the gene ompW, the cholera toxin (CT) coding gene ctxA, the O1 serogroup specific gene rfbN, and the O139 serogroup specific gene wbfR of V. cholerae. The other, BDM-VP, targets the gene toxR and the toxin coding genes tdh and trh of V. parahaemolyticus. In addition, each reaction contains a sample process control. When evaluated with spiked stool samples, the detection limit of the BD MAX assay was 195–780 CFU/ml for V. cholerae and 46–184 CFU/ml for V. parahaemolyticus, and the amplification efficiency of all genes was between 95 and 115%. The assay showed 100% analytical specificity, using 63 isolates. The BD MAX assay was evaluated for its performance compared with conventional real-time PCR after automated DNA extraction steps, using 164 retrospective stool samples. The overall percent agreement between the BD MAX assay and real-time PCR was ≥ 98.8%; the positive percent agreement was 85.7% for ompW, 100% for toxR/tdh, and lower (66.7%) for trh because of a false negative. This is the first report to evaluate the usage of the BD MAX open system in detection and differentiation of V. cholerae and V. parahaemolyticus directly from human samples.

Published
2021
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15. A multiplex PCR assay for the detection of five human pathogenic Vibrio species and Plesiomonas

Author

Haijian Zhou, Duochun Wang, Hongqun Zhao, He Gao, Jingyun Zhang, Hongxia Guan, Dan Sha, Panpan Xue, Jie Li, Baowei Diao, and Biao Kan

Subjects
0303 health sciences, biology, 030306 microbiology, Electrophoresis, Capillary, Cell Biology, biology.organism_classification, Sensitivity and Specificity, Vibrio, Pathogenic vibrio, Microbiology, 03 medical and health sciences, Plesiomonas shigelloides, 23S ribosomal RNA, Multiplex polymerase chain reaction, Humans, Plesiomonas, Estuaries, Water Microbiology, Molecular Biology, Multiplex Polymerase Chain Reaction, 030304 developmental biology
Abstract

A multiplex PCR (mPCR) assay was established to detect five pathogenic Vibrio species and Plesiomonas shigelloides. Twelve genes were included: ompW, ctxA, rfbN, and wbfR from V. cholerae; tl, tdh, and trh from V. parahaemolyticus; toxR and vmhA from V. mimicus; toxR from V. fluvialis; vvhA from V. vulnificus; and the 23S rRNA gene from P. shigelloides. The specificity of the mPCR assay was 100% for the detection of 136 strains and the limits of detection (LoD) were 12.5-50 pg/reaction. The assay exhibited higher sensitivity than cultivation methods in the detection of APW cultures of 113 diarrhea samples. In the analysis of 369 suspected Vibrio populations from estuarine water samples, the specificity of the mPCR for V. cholerae and V. parahaemolyticus was 100% for both, while the sensitivities were 100% and 96.1%, respectively. The assay can be applied to screen enrichment cultures and suspected colonies from environmental and clinical samples.

Published
2020

16. A novel mechanism of streptomycin resistance in Yersinia pestis: Mutation in the rpsL gene

Author

He Gao, Qi Zhang, Wei Li, Xiaoyan Yang, Juan Jin, Ruixia Dai, Xuefei Zhang, Sheng Li, Jianguo Xu, Juan Li, Xi Zha, Youquan Xin, Yumeng Wang, Qingwen Zhang, Bai Jixiang, Hailian Wu, Baiqing Wei, Yiting Wang, Jian He, and Yao Peng

Subjects
0301 basic medicine, Bacterial Diseases, Biovar, RC955-962, Tibet, Pathology and Laboratory Medicine, Biochemistry, Plasmid, Medical Conditions, Antibiotics, Arctic medicine. Tropical medicine, Mobile Genetic Elements, Medicine and Health Sciences, biology, Antimicrobials, Drugs, Genomics, Yersinia, Anti-Bacterial Agents, Bacterial Pathogens, Nucleic acids, Infectious Diseases, Streptomycin, Medical Microbiology, Public aspects of medicine, RA1-1270, Pathogens, medicine.drug, Plasmids, Research Article, Pneumonic plague, DNA, Bacterial, Substitution Mutation, Yersinia Pestis, Forms of DNA, 030106 microbiology, Pneumonic Plagues, Microbial Sensitivity Tests, Bubonic plague, Microbiology, Mycobacterium tuberculosis, 03 medical and health sciences, Antibiotic resistance, Genetic Elements, Microbial Control, medicine, Genetics, Animals, Microbial Pathogens, Pharmacology, Plague, Bacteria, Public Health, Environmental and Occupational Health, Organisms, Biology and Life Sciences, DNA, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, medicine.disease, Plagues, 030104 developmental biology, Yersinia pestis, Marmota, Antibiotic Resistance, Mutation, Antimicrobial Resistance
Abstract

Streptomycin is considered to be one of the effective antibiotics for the treatment of plague. In order to investigate the streptomycin resistance of Y. pestis in China, we evaluated streptomycin susceptibility of 536 Y. pestis strains in China in vitro using the minimal inhibitory concentration (MIC) and screened streptomycin resistance-associated genes (strA and strB) by PCR method. A clinical Y. pestis isolate (S19960127) exhibited high-level resistance to streptomycin (the MIC was 4,096 mg/L). The strain (biovar antiqua) was isolated from a pneumonic plague outbreak in 1996 in Tibet Autonomous Region, China, belonging to the Marmota himalayana Qinghai–Tibet Plateau plague focus. In contrast to previously reported streptomycin resistance mediated by conjugative plasmids, the genome sequencing and allelic replacement experiments demonstrated that an rpsL gene (ribosomal protein S12) mutation with substitution of amino-acid 43 (K43R) was responsible for the high-level resistance to streptomycin in strain S19960127, which is consistent with the mutation reported in some streptomycin-resistant Mycobacterium tuberculosis strains. Streptomycin is used as the first-line treatment against plague in many countries. The emergence of streptomycin resistance in Y. pestis represents a critical public health problem. So streptomycin susceptibility monitoring of Y. pestis isolates should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation, especially when treatment failure is suspected due to antibiotic resistance., Author summary The plague natural foci are widely distributed in the world, and correspondingly, the plague still poses a significant threat to human health in some countries with endemic plague foci. Streptomycin is used as the first-line treatment against plague in many countries for the antibiotic is considered to be one of the effective antibiotics, particularly for the treatment of pneumonic plague. The resistance to streptomycin had been reported in Y. pestis strains from Madagascar in previous studies. In this study, we reported the high-level resistance to streptomycin in a clinical isolate of Y. pestis from a pneumonic patient in Tibet Autonomous Region, China, and a novel mechanism of streptomycin resistance, i.e. mutation in the rpsL gene were identified. The knowledge acquired about streptomycin resistance in Y. pestis will remain of great practical value. For the emergence of resistance to streptomycin in Y. pestis would render the treatment failure, thus corresponding antibiotic monitoring should be routinely carried out in countries threatened by plague. In addition, based on our further understanding about streptomycin resistance of Y. pestis isolates, such monitoring should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation in Y. pestis isolates.

Published
2020

17. Fur Represses Vibrio cholerae Biofilm Formation via Direct Regulation of vieSAB, cdgD, vpsU, and vpsA-K Transcription

Author

Yiquan Zhang, Hongqun Zhao, Jing Lou, Baowei Diao, Qin Qin, Jie Li, Biao Kan, Yue Qiu, He Gao, Jingyun Zhang, Qiannan Shi, and Lizhi Ma

Subjects
Microbiology (medical), lcsh:QR1-502, Repressor, medicine.disease_cause, Microbiology, biofilm, lcsh:Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Transcription (biology), medicine, Electrophoretic mobility shift assay, Gene, Vibrio cholerae, Fur, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Biofilm, c-di-GMP, biology.organism_classification, Vibrio, Cell biology, chemistry, vps, DNA
Abstract

Attached Vibrio cholerae biofilms are essential for environmental persistence and infectivity. The vps loci (vpsU, vpsA-K, and vpsL-Q) are required for mature biofilm formation and are responsible for the synthesis of exopolysaccharide. Transcription of vps genes is activated by the signaling molecule bis-(3'-5')-cyclic di-GMP (c-di-GMP), whose metabolism is controlled by the proteins containing the GGDEF and/or EAL domains. The ferric uptake regulator (Fur) plays key roles in the transcription of many genes involved in iron metabolism and non-iron functions. However, roles for Fur in Vibrio biofilm production have not been documented. In this study, phenotypic assays demonstrated that Fur, independent of iron, decreases in vivo c-di-GMP levels and inhibits in vitro biofilm formation by Vibrio cholerae. The Fur box-like sequences were detected within the promoter-proximal DNA regions of vpsU, vpsA-K, vieSAB, and cdgD, suggesting that transcription of these genes may be under the direct control of Fur. Indeed, the results of luminescence, quantitative PCR (qPCR), electrophoretic mobility shift assay (EMSA), and DNase I footprinting assays demonstrated Fur to bind to the promoter-proximal DNA regions of vpsU, vpsA-K, and cdgD to repress their transcription. In contrast, Fur activates the transcription of vieSAB in a direct manner. The cdgD and vieSAB encode proteins with GGDEF and EAL domains, respectively. Thus, data presented here highlight a new physiological role for Fur wherein it acts as a repressor of V. cholerae biofilm formation mediated by decreasing the production of exopolysaccharide and the intracellular levels of c-di-GMP.

Published
2020
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18. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author

Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)

Subjects
0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Published
2020
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19. Characterization of an antigenic serine protease in the Trichinella spiralis adult

Author

Haining Shi, Xue Bai, Bin Tang, Libo Wang, Mingyuan Liu, He Gao, Xiu-Ping Wu, Wang Xuelin, and Xiaolei Liu

Subjects
0301 basic medicine, Proteases, medicine.medical_treatment, Blotting, Western, Muscle Fibers, Skeletal, 030231 tropical medicine, Immunology, Trichinella spiralis, Biology, Real-Time Polymerase Chain Reaction, Host-Parasite Interactions, Serine, Mice, 03 medical and health sciences, 0302 clinical medicine, Western blot, medicine, Animals, Humans, Amino Acid Sequence, Rats, Wistar, Muscle, Skeletal, Blood Coagulation, Serine protease, Mice, Inbred BALB C, Protease, medicine.diagnostic_test, cDNA library, Immune Sera, Serine Endopeptidases, General Medicine, Kallikrein, biology.organism_classification, Molecular biology, Rats, 030104 developmental biology, Infectious Diseases, Antigens, Helminth, Larva, biology.protein, Electrophoresis, Polyacrylamide Gel, Female, Parasitology, Rabbits, Serine Proteases, Sequence Alignment
Abstract

Serine proteases have been identified as important molecules that are involved in many parasitic infections, and these molecules have also been suggested to play important roles in Trichinella spiralis infections. In the present study, the antigenic serine protease gene Ts-ADSp-7, which was screened from a cDNA library of Trichinella spiralis Adults at 3 days post-infection (p.i.), was cloned and expressed in Escherichia coli. The encoded protein, Ts-ADSp-7, revealed a potential trypsin-like serine protease domain but lacked substrate banding site at position 227 and protease activity. Transcription could be detected in the Adult and muscle larval stage but not in the newborn larval stage, where no fluorescent signal was detected. Western blot analysis revealed that the 3 days p.i. Adults and muscle larvae could secrete Ts-ADSp-7. Interestingly, strong fluorescent signal of Ts-ADSp-7 could be detected in the nucleoli of the enlarged muscle cell nuclei from 12 to 16 days p.i. and in the β-stichosomes of the muscle larvae from 16 to 35 days p.i.. The coagulation assay indicated that Ts-ADSp-7 could inhibit intrinsic coagulation pathway. Regarding the putatively important function of the serine protease in the helminth infection to hosts, a total of 81 serine proteases were found in the parasite and mainly comprised eight subfamilies. These subfamilies exhibited high similarity to transmembrane serine protease, coagulation factor XI, lipocalin, guanylin, ceropin, kallikrein, and plasminogen. Moreover, stage specificity was detected in several subfamilies. In summary, the putatively inactive serine protease-like protein Ts-ADSp-7 could inhibit blood coagulation, and the protein is located in the enlarged nuclei of nurse cells during capsule formation. Furthermore, members of the serine protease family in the parasite might be important molecules in the parasite-host interaction.

Published
2018
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20. Bifidobacterium breve CCFM683 could ameliorate DSS-induced colitis in mice primarily via conjugated linoleic acid production and gut microbiota modulation

Author

Bo Yang, Wei Chen, He Gao, Catherine Stanton, Haiqin Chen, Juntong Wang, R. Paul Ross, and Hao Zhang

Subjects
0301 basic medicine, Conjugated linoleic acid, medicine.medical_treatment, ved/biology.organism_classification_rank.species, Porphyromonadaceae, Medicine (miscellaneous), Gut microbiota, Bifidobacterium breve, Gut flora, Pharmacology, Amelioration, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, TX341-641, Colitis, Nutrition and Dietetics, biology, Nutrition. Foods and food supply, ved/biology, Myeloperoxidase activity, medicine.disease, biology.organism_classification, 030104 developmental biology, Cytokine, Nuclear receptor, chemistry, 030211 gastroenterology & hepatology, Food Science
Abstract

Probiotics have been proposed as the alternative therapy for IBD, but with strong strain-dependent effects. The current work aims to investigate the protective effect of B. breve CCFM683 on a DSS-induced colitis. CCFM683 significantly inhibited disease activity index, colon shortening and myeloperoxidase activity. Additionally, CCFM683 improved the histological damage, protected the colonic mucous layer integrity and significantly attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), while up-regulated the expression of colonic anti-inflammatory cytokine IL-10 and nuclear receptor PPARγ. Meanwhile, the concentration of colonic conjugated linoleic acid (CLA) was significantly increased in response to CCFM683 supplementation, which demonstrates that CCFM683 prevents colitis in correlation with local CLA production. Furthermore, CCFM683 could rebalance the gut microbial composition damaged by DSS, including reducing the abundance of Romboutsia, Porphyromonadaceae, Desulfovibrionaceae as well as increasing the abundance of Peptostreptococcaceae, which indicated that gut microbiota reconstruction might be another factor for CCFM683 protection against colitis.

Published
2018
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21. A fluorescent τ-probe: quantitative imaging of ultra-trace endogenous hydrogen polysulfide in cells and in vivo

Author

Bin Kang, He Gao, Xiao-Yang Sun, Hong-Yuan Chen, Rui-Bing An, Fan Yang, Jing-Juan Xu, and Shanshan Li

Subjects
Detection limit, Cell signaling, biology, 010405 organic chemistry, Endogeny, General Chemistry, 010402 general chemistry, biology.organism_classification, 01 natural sciences, Fluorescence, 0104 chemical sciences, Transduction (genetics), chemistry.chemical_compound, chemistry, In vivo, Biophysics, Zebrafish, Polysulfide
Abstract

Hydrogen sulfide (H2S) has been recognized as an important endogenous gasotransmitter associated with biological signaling transduction. However, recent biological studies implied that the H2S-related cellular signaling might actually be mediated by hydrogen polysulfides (H2Sn, n > 1), not H2S itself. Unraveling such a mystery strongly demanded the quantification of endogenous H2Sn in living systems. However, endogenous H2Sn has been undetectable thus far, due to its extremely low concentration within cells. Herein, we demonstrated a strategy to detect ultra-trace endogenous H2Snvia a fluorescent τ-probe, through changes of fluorescence lifetime instead of fluorescence intensity. This τ-probe exhibited an ultrasensitive response to H2Sn, bringing about the lowest value of the detection limit (2 nM) and a lower limit of quantification (10 nM) to date. With such merits, we quantified and mapped endogenous H2Sn within cells and zebrafish. The quantitative information about endogenous H2Sn in cells and in vivo may have a significant implication for future research on the role of H2Sn in biology. The methodology of the τ-probe established here might provide a general insight into the design and application of any fluorescent probes, beyond the limit of utilizing fluorescence intensity.

Published
2018
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22. Physicochemical characterization, antioxidant activity of polysaccharides from Mesona chinensis Benth and their protective effect on injured NCTC-1469 cells induced by H2O2

Author

Lihua Lin, Mingyue Shen, Bruce R. Hamaker, Wei Tang, Mengxia Du, Mingyong Xie, Dan Liu, He Gao, and Jianhua Xie

Subjects
chemistry.chemical_classification, Chromatography, Antioxidant, Polymers and Plastics, biology, DPPH, medicine.medical_treatment, Organic Chemistry, Extraction (chemistry), 04 agricultural and veterinary sciences, 02 engineering and technology, 021001 nanoscience & nanotechnology, biology.organism_classification, Polysaccharide, 040401 food science, Mesona chinensis, Ingredient, chemistry.chemical_compound, 0404 agricultural biotechnology, chemistry, Galactose, Materials Chemistry, medicine, Monosaccharide, 0210 nano-technology
Abstract

Polysaccharides MP-A, MP-U and MP-C were extracted from Mesona chinensis Benth by hot-alkali extraction (HAE), ultrasonic-assisted extraction (UAE) and cellulose-enzyme assisted extraction (CAE), respectively. The yields, physicochemical properties and antioxidant of polysaccharides were investigated. Results showed that the yields of MP-A (11.14%), MP-U (10.62%) and MP-C (9.70%) were similar, and they were all heteropolysaccharides with average molecular weights of 1.9×105Da, 1.5×105Da, 1.4×105Da. Glucose, galactose, and galacturonic acid were the main monosaccharides in MP-A, MP-U and MP-C with molar ratios of 1.00:1.34:0.25, 1.00:2.49:0.19 and 1.00:2.95:0.84, respectively. MP-C extracted by CAE exhibited higher antioxidant activities in FRAP, DPPH, hydroxyl radical assays and the H2O2-induced injury cell model. The three extraction methods had only slight effects on chemical composition, while MP-C extracted by CAE exhibited the highest antioxidant activity, which could potentially be used for an addition ingredient as it was previously shown to have good gelling property in food products.

Published
2017
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23. Plant non-starch polysaccharides that inhibit key enzymes linked to type 2 diabetes mellitus

Author

He Gao, Shaoping Nie, Wei Tang, and Dan Liu

Subjects
0301 basic medicine, chemistry.chemical_classification, endocrine system diseases, biology, Non starch polysaccharides, General Neuroscience, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Context (language use), Lipid metabolism, 04 agricultural and veterinary sciences, Polysaccharide, 040401 food science, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0404 agricultural biotechnology, Enzyme, History and Philosophy of Science, Biochemistry, chemistry, biology.protein, Lipase, Adverse effect
Abstract

Type 2 diabetes mellitus (T2DM), a metabolic disease becoming ever more common, is the result of disturbed glyco- and lipid metabolism. On the basis of their inhibitory effects against several key enzymes linked to T2DM, synthetic antidiabetic agents have been developed and used for diabetic therapy, some with adverse side effects. Fortunately, many plant non-starch polysaccharides (NSPs) have been shown to possess inhibitory effects on the same T2DM-related enzymes. Through a simple literature search we found that α-amylase, α-glucosidase, lipase, and dipeptidyl-peptidase IV are the enzymes most often reported in the context of T2DM. In this short review we discuss published evidence for inhibition of these enzymes and the implications for treating T2DM.

Published
2017
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24. Regulatory actions of ToxR and CalR on their own genes and type III secretion system 1 in Vibrio parahaemolyticus

Author

Yin Zhe, Wenhui Yang, He Gao, Dongsheng Zhou, Xinxiang Huang, Huiying Yang, George Osei-Adjei, Yiquan Zhang, Ying Zhang, and Lingyu Zhang

Subjects
0301 basic medicine, Genetics, Communicable disease, Operon, Vibrio parahaemolyticus, 030106 microbiology, ToxR, Promoter, Biology, biology.organism_classification, calR, Microbiology, Type three secretion system, T3SS1, 03 medical and health sciences, 030104 developmental biology, Oncology, Transcription (biology), Transcriptional regulation, Gene, Research Paper
Abstract

// George Osei-Adjei 1, * , He Gao 3, * , Ying Zhang 1 , Lingyu Zhang 1 , Wenhui Yang 2 , Huiying Yang 2 , Zhe Yin 2 , Xinxiang Huang 1 , Yiquan Zhang 1 and Dongsheng Zhou 2 1 School of Medicine, Jiangsu University, Zhenjiang 212013, China 2 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China 3 State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China * These authors have contributed equally to this work Correspondence to: Dongsheng Zhou, email: dongshengzhou1977@gmail.com Yiquan Zhang, email: zhangyiquanq@163.com Xinxiang Huang, email: huxinx@ujs.edu.cn Keywords: Vibrio parahaemolyticus, calR, ToxR, T3SS1 Received: May 10, 2017 Accepted: June 20, 2017 Published: July 22, 2017 ABSTRACT Vibrio parahaemolyticus is the leading cause of seafood-associated gastroenteritis. Type III secretion system 1 (T3SS1) is one of the virulence determinants of this bacteria. T3SS1 expression is regulated by ToxR and CalR. ToxR represses the transcription of T3SS1 genes via activation of CalR, which acts as a transcriptional repressor of T3SS1 genes. However, the transcriptional regulation mechanisms have not been elucidated. As showing in the present work, ToxR binds to the promoter DNA region of calR to activate its transcription. CalR occupies the promoter-proximal regions of each detected target operons in T3SS1 loci to repress their transcription, and thereby inhibiting T3SS1-dependent cytotoxicity. Moreover, a feedback CalR inhibits toxR and its own gene in a direct manner. Collectively, this work reported an interesting gene regulatory network involving the reciprocal regulation of ToxR and CalR, and their regulation on T3SS1 genes transcription in V. parahaemolyticus .

Published
2017

25. Associations of autozygosity with a broad range of human phenotypes

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. 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Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. 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RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019
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26. A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Author

Bamidele O. Tayo, RJ Waken, Mario Sims, Diane M. Becker, Tõnu Esko, Yingchang Lu, Pamela J. Schreiner, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Archie Campbell, Ozren Polasek, Salman M. Tajuddin, Jing Hua Zhao, Barbara V. Howard, Saima Afaq, Vilmundur Gudnason, Lynda M. Rose, Francis S. Collins, Massimiliano Cocca, Ruth J. F. Loos, Yii-Der Ida Chen, W. James Gauderman, Jaspal S. Kooner, Lawrence F. Bielak, Ulrich Broeckel, Anuradhani Kasturiratne, Melissa A. Richard, Tomohiro Katsuya, Nicola D. Kerrison, Tin Aung, Lisa de las Fuentes, Lynne E. Wagenknecht, Oscar H. Franco, Yongmei Liu, Eric Boerwinkle, Nana Matoba, Saskia P. Hagenaars, Rob M. van Dam, Tibor V. Varga, Nilesh J. Samani, Tangchun Wu, Thomas H. Mosley, Caroline Hayward, Joseph H. Lee, Frida Renström, Tamara B. Harris, Alena Stančáková, Adesola Ogunniyi, Wen Bin Wei, Lenore J. Launer, Marcus Dörr, Xiuqing Guo, Jennifer A. Smith, Terho Lehtimäki, Dan E. Arking, Fang-Chi Hsu, Karin Leander, Martin Farrall, Konstantin Strauch, Albert V. Smith, Richard S. Cooper, Chiea Chuen Khor, Changwei Li, James E. Hixson, Sami Heikkinen, David R. Weir, Pirjo Komulainen, Renée de Mutsert, Raymond Noordam, Ubaydah Nasri, Paul M. Ridker, C. Charles Gu, Tamuno Alfred, Jerome I. Rotter, Nora Franceschini, Nita G. Forouhi, Lihua Wang, Alanna C. Morrison, Jian-Min Yuan, Ching-Yu Cheng, Peter S. Braund, Paul Elliott, Gregory P. Wilson, Jianjun Liu, Xiaofeng Zhu, Markku Laakso, Christian Gieger, Yukihide Momozawa, Rainer Rettig, Carsten Oliver Schmidt, Amy R. Bentley, Wei Zhao, Ioanna Ntalla, Kenneth Rice, Yoichiro Kamatani, Andres Metspalu, Helen R. Warren, Yechiel Friedlander, Susan Redline, Kurt Lohman, Cornelia M. van Duijn, Aravinda Chakravarti, Traci M. Bartz, Sarah E. Harris, Yih Chung Tham, He Gao, Mike A. Nalls, Mathilde Boissel, Donna K. Arnett, Harold Snieder, James S. Pankow, Babatunde L. Salako, Laura J. Bierut, Tin Louie, Albertine J. Oldehinkel, Xueling Sim, Thomas Meitinger, Maris Alver, Claudia Langenberg, Stephen B. Kritchevsky, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Alexandre C. Pereira, Michael R. Brown, Karen Schwander, Charles Kooperberg, Blair H. Smith, Annette Peters, Fernando Pires Hartwig, Yanhua Zhou, Jie Yao, Alisa K. Manning, Keng-Hung Lin, Dennis O. Mook-Kanamori, Ervin R. Fox, Tuomo Rankinen, Timo A. Lakka, Charles N. Rotimi, Nicholette D. Palmer, Jiang He, Nicholas J. Wareham, Jingmin Liu, Yun Ju Sung, Cathy C. Laurie, Donald W. Bowden, Yong-Bing Xiang, Lisa R. Yanek, B. Kuhnel, Nancy L. Pedersen, Yajuan Wang, Ananda R. Wickremasinghe, Jonathan Marten, Yi-Jen Hung, Dabeeru C. Rao, Bernardo L. Horta, Joel D. Kaufman, Barry I. Freedman, Chuan Gao, Olli T. Raitakari, Reedik Mägi, Solomon K. Musani, Albert Hofman, Wanqing Wen, Heming Wang, Xiao-Ou Shu, Y Liu, Mark J. Caulfield, Meian He, Daniel I. Chasman, Carl D. Langefeld, Charumathi Sabanayagam, Bruce M. Psaty, Jasmin Divers, R. Graham Barr, Chew-Kiat Heng, Stella Aslibekyan, John M. Starr, Stefan Weiss, Anuj Goel, Tuomas O. Kilpeläinen, Terrence Forrester, Mary F. Feitosa, Jost B. Jonas, Kae-Woei Liang, Colleen M. Sitlani, Daniel Levy, Marie Loh, Qing Duan, Aldi T. Kraja, Tien Yin Wong, Myriam Fornage, Andrea R. V. R. Horimoto, Michele K. Evans, David J. Porteous, Dina Vojinovic, Hua Tang, Michael A. Province, Ching-Ti Liu, Rainer Rauramaa, William R. Scott, Cora E. Lewis, Charles B. Eaton, Sharon L.R. Kardia, Michael Boehnke, James Scott, Colin A McKenzie, Jin-Fang Chai, Woon-Puay Koh, Yucheng Jia, Claude Bouchard, Peter S. Sever, Koichi Matsuda, Najaf Amin, Ulf de Faire, Walter Palmas, André G. Uitterlinden, Thomas T. Perls, Erin B. Ware, Wayne Huey-Herng Sheu, Michiaki Kubo, Ya Xing Wang, Hugh Watkins, Steven C. Hunt, Weihua Zhang, Johanna Kuusisto, Lili Milani, Rajkumar Dorajoo, Georg Ehret, L. Adrienne Cupples, Franco Giulianini, Zoltán Kutalik, Jose E Krieger, Kevin Sandow, Bruna Gigante, Alexander P. Reiner, Preeti Gupta, Heikki A. Koistinen, Treva Rice, Patricia B. Munroe, Wen-Jane Lee, Jennifer A. Brody, Paolo Gasparini, Paul W. Franks, Yik Ying Teo, Leo-Pekka Lyytikäinen, Thomas W. Winkler, Patricia A. Peyser, Ian J. Deary, Jessica D. Faul, Sing Hui Lim, Fumihiko Takeuchi, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, E. Shyong Tai, Candace M Kammerer, Mary K. Wojczynski, Pim van der Harst, Marzyeh Amini, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Benjamin Lehne, M. Waldenberger, Jeffrey R. O'Connell, Hugues Aschard, Ilaria Gandin, Kent D. Taylor, Igor Rudan, Christopher P. Nelson, John M. C. Connell, Jian'an Luan, Mickaël Canouil, Robert A. Scott, Yize Li, Marguerite R. Irvin, Sung, Yun Ju, de Las Fuentes, Lisa, Winkler, Thomas W, Chasman, Daniel I, Bentley, Amy R, Kraja, Aldi T, Ntalla, Ioanna, Warren, Helen R, Guo, Xiuqing, Schwander, Karen, Manning, Alisa K, Brown, Michael R, Aschard, Hugue, Feitosa, Mary F, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Kilpeläinen, Tuomas O, Richard, Melissa A, Aslibekyan, Stella, Bartz, Traci M, Dorajoo, Rajkumar, Li, Changwei, Liu, Yongmei, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kammerer, Candace M, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Mckenzie, Colin A, Nelson, Christopher P, Noordam, Raymond, Scott, Robert A, Sheu, Wayne H H, Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J, Varga, Tibor V, Waken, Robert J, Wang, Heming, Wang, Yajuan, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan E, Aung, Tin, Barr, R Graham, Bielak, Lawrence F, Boerwinkle, Eric, Bottinger, Erwin P, Braund, Peter S, Brody, Jennifer A, Broeckel, Ulrich, Cade, Brian, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Cocca, Massimiliano, Collins, Francis S, Connell, John M, de Mutsert, Renée, de Silva, H Janaka, Dörr, Marcu, Duan, Qing, Eaton, Charles B, Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D, Forouhi, Nita G, Franco, Oscar H, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Gu, C Charle, Gupta, Preeti, Hagenaars, Saskia P, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hofman, Albert, Howard, Barbara V, Hunt, Steven C, Irvin, Marguerite R, Jia, Yucheng, Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D, Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A, Kooperberg, Charles B, Krieger, Jose E, Kubo, Michiaki, Kutalik, Zoltan, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Joseph H, Lehne, Benjamin, Levy, Daniel, Lewis, Cora E, Li, Yize, Lim, Sing Hui, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Yeheng, Loh, Marie, Lohman, Kurt K, Louie, Tin, Mägi, Reedik, Matsuda, Koichi, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Mosley, Thomas H, Nalls, Mike A, Nasri, Ubaydah, O'Connell, Jeff R, Ogunniyi, Adesola, Palmas, Walter R, Palmer, Nicholette D, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Porteous, David, Raitakari, Olli T, Renström, Frida, Rice, Treva K, Ridker, Paul M, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L, Sandow, Kevin, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Sims, Mario, Sitlani, Colleen M, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tang, Hua, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Wojczynski, Mary K, Xiang, Yong-Bing, Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Chen, Yii-Der Ida, Weir, David R, de Faire, Ulf, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost Bruno, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K E, Oldehinkel, Albertine J, Pereira, Alexandre C, Perls, Thoma, Rauramaa, Rainer, Redline, Susan, Rettig, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wareham, Nicholas J, Watkins, Hugh, Wickremasinghe, Ananda R, Wu, Tangchun, Kamatani, Yoichiro, Laurie, Cathy C, Bouchard, Claude, Cooper, Richard S, Evans, Michele K, Gudnason, Vilmundur, Hixson, Jame, Kardia, Sharon L R, Kritchevsky, Stephen B, Psaty, Bruce M, van Dam, Rob M, Arnett, Donna K, Mook-Kanamori, Dennis O, Fornage, Myriam, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Loos, Ruth J F, Reiner, Alex P, Rotimi, Charles N, Bierut, Laura J, Zhu, Xiaofeng, Cupples, L Adrienne, Province, Michael A, Rotter, Jerome I, Franks, Paul W, Rice, Kenneth, Elliott, Paul, Caulfield, Mark J, Gauderman, W Jame, Munroe, Patricia B, Rao, Dabeeru C, Morrison, Alanna C, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.), National Institutes of Health (R01HL118305), We thank anonymous reviewers for critical reading and providing constructive and insightful comments, which substantially improved the article. This project, like several other projects, was carried out as part of the CHARGE Gene–Lifestyle Interactions Working Group., Conflict of Interest statement. The authors declare no competing financial interests except for the following: B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson, O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health), L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction, P.S. has received research awards from Pfizer Inc, J.B.J. is a consultant for Mundipharma Co. (Cambridge, UK), Patent holder with Biocompatibles UK Ltd (Franham, Surrey, UK) (title: treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor, Patent number: 20120263794) and Patent application with University of Heidelberg (Heidelberg, Germany) (title: agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia, Europäische Patentanmeldung 15000771.4), P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative project, M.A.N.'s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, M.A.N. also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and M.J. C. is chief scientist for Genomics England, a UK government company., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), University Management, Department of Medicine, University of Helsinki, HUS Abdominal Center, Endokrinologian yksikkö, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)

Subjects
Male, Receptors, Vasopressin, multi-ancestry, Genome-wide association study, Blood Pressure, HYDROCARBON RECEPTOR AHR, 030204 cardiovascular system & hematology, Antiporters, gene-smoking interaction, 0302 clinical medicine, Polymorphism (computer science), genome-wide study, Ethnicity, OXIDATIVE STRESS, Association Studies Article, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Genetics, ddc:616, Aged, 80 and over, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], DEPENDENT HYPERTENSION, CARDIOVASCULAR RISK, Smoking, 1184 Genetics, developmental biology, physiology, General Medicine, ASSOCIATION, Middle Aged, Caspase 9, 3. Good health, Pulse pressure, ENVIRONMENT INTERACTION, Sulfate Transporters, T-CADHERIN, Hypertension, Female, Life Sciences & Biomedicine, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Biochemistry & Molecular Biology, Mean arterial pressure, Adolescent, Diastole, Biology, elevated blood pressure, gene-smoking interactions, 03 medical and health sciences, Young Adult, Insulin resistance, Lifelines Cohort Study, medicine, Humans, Arterial Pressure, Molecular Biology, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, Polymorphism, Genetic, Tumor Suppressor Proteins, Racial Groups, Membrane Proteins, 06 Biological Sciences, SYSTOLIC BLOOD-PRESSURE, BODY-MASS INDEX, medicine.disease, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Heart failure, 1182 Biochemistry, cell and molecular biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Gene-Environment Interaction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome-Wide Association Study
Abstract

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P

Published
2019
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27. Role of 10-hydroxy-cis-12-octadecenic acid in transforming linoleic acid into conjugated linoleic acid by bifidobacteria

Author

Wei Chen, Catherine Stanton, He Gao, R. Paul Ross, Hao Zhang, Haiqin Chen, and Bo Yang

Subjects
Octadecenoic Acid, Linoleic acid, Conjugated linoleic acid, Oleic Acids, Conjugated system, Applied Microbiology and Biotechnology, Catalysis, law.invention, Linoleic Acid, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Species Specificity, law, Linoleic Acids, Conjugated, Food science, Biotransformation, Hydro-Lyases, 030304 developmental biology, Bifidobacterium, 0303 health sciences, biology, 030306 microbiology, Substrate (chemistry), General Medicine, biology.organism_classification, chemistry, Recombinant DNA, Biotechnology
Abstract

10-hydroxy-cis-12 octadecenoic acid (10-HOE) is a type of octadecenoic acid with a hydroxyl on the C10 carbon. It is generated from linoleic acid (LA) catalyzed by linoleate hydratase in lactobacilli, which was initially named as myosin-cross-reactive antigen (MCRA). In lactobacilli, 10-HOE is the first intermediate in the production of conjugated LA (CLA). Although MCRA from bifidobacteria can generate 10-HOE, the precise role of 10-HOE in CLA production in bifidobacteria remains unknown. In the current work, 10-HOE and LA were added to the medium as the substrate both separately and synchronously to analyze their influence on CLA production. Using 10-HOE as the substrate, bifidobacteria were able to generate CLA by first converting it to LA, followed by CLA accumulation. Recombinant MCRA catalyzed the conversion of 10-HOE to LA, indicating that bifidobacterial MCRA can account for the reversible conversion between LA and 10-HOE. This is the first report to demonstrate the precise role of 10-HOE in the process of CLA production among bifidobacteria.

Published
2019

28. Genetic determinates for conjugated linolenic acid production in Lactobacillus plantarum ZS2058

Author

He Gao, H. Chen, Hao Zhang, Wei Chen, Bo Yang, and Qing Ren

Subjects
Linolenic acid, Mutant, Oleic Acids, Isomerase, Applied Microbiology and Biotechnology, 03 medical and health sciences, Acetoacetate decarboxylase, Bacterial Proteins, Oxidoreductase, Multienzyme Complexes, Escherichia coli, Linoleic Acids, Conjugated, Isomerases, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, 030306 microbiology, Fatty Acids, Fatty acid, alpha-Linolenic Acid, General Medicine, biology.organism_classification, Recombinant Proteins, Complementation, chemistry, Biochemistry, Lactobacillus plantarum, Biotechnology
Abstract

Aims To investigate the genetic determinates for conjugated linolenic acid (CLNA) production in Lactobacillus plantarum ZS2058, a high CLNA producer. Methods and results After culturing with α-linolenic acid (ALA) in the medium, the fatty acid compositions of supernatant fluid and cell pellets were analysed via GC-MS. cis9,trans11,cis15-CLNA was identified to be the predominant isomer. And during CLNA production, 10-hydroxy-cis12-cis15-octadecenoic acid (10-HOEA) and 10-oxo-cis12-cis15-octadecenoic acid (10-OXOA) were accumulated. The E. coli recombinants harbouring genes encoding myosin-cross-reactive antigen (MCRA), short-chain dehydrogenase/oxidoreductase (DH) and acetoacetate decarboxylase (DC), respectively, were analysed for their roles in CLNA production. The results indicated that MCRA converted ALA to 10-HOEA, following converted to 10-OXOA by DH. While with the combination of three recombinants, ALA could be transformed into CLNA plus 10-HOEA and 10-OXOA. When the three genes were deleted, none of the L. plantarum ZS2058 knockout mutants could produce any CLNA, after complementation, and all the complementary mutants recovered the CLNA-production ability at similar levels as the wild strain. Conclusions Lactobacillus plantarum ZS2058 produced CLNA from ALA with 10-HOEA and 10-OXOA as intermediates. The triple-component isomerase of MCRA, DH and DC was the unique genetic determinant for CLNA generation. Significance and impact of the study The current results firstly provided conclusive evidence that the triple-component isomerase complex was shared by both CLA and CLNA production in lactobacilli.

Published
2019

29. Floral regulators FLC and SOC1 directly regulate expression of the B3-type transcription factor TARGET OF FLC AND SVP 1 at the Arabidopsis shoot apex via antagonistic chromatin modifications

Author

Atsuko Kinoshita, He Gao, Rafael Martinez-Gallegos, René Richter, Annabel D. van Driel, Julieta L. Mateos, Youbong Hyun, Coral Vincent, and George Coupland

Subjects
Cancer Research, Arabidopsis, purl.org/becyt/ford/1 [https], 0302 clinical medicine, Transcription (biology), Gene Expression Regulation, Plant, hemic and lymphatic diseases, Flowering Locus C, Transcriptional regulation, Genetics (clinical), MADS-box, Adenosine Triphosphatases, 0303 health sciences, biology, Polycomb Repressive Complex 2, food and beverages, Gene Expression Regulation, Developmental, Bioquímica y Biología Molecular, Plants, Genetically Modified, Chromatin, Cell biology, FLC, Histone Code, TRANSCRIPTION FACTORS, CIENCIAS NATURALES Y EXACTAS, Plant Shoots, SVP, lcsh:QH426-470, Meristem, Repressor, MADS Domain Proteins, Flowers, Genes, Plant, Models, Biological, Ciencias Biológicas, 03 medical and health sciences, Genetics, purl.org/becyt/ford/1.6 [https], Molecular Biology, Transcription factor, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Arabidopsis Proteins, fungi, FLOWERING, biology.organism_classification, Repressor Proteins, lcsh:Genetics, Trans-Activators, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Integration of environmental and endogenous cues at plant shoot meristems determines the timing of flowering and reproductive development. The MADS box transcription factor FLOWERING LOCUS C (FLC) of Arabidopsis thaliana is an important repressor of floral transition, which blocks flowering until plants are exposed to winter cold. However, the target genes of FLC have not been thoroughly described, and our understanding of the mechanisms by which FLC represses transcription of these targets and how this repression is overcome during floral transition is still fragmentary. Here, we identify and characterize TARGET OF FLC AND SVP1 (TFS1), a novel target gene of FLC and its interacting protein SHORT VEGETATIVE PHASE (SVP). TFS1 encodes a B3-type transcription factor, and we show that tfs1 mutants are later flowering than wild-type, particularly under short days. FLC and SVP repress TFS1 transcription leading to deposition of trimethylation of Iysine 27 of histone 3 (H3K27me3) by the Polycomb Repressive Complex 2 at the TFS1 locus. During floral transition, after downregulation of FLC by cold, TFS1 transcription is promoted by SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1), a MADS box protein encoded by another target of FLC/SVP. SOC1 opposes PRC function at TFS1 through recruitment of the histone demethylase RELATIVE OF EARLY FLOWERING 6 (REF6) and the SWI/SNF chromatin remodeler ATPase BRAHMA (BRM). This recruitment of BRM is also strictly required for SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 9 (SPL9) binding at TFS1 to coordinate RNAPII recruitment through the Mediator complex. Thus, we show that antagonistic chromatin modifications mediated by different MADS box transcription factor complexes play a crucial role in defining the temporal and spatial patterns of transcription of genes within a network of interactions downstream of FLC/SVP during floral transition. Fil: Richter, René. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: Kinoshita, Atsuko. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: Vincent, Coral. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: Martinez Gallegos, Rafael. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: Gao, He. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: van Driel, Annabel D.. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: Hyun, Youbong. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania Fil: Mateos, Julieta Lisa. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Coupland, George. Max Planck Institute for Plant Breeding. Department of Plant Developmental Biology; Alemania

Published
2019

30. Genetic Operation System of Lactic Acid Bacteria and Its Applications

Author

Chunqing Ai, Chen Chen, Chengcheng Ren, Haiqin Chen, and He Gao

Subjects
chemistry.chemical_compound, Fermentation starter, chemistry, Functional food, Microorganism, Computational biology, Biology, biology.organism_classification, Genome, Gene, DNA sequencing, Bacteria, Lactic acid
Abstract

Lactic acid bacteria (LAB), a class of commonly existing microorganisms in nature, are important components of gut commensal microflora in humans and animals. Previous studies suggested that LAB exerted specific physiological and biochemical functions on the host such as improving intestinal microbial balance, immunomodulation, inhibiting tumor growth, lowering cholesterol levels, as well as regulating blood pressure and are therefore widely used in food manufacturing and functional food development. Due to the continuous development of modern molecular biology techniques, studies regarding exploiting LAB as expression hosts in addition to fermentation starter cultures and probiotics have received increasing attention from both academia and industry. In the 1980s, some researchers initiated molecular genetic research for LAB. They characterized lactose metabolism-related genes and proteins in LAB and established preliminary DNA delivery systems for LAB. Over the past decades, owing to the advances in modern DNA sequencing and gene characterization techniques, structures and functions of LAB genomes and plasmid-related genes have been further elucidated, which lays a solid theoretical foundation for the further development of LAB-based gene expression systems (Bolotin et al. 2001; Altermann et al. 2005).

Published
2019
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31. Transcriptional regulation of the mannitol phosphotransferase system operon by the ferric uptake regulator (Fur) in Vibrio cholerae El Tor serogroup O1

Author

Yiquan Zhang, Biao Kan, Qin Qin, Han Wang, Jing Lou, Jie Li, Baowei Diao, Yue Gao, Yue Qiu, He Gao, and Jingyun Zhang

Subjects
Operon, Biology, medicine.disease_cause, Microbiology, El Tor, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, medicine, Transcriptional regulation, Mannitol, Molecular Biology, 030304 developmental biology, 0303 health sciences, Growth medium, 030306 microbiology, Phosphotransferases, Vibrio cholerae O1, Gene Expression Regulation, Bacterial, General Medicine, PEP group translocation, biology.organism_classification, Repressor Proteins, Biochemistry, chemistry, Vibrio cholerae, bacteria, Phosphoenolpyruvate carboxykinase, medicine.drug
Abstract

The phosphoenolpyruvate (PEP): carbohydrate phosphotransferase system (PTS) allows bacteria to use various carbohydrates as energy resources including mannitol. The mannitol-specific PTS transporter in Vibrio cholerae is encoded by the mtlADR operon. Expression of the mtl operon has been shown to be strictly regulated by CRP, MtlS, and MtlR. In the present study, we investigated the regulation of mtlADR by the ferric uptake regulator (Fur). The results showed that Fur binds to the promoter-proximal DNA region of mtlADR to repress its transcription independent of iron, in mannitol-containing growth medium. The capacity for mannitol fermentation was significantly increased in Δfur relative to that of WT for normal and iron-replete growth media. The level of organic acids produced by Δfur was significantly enhanced relative to that produced by the WT strain in the normal and iron-replete media but not in an iron-starved medium. The results provided for a deeper understanding of the regulation of mtlADR in V. cholerae.

Published
2021
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32. The Master Quorum-Sensing Regulator OpaR is Activated Indirectly by H-NS in Vibrio parahaemolyticus

Author

Xinxiang Huang, Shuning Hou, He Gao, Lingyu Zhang, Yiquan Zhang, and Fengjun Sun

Subjects
0301 basic medicine, Vibrio parahaemolyticus, 030106 microbiology, Quorum Sensing, Repressor, lac operon, Gene Expression Regulation, Bacterial, General Medicine, Biology, biology.organism_classification, Applied Microbiology and Biotechnology, Microbiology, Molecular biology, Primer extension, DNA-Binding Proteins, 03 medical and health sciences, Quorum sensing, 030104 developmental biology, Bacterial Proteins, Transcription (biology), Nucleoid, Electrophoretic mobility shift assay, Promoter Regions, Genetic, Transcription Factors
Abstract

AphA and OpaR are the master regulators of quorum sensing in Vibrio parahaemolyticus and there is reciprocal negative regulation between AphA and OpaR. The histone-like nucleoid structure (H-NS) protein is a global transcriptional repressor of horizontally transferred genes, but a few prokaryotic genes, for example flagella genes, are stimulated by H-NS. The regulation of opaR by H-NS was investigated using the following methods: primer extension, LacZ fusion, quantitative RT-PCR, and electrophoretic mobility shift assay. One transcription start site located at 74 bp upstream of opaR was detected and its activity was induced by H-NS. Therefore, a single H-NS-dependent promoter was transcribed for opaR in V. parahaemolyticus. Because the H-NS protein could not bind to the upstream region of opaR and H-NS does not regulate aphA, indirect activation of the transcription of opaR by H-NS cannot be mediated by the AphA repressor.

Published
2016
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33. Characterization of the life cycle of the tick Haemaphysalis tibetensis under field conditions in Qinghai-Tibet plateau

Author

Jingze Liu, Xiao-He Gao, Rongrong Wang, Ningxin Li, Zhijun Yu, Hui Wang, Tuo Li, Chun-Wei Zuo, and Ming Liu

Subjects
Male, Nymph, 0106 biological sciences, Veterinary medicine, Ixodidae, Oviposition, 030231 tropical medicine, Molting, Biology, Tick, Tibet, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Animals, Larva, geography, Plateau, geography.geographical_feature_category, Ecology, Reproductive success, Feeding Behavior, General Medicine, biology.organism_classification, Haemaphysalis, Tick Infestations, 010602 entomology, Animal ecology, Insect Science, Female, Rabbits, Moulting
Abstract

The tick Haemaphysalis tibetensis Hoogstraal is found uniquely in the Qinghai-Tibet plateau of Tibet and Gansu of China. Not much is known of this tick. Therefore, in this study we investigated the life cycle of H. tibetensis under field conditions from March 2014 to March 2015 in Damxung County, north Lhasa City in Tibet (Autonomous Region in China). The results of the study demonstrated that the tick H. tibetensis requires an average of 177.8 days (range 129-202 days) to complete a life cycle, with rabbits supplied as hosts in the field plot. Under natural lighting and climate conditions, the feeding period of females was an average of 7.7 days, and the pre-oviposition period was 9.4 days, followed by 28.2 days for oviposition. The premolting period of nymphs lasted 52.7 days, which was the longest life cycle phase. The average weight ratio of engorged to unfed females was 58.2. Additionally, there was a highly positive correlation between the weight of engorged and the number of the eggs that were laid (r = 0.83, P < 0.05). The reproductive efficiency index and reproductive fitness index in females were 5.1 and 4.7, respectively.

Published
2016
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34. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Author

Anne-Claire Vergnaud, Nauder Faraday, Tim Kacprowski, Lisa R. Yanek, Oscar H. Franco, Yongmei Liu, Andreas Greinacher, Gina M. Peloso, Cristen J. Willer, Leslie A. Lange, Eric S. Torstenson, Reedik Mägi, Jeanette Erdmann, Ethan M. Lange, Deborah A. Nickerson, Henry Völzke, David R. Crosslin, Gunnar Engström, Albert V. Smith, André G. Uitterlinden, Salman M. Tajuddin, W. David Hill, Diane M. Becker, Paul Elliot, Caterina Vacchi-Suzzi, Linda M. Polfus, Traci M. Bartz, Nathalie Chami, Abbas Dehghan, Mike A. Nalls, John D. Eicher, Leo-Pekka Lyytikäinen, Evelin Mihailov, Uwe Völker, Caroline Hayward, Ioanna Tzoulaki, Myriam Fornage, Marju Orho-Melander, Mary Cushman, Lars Wallentin, Terho Lehtimäki, Ayush Giri, Laura M. Raffield, Lewis C. Becker, Yingchang Lu, Emma Raitoharju, Sekar Kathiresan, Simon de Denus, Ruth J. F. Loos, James S. Floyd, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Lenore J. Launer, Andrew D. Johnson, Andrew J. Slater, Jean-Claude Tardif, Raha Pazoki, Evangelos Evangelou, Kenneth Rice, Harvey D. White, Marie-Pierre Dubé, Frank J. A. van Rooij, Akihiro Nomura, Tamara B. Harris, Vilmundur Gudnason, Gonçalo R. Abecasis, Alan B. Zonderman, Guillaume Lettre, Todd L. Edwards, Amber A. Burt, Ani Manichaikul, Heribert Schunkert, Ming-Huei Chen, Ian J. Deary, Michelle L. O'Donoghue, Jennifer A. Brody, Russell P. Tracy, Tõnu Esko, Mika Kähönen, Panos Deloukas, Eric Boerwinkle, Rasika A. Mathias, Dajiang J. Liu, Jin Li, Santhi K. Ganesh, David C. Liewald, Paul L. Auer, Digna R. Velez Edwards, Erwin P. Bottinger, Nina Mononen, Claudia Schurmann, Michele K. Evans, John M. Starr, Thomas Thiele, Jussi Hernesniemi, Jerome I. Rotter, Rakale C. Quarells, He Gao, Kjell Nikus, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Ursula M. Schick, Andres Metspalu, Melissa A. Richard, Neil A. Zakai, Olle Melander, John D. Rioux, Olli T. Raitakari, Alexander P. Reiner, Joel N. Hirschhorn, Nilesh J. Samani, Epidemiology, Internal Medicine, Home Office, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Blood Platelets, Male, CARDIoGRAM Exome Consortium, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Myocardial Infarction Genetics Consortium, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Platelet, Exome, Genetics(clinical), Mean platelet volume, Allele frequency, Genotyping, Genetics (clinical), Genetics & Heredity, Platelet Count, ta1184, Genetic Variation, Global Lipids Genetics Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, FCER1A, Genetic architecture, 030104 developmental biology, Hemostasis, Immunology, Female, Mean Platelet Volume, Genome-Wide Association Study
Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Published
2016
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35. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Author

Yingchang Lu, Lisa R. Yanek, Evangelos Evangelou, Andreas Greinacher, Leslie A. Lange, Albert Hofman, Rakale C. Quarells, Christopher J. O'Donnell, Simon de Denus, Marcus Dörr, Tamara B. Harris, Mary Cushman, Lars Wallentin, Digna R. Velez Edwards, Michelle L. O'Donoghue, Deborah A. Nickerson, Lisa Bastarache, Caterina Vacchi-Suzzi, Harvey D. White, Rasika A. Mathias, Jin Li, Santhi K. Ganesh, Leo-Pekka Lyytikäinen, Kjell Nikus, Ayush Giri, Paul Elliott, John M. Starr, Ruth J. F. Loos, Vilmundur Gudnason, Ioanna Tzoulaki, Myriam Fornage, Joshua C. Denny, Alan B. Zonderman, Caroline Hayward, Lewis C. Becker, Raha Pazoki, Guillaume Lettre, Lenore J. Launer, Ursula M. Schick, Michele K. Evans, Andrew J. Slater, Diane M. Becker, Jean-Claude Tardif, Ethan M. Lange, John D. Eicher, He Gao, James S. Floyd, Eric Boerwinkle, Paul L. Auer, Nathalie Chami, Frank J. A. van Rooij, Claudia Schurmann, Nele Friedrich, Kent D. Taylor, Andres Metspalu, Todd L. Edwards, Anne-Claire Vergnaud, Yongmei Liu, W. David Hill, Nauder Faraday, Terho Lehtimäki, Amber A. Burt, Jerome I. Rotter, Albert V. Smith, Tõnu Esko, Traci M. Bartz, Tim Kacprowski, Mike A. Nalls, Alexander P. Reiner, Ani Manichaikul, Ian J. Deary, Eric S. Torstenson, Laura M. Raffield, David C. Liewald, Ming-Huei Chen, Erwin P. Bottinger, Reedik Mägi, Andrew D. Johnson, Melissa A. Richard, Neil A. Zakai, John D. Rioux, Mika Kähönen, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Joel N. Hirschhorn, Salman M. Tajuddin, Linda M. Polfus, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Abbas Dehghan, Evelin Mihailov, David R. Crosslin, André G. Uitterlinden, Georg Homuth, Jennifer A. Brody, Gastroenterology & Hepatology, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Quality Control, Myeloid, 1.1 Normal biological development and functioning, Genome-wide association study, Biology, Autoimmune Disease, Medical and Health Sciences, Article, 03 medical and health sciences, Underpinning research, White blood cell, medicine, Leukocytes, Genetics, Humans, 2.1 Biological and endogenous factors, Genetics(clinical), Exome, Aetiology, Genetics (clinical), Genetic association, Genetics & Heredity, Medical And Health Sciences, Neutrophil clearance, Hematopoietic stem cell differentiation, Inflammatory and immune system, Human Genome, Genetic Pleiotropy, Hematology, Biological Sciences, Acquired immune system, Stem Cell Research, 3. Good health, Blood Cell Count, 030104 developmental biology, medicine.anatomical_structure, Immune System Diseases, Genetic Loci, Immunology, Stem Cell Research - Nonembryonic - Non-Human, Genome-Wide Association Study
Abstract

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Published
2016
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36. A novel pre-CTX prophage in the Vibrio cholerae serogroup O139 strain

Author

Jie Li, Long Chen, He Gao, Weili Liang, Bo Pang, Lin Zhao, Biao Kan, Fenxia Fan, Yufeng Fan, Xu Li, and Zhe Li

Subjects
0301 basic medicine, Microbiology (medical), Cholera Toxin, Genes, Viral, Prophages, 030106 microbiology, Genome, Viral, medicine.disease_cause, Microbiology, Genome, Vibrio cholerae O139, Bacteriophage, Viral Proteins, 03 medical and health sciences, Cholera, Lysogenic cycle, Genetics, medicine, Bacteriophages, Lysogeny, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Prophage, Whole genome sequencing, biology, Cholera toxin, Vibrio cholerae O1, biology.organism_classification, 030104 developmental biology, Infectious Diseases, Vibrio cholerae, DNA, Viral
Abstract

In Vibrio cholerae, the lysogenic bacteriophage CTXΦ carries the cholera toxin genes ctxAB, which can be transferred from toxigenic strains to nontoxigenic strains through infection and lysogenic conversion of CTXΦ. This phage also has the precursor genome which does not harbor ctxAB, named pre-CTXΦ. Based on the sequences of the transcriptional regulator-encoding gene rstR alleles in CTXΦ/pre-CTXΦ, multiple types of these prophages have been classified and identified in toxigenic and nontoxigenic V. cholerae strains. In this study, by combining the short-read and long-read sequencing approaches of next generation sequencing, we obtained the complete genome sequence of the studied V. cholerae toxigenic serogroup O139 strain and identified the CTXΦ and a pre-CTXΦ genome type encoding a novel rstR allele, pre-CTXZHJΦ. This pre-CTX prophage integrates into the small chromosome of the V. cholerae host strain and coexists with a typical CTXETΦ prophage present in the large chromosome, which is commonly present in the seventh pandemic serogroup O1 and toxigenic serogroup O139 strains. RstRZHJ could bind to the ig-2 region in the RstAB promotor in the pre-CTXZHJΦ genome, and could repress the expression of its own rstAB genes but could not repress rstAB expression in CTXETΦ and CTXclassΦ, suggesting that the V. cholerae strains carrying the pre-CTXZHJΦ prophage cannot prevent the infection of these epidemic CTXΦs, hence have the potentiality to become toxigenic by acquiring and lysogenic conversion of CTXΦs. Our study identified a novel pre-CTXΦ type, and presents the new evidence for the complexity and diversity of the CTXΦ/pre-CTXΦ family in V. cholerae.

Published
2020
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37. Characteristics of bifidobacterial conjugated fatty acid and hydroxy fatty acid production and its potential application in fermented milk

Author

Catherine Stanton, R. Paul Ross, Bo Yang, Wei Chen, Zhenmin Liu, Haiqin Chen, He Gao, and Hao Zhang

Subjects
0106 biological sciences, Bifidobacterium longum, Bifidobacterium breve, biology, ved/biology, ved/biology.organism_classification_rank.species, 04 agricultural and veterinary sciences, biology.organism_classification, 040401 food science, 01 natural sciences, Bifidobacterium dentium, Conjugated fatty acid, chemistry.chemical_compound, 0404 agricultural biotechnology, Starter, chemistry, 010608 biotechnology, Hydroxy fatty acid, Fermentation, Food science, Food Science, Bifidobacterium
Abstract

This is the first study to elucidate bifidobacterial conjugated fatty acid and hydroxy fatty acid production as well as its potential in fermented milk. One hundred and fifty-two bifidobacteria belonging to seven species were assayed in this study. The results showed that only Bifidobacterium breve (B. breve), Bifidobacterium longum (B. longum), Bifidobacterium pesudocatenulatum (B. pseudocatenulatum) and Bifidobacterium dentium (B. dentium) generated CLA and CLNA, while nearly all the strains could convert free LA into 10-HOE. B. breve showed the highest CLA- and CLNA-generation ability (the highest conversion rate, 90.1%, for B. breve CCFM683), while B. pseudocatenulatum revealed higher 10-HOE-producing ability. Further study demonstrated that 10-HOE competition could influence the CLA generation in Bifidobacterium. Furthermore, B. breve CCFM683, as the highest CLA- and CLNA-producer, could increase the content of CLA and CLNA to 0.14 mg/mL and 0.065 mg/mL in fermented milk, presenting as a potentially ideal starter culture increasing conjugated fatty acid contents in milk.

Published
2020
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38. Network pharmacology-based study of chinese herbal qixiong formula in treating oligoasthenospermia

Author

Jun Guo, Sheng-Jing Liu, Guan-Chao Du, Ji-Wei Zhang, Fu Wang, Qing-He Gao, and Feng Zhao

Subjects
Complementary and alternative medicine, Interaction network, Mechanism (biology), Traditional Chinese medicine, Computational biology, KEGG, Biology, DrugBank, PI3K/AKT/mTOR pathway, Systems pharmacology, GeneCards
Abstract

Objective: The objective is to study the network pharmacology of Qixiong formula (QXF) and explore the mechanism of QXF in the treatment of oligoasthenospermia. Materials and Methods: Using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-traditional Chinese medicine), and an encyclopaedia of traditional Chinese medicine (ETCM) databases as well as data from relevant studies, the effective components and targets of QXF were obtained. Genes associated with oligospermia were screened using GeneCards, OMIM, DisGeNet, DrugBank, and GAD databases. The intersection target was obtained by mapping the target to the gene, and the protein interaction network was created using the STRING database to screen the core target of QXF in the treatment of oligospermia. The intersection target was enriched using gene ontology (GO) and the Kyoto Encyclopedia of genes and genomes (KEGG) pathway analysis with the DAVID database. The network of the disease drug target pathway was drawn using Cytoscape software. Results: Overall, 536 active components of QXF and 40 core targets for the treatment of oligoasthenozoospermia were obtained. The analysis of GO and KEGG showed that QXF is mainly involved in oxidative stress, cell motility, nutritional response, and other biological processes. Through the regulation of FOXO, p53, PI3K/Akt, MAPK, mammalian target of rapamycin, Foxo, Wnt, and other signaling pathways, QXF played a role in the treatment of oligoasthenospermia. Conclusion: QXF has multi-component, multi-target, and multi-channel characteristics, providing a new way to study the mechanism of QXF in the treatment of oligoasthenospermia.

Published
2020
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39. Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Author

Raha Pazoki, Michael R. Brown, Albertine J. Oldehinkel, Evangelos Evangelou, Bruce M. Psaty, Caroline Hayward, Penelope A. Lind, Harry Campbell, Sylvane Desrivières, Leo-Pekka Lyytikäinen, Harold Snieder, Niek Verweij, Igor Rudan, Rozenn N. Lemaitre, Andrianos M. Yiorkas, David Conen, Ozren Polasek, Mia-Maria Perälä, Jennifer A. Smith, Christopher P. Nelson, Wei Zhao, Ilja M. Nolte, Michael Kühne, Mika Kähönen, Jessica D. Faul, Sharon L.R. Kardia, Peter K. Joshi, Ibrahim Karaman, Paul M. Matthews, Adrian Rothenfluh, Jari Lahti, Alexandra I. F. Blakemore, John Whitfield, Alexander Teumer, James F. Wilson, Alena Stančáková, Marjo-Riitta Järvelin, David R. Weir, Peter S. Braund, Andrew M. McIntosh, Scott M. Ratliff, Nicholas G. Martin, Hideaki Suzuki, Georgios Ntritsos, Niki Dimou, Bing Yu, Andrew R. Butts, Alanna C. Morrison, Gunter Schumann, Michael Boehnke, Paul Elliott, Samuli Tuominen, Paul Blakeley, Xiuqing Guo, Massimo Mangino, Yuri Milaneschi, Brenda W.J.H. Penninx, Daniel Levy, Juha Auvinen, Jie Yao, Hans J. Grabe, David J. Porteous, Laura J. Scott, Lorenz Risch, Katherine A. Kentistou, Jagadish Vangipurapu, Stefanie Aeschbacher, Terho Lehtimäki, Markku Laakso, Jimmy D. Bell, Fotios Koskeridis, Anne U. Jackson, Karen L. Mohlke, Catharina A. Hartman, Ioanna Tzoulaki, Sebastian E. Baumeister, Dan E. Arking, Alexis C. Wood, Sébastien Thériault, Johanna Kuusisto, Pim van der Harst, Chunyu Liu, Juha Veijola, Georg Homuth, Jennifer A. Brody, Traci M. Bartz, Andrew C. Heath, He Gao, Toni-Kim Clarke, Jerome I. Rotter, Tim D. Spector, Congying Chu, Johan G. Eriksson, Minna Männikkö, Olli T. Raitakari, Nilesh J. Samani, and Joshua Elliott

Subjects
Genetics, 0303 health sciences, Genome-wide association study, Biology, medicine.disease, Excessive alcohol consumption, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Trait, medicine, Functional significance, Functional studies, Alcohol consumption, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.

Published
2018
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40. Estimation of TETRA radio use in the Airwave Health Monitoring Study of the British police forces

Author

Jeanette Spear, James R. Carpenter, Håvard Wahl Kongsgård, Paul Elliott, Anne-Claire Vergnaud, Dennis McRobie, He Gao, Maria Aresu, Andy Heard, Deepa Singh, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd

Subjects
Male, Computer science, Radio Waves, 05 Environmental Sciences, 010501 environmental sciences, Toxicology, 01 natural sciences, Biochemistry, Spearman's rank correlation coefficient, Radiofrequency electromagnetic fields, 03 medical and health sciences, 0302 clinical medicine, Terrestrial Trunked Radio, Statistics, Missing value imputation, Humans, 030212 general & internal medicine, Imputation (statistics), 0105 earth and related environmental sciences, General Environmental Science, Estimation, biology, TETRA, Occupational exposure, 06 Biological Sciences, biology.organism_classification, Confidence interval, Police, United Kingdom, Data Accuracy, Occupational cohort, Cohort, Tetra, Female, Self Report, 03 Chemical Sciences
Abstract

Background The Airwave Health Monitoring Study aims to investigate the possible long-term health effects of Terrestrial Trunked Radio (TETRA) use among the police forces in Great Britain. Here, we investigate whether objective data from the network operator could be used to correct for misreporting in self-reported data and expand the radio usage availability in our cohort. Methods We estimated average monthly usage of personal radio in the 12 months prior to enrolment from a missing value imputation model and evaluated its performance against objective and self-reported data. Factors associated with TETRA radio usage variables were investigated using Chi-square tests and analysis of variance. Results The imputed data were better correlated with objective than self-reported usage (Spearman correlation coefficient = 0.72 vs. 0. 52 and kappa 0.56 [95% confidence interval 0.55, 0.56] vs. 0.46 [0.45, 0.47]), although the imputation model tended to under-estimate use for higher users. Participants with higher personal radio usage were more likely to be younger, men vs. women and officer vs. staff. The median average monthly usage level for the entire cohort was estimated to be 29.3 min (95% CI: [7.2, 66.6]). Conclusion The availability of objective personal radio records for a large proportion of users allowed us to develop a robust imputation model and hence obtain personal radio usage estimates for ~50,000 participants. This substantially reduced exposure misclassification compared to using self-reported data and will allow us to carry out analyses of TETRA usage for the entire cohort in future work.

Published
2018

41. Expression of Hemolysin Is Regulated Under the Collective Actions of HapR, Fur, and HlyU in Vibrio cholerae El Tor Serogroup O1

Author

He Gao, Yiquan Zhang, Xin Lu, Hongqun Zhao, Jing Lou, Jie Li, Baowei Diao, Biao Kan, Jialiang Xu, and Qiannan Shi

Subjects
0301 basic medicine, Microbiology (medical), lcsh:QR1-502, Biology, medicine.disease_cause, urologic and male genital diseases, El Tor, Microbiology, lcsh:Microbiology, 03 medical and health sciences, fluids and secretions, Transcription (biology), medicine, Gene, Vibrio cholerae, HlyU, Fur, Original Research, HlyA, Toxin, quorum sensing, Hemolysin, Promoter, regulation, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, bacterial infections and mycoses, HapR, Quorum sensing, 030104 developmental biology, bacteria
Abstract

The biotype El Tor of serogroup O1 and most of the non-O1/non-O139 strains of Vibrio cholerae can produce an extracellular pore-forming toxin known as cholera hemolysin (HlyA). Expression of HlyA has been previously reported to be regulated by the quorum sensing (QS) and the regulatory proteins HlyU and Fur, but lacks the direct evidence for their binding to the promoter of hlyA. In the present work, we showed that the QS regulator HapR, along with Fur and HlyU, regulates the transcription of hlyA in V. cholerae El Tor biotype. At the late mid-logarithmic growth phase, HapR binds to the three promoters of fur, hlyU, and hlyA to repress their transcription. At the early mid-logarithmic growth phase, Fur binds to the promoters of hlyU and hlyA to repress their transcription; meanwhile, HlyU binds to the promoter of hlyA to activate its transcription, but it manifests direct inhibition of its own gene. The highest transcriptional level of hlyA occurs at an OD600 value of around 0.6-0.7, which may be due to the subtle regulation of HapR, Fur, and HlyU. The complex regulation of HapR, Fur, and HlyU on hlyA would be beneficial to the invasion and pathogenesis of V. cholerae during the different infection stages.

Published
2018

42. Polysaccharide from fermented Momordica charantia L. with Lactobacillus plantarum NCU116 ameliorates type 2 diabetes in rats

Author

He Gao, Haihong Chen, Tao Xiong, Qixing Nie, Jielun Hu, Mingyong Xie, Jia-Jia Wen, and Shaoping Nie

Subjects
0301 basic medicine, Male, Polymers and Plastics, Momordica charantia, Gut flora, medicine.disease_cause, Polysaccharide, Diabetes Mellitus, Experimental, 03 medical and health sciences, Polysaccharides, Lactobacillus, Hyperlipidemia, Materials Chemistry, medicine, Monosaccharide, Animals, Hypoglycemic Agents, Food science, Rats, Wistar, chemistry.chemical_classification, 030109 nutrition & dietetics, Momordica, biology, Organic Chemistry, food and beverages, biology.organism_classification, medicine.disease, Rats, 030104 developmental biology, chemistry, Diabetes Mellitus, Type 2, Oxidative stress, Lactobacillus plantarum
Abstract

The influence of Lactobacillus plantarum-fermentation on the structure and anti-diabetic effects of Momordica charantia polysaccharides were evaluated. High-fat diet and streptozotocin-induced type 2 diabetic rats were administrated with polysaccharides from fermented and non-fermented Momordica charantia (FP and NFP) for 4 weeks. Fermentation affected the physicochemical characterization, monosaccharide composition, molecular weight, and viscosity of Momordica charantia polysaccharides. Treatment with FP significantly ameliorated hyperglycemia, hyperinsulinemia, hyperlipidemia, and oxidative stress in diabetic rats compared with NFP. Moreover, the diversity and abundance of gut microbiota (Lactococcus laudensis and Prevotella loescheii) in diabetic rats were notably increased by treatment with FP in comparison to NFP. Meanwhile, FP-treated diabetic rats exhibited more colonic short-chain fatty acids (SCFAs) and lower pH values than that in NFP-treated rats. Overall, Lactobacillus plantarum-fermentation could enhance the anti-diabetes effects of Momordica charantia polysaccharides in rats by modifying the structure of polysaccharides to optimize gut microbiota and heighten the production of SCFAs.

Published
2018

43. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Author

Patricia A. Peyser, Jessica D. Faul, Sing Hui Lim, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, W. James Gauderman, Wei Zhao, Andres Metspalu, R. Graham Barr, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Daniel I. Chasman, Jasmin Divers, Fernando Pires Hartwig, Jing Hua Zhao, Yu Caizheng, Roby Joehanes, Nora Franceschini, Nita G. Forouhi, Charumathi Sabanayagam, Paul M. Ridker, Yun J. Sung, Mary F. Feitosa, Barbara V. Howard, Vilmundur Gudnason, Jost B. Jonas, Hua Tang, Yukihide Momozawa, Michael R. Brown, Tibor V. Varga, Franco Giulianini, Francis S. Collins, Alexander P. Reiner, Ulrich Broeckel, Tuomo Rankinen, Preeti Gupta, Tin Louie, Eric Boerwinkle, Saskia P. Hagenaars, Mark J. Caulfield, Albert Hofman, Aravinda Chakravarti, Paul W. Franks, Nicole Schupf, E. Shyong Tai, Carl D. Langefeld, Carsten Oliver Schmidt, Lawrence F. Bielak, Treva Rice, Anne B. Newman, Ioanna Ntalla, Kae-Woei Liang, Nilesh J. Samani, Alena Stančáková, Thomas H. Mosley, Dan E. Arking, Kenneth Rice, Bruce M. Psaty, Jirong Long, Yechiel Friedlander, Jianjun Liu, Donna K. Arnett, Ya X. Wang, Xiuqing Guo, Anne E. Justice, Pamela J. Schreiner, Renée de Mutsert, Lisa de las Fuentes, Marcus Dörr, Amy R. Bentley, Susan Redline, Cornelia M. van Duijn, Melissa A. Richard, Sarah E. Harris, Pirjo Komulainen, Nicholette D. Palmer, Alexandre C. Pereira, Michele K. Evans, Jie Yao, Adesola Ogunniyi, Wen Bin Wei, Anuradhani Kasturiratne, Yoichiro Kamatani, Charles Kooperberg, Helen R. Warren, Shiow Lin, Ozren Polasek, Makoto Hirata, Anubha Mahajan, Yingchang Lu, Jonathan Marten, Claudia P. Cabrera, Chuan Gao, Oscar H. Franco, Yongmei Liu, Mathilde Boissel, Olli T. Raitakari, Xiao-Ou Shu, Yii-Der Ida Chen, Y Liu, Claudia Langenberg, C. Charles Gu, Cathy C. Laurie, Tamuno Alfred, L. Adrienne Cupples, Yajuan Wang, Colin A. McKenzie, Mika Kähönen, Yize Li, Xiaofeng Zhu, Nana Matoba, James Scott, Marguerite R. Irvin, Markku Laakso, Frida Renström, Woon-Puay Koh, Dabeeru C. Rao, Yucheng Jia, Paul Elliott, Tangchun Wu, Caroline Hayward, Tamara B. Harris, Alison D. Murray, Karin Leander, Reedik Mägi, Keng-Hung Lin, Harold Snieder, Laura J. Bierut, Christine Williams, Solomon K. Musani, Michael A. Province, Charles B. Eaton, Sharon L.R. Kardia, Mario Sims, Steven C. Hunt, Stephen B. Kritchevsky, Weihua Zhang, David R. Weir, Andrea R. V. R. Horimoto, Saima Afaq, Hugues Aschard, Ilaria Gandin, Michiaki Kubo, Jaspal S. Kooner, Peter S. Braund, Jeffrey R. O'Connell, Kent D. Taylor, Annette Peters, Wei Zheng, Rainer Rettig, Nicola D. Kerrison, Donald W. Bowden, Ruth J. F. Loos, Tanika N. Kelly, Dennis O. Mook-Kanamori, Terrence Forrester, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, Ching-Yu Cheng, Alanna C. Morrison, Tuomas O. Kilpeläinen, Jian-Min Yuan, Bruna Gigante, Lisa R. Yanek, Ching-Ti Liu, Ananda R. Wickremasinghe, Michael Boehnke, Tin Aung, Jin-Fang Chai, Kaare Christensen, Wen-Jane Lee, Stéphanie Debette, Jennifer A. Brody, Wayne Huey-Herng Sheu, John M. C. Connell, Ganesh Chauhan, Jian'an Luan, Melanie Waldenberger, Erin B. Ware, Paolo Gasparini, Chew-Kiat Heng, Lili Milani, Alisa K. Manning, José Eduardo Krieger, Kiang Liu, Mickaël Canouil, Robert A. Scott, Yik Ying Teo, Gregory P. Wilson, Stella Aslibekyan, Andrew P. Morris, Thomas Meitinger, Jennifer A. Smith, Yi-Jen Hung, Myriam Fornage, Dina Vojinovic, William R. Scott, Virginia Fisher, Peter S. Sever, André G. Uitterlinden, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Rajkumar Dorajoo, Georg Ehret, Heming Wang, Sandosh Padmanabhan, Jingmin Liu, Colleen M. Sitlani, Anuj Goel, Bamidele O. Tayo, Daniel Levy, Barry I. Freedman, Marie Loh, Yanhua Zhou, Charles N. Rotimi, Qing Duan, Aldi T. Kraja, He Meian, Archie Campbell, Kari E. North, Tien Yin Wong, Salman M. Tajuddin, Traci M. Bartz, Mike A. Nalls, Misa Graff, Dongfeng Gu, Sudha Seshadri, Tõnu Esko, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Fang-Chi Hsu, Chiea Chuen Khor, Changwei Li, Sami Heikkinen, Maris Alver, Karen Schwander, Wanqing Wen, Rainer Rauramaa, Lynne E. Wagenknecht, Ubaydah Nasri, Peter J. Munson, He Gao, Evangelos Evangelou, Philippe Froguel, Ervin R. Fox, Christian Gieger, Kurt Lohman, James S. Pankow, Nicholas J. Wareham, Lynda M. Rose, Massimiliano Cocca, Rob M. van Dam, John M. Starr, Martin Farrall, Stefan Weiss, Konstantin Strauch, Albert V. Smith, Jill M. Norris, Raymond Noordam, Cora E. Lewis, Claude Bouchard, Ulf de Faire, Walter Palmas, Diane M. Becker, Kevin Sandow, Tomohiro Katsuya, Jiang He, Nancy L. Pedersen, Bernardo L. Horta, Joel D. Kaufman, Terho Lehtimäki, Heikki A. Koistinen, Thomas W. Winkler, Ian J. Deary, Richard S. Cooper, Fumihiko Takeuchi, Jerome I. Rotter, Lihua Wang, Yih Chung Tham, Babatunde L. Salako, Mary K. Wojczynski, Pim van der Harst, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Patricia B. Munroe, Ehret, Georg Benedikt, Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The various Gene-Lifestyle Interaction projects, including this one, are largely supported by a grant from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305. A Career Development Award (K25HL121091), also from the NHLBI, enabled Y.J.S. to lead this project. Full set of study-specific funding sources and acknowledgments appear in the Supplemental Note., Sung, Yun J., Winkler, Thomas W., de las Fuentes, Lisa, Bentley, Amy R., Brown, Michael R., Kraja, Aldi T., Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Feitosa, Mary F., Kilpeläinen, Tuomas O., Richard, Melissa A., Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugue, Bartz, Traci M., Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K., Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M., Tayo, Bamidele O., Warren, Helen R., Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E., Hartwig, Fernando Pire, Horimoto, Andrea R. V. R., Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, ’an Luan, Jian, Mckenzie, Colin A., Meian, He, Nelson, Christopher P., Rauramaa, Rainer, Schupf, Nicole, Scott, Robert A., Sheu, Wayne H. H., Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Wang, Heming, Wang, Yajuan, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan, Aung, Tin, Barr, R. Graham, Bielak, Lawrence F., Boerwinkle, Eric, Bottinger, Erwin P., Braund, Peter S., Brody, Jennifer A., Broeckel, Ulrich, Cabrera, Claudia P., Cade, Brian, Caizheng, Yu, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Chauhan, Ganesh, Christensen, Kaare, Cocca, Massimiliano, Collins, Francis S., Connell, John M., de Mutsert, Renée, de Silva, H. Janaka, Debette, Stephanie, Dörr, Marcu, Duan, Qing, Eaton, Charles B., Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D., Fisher, Virginia A., Forouhi, Nita G., Franco, Oscar H., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Graff, Misa, Gu, C. Charle, Gu, Dongfeng, Gupta, Preeti, Hagenaars, Saskia P., Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hofman, Albert, Howard, Barbara V., Hunt, Steven, Irvin, Marguerite R., Jia, Yucheng, Joehanes, Roby, Justice, Anne E., Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D., Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A., Komulainen, Pirjo, Kooperberg, Charle, Krieger, Jose E., Kubo, Michiaki, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lim, Sing Hui, Lin, Shiow, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Kiang, Liu, Yeheng, Loh, Marie, Lohman, Kurt K., Long, Jirong, Louie, Tin, Mägi, Reedik, Mahajan, Anubha, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Morris, Andrew P., Mosley, Thomas H., Munson, Peter, Murray, Alison D., Nalls, Mike A., Nasri, Ubaydah, Norris, Jill M., North, Kari, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Palmer, Nicholette D., Pankow, James S., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Raitakari, Olli T., Renström, Frida, Rice, Treva K., Ridker, Paul M., Robino, Antonietta, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L., Sandow, Kevin, Schmidt, Carsten O., Schreiner, Pamela J., Scott, William R., Seshadri, Sudha, Sever, Peter, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G., Waldenberger, Melanie, Wang, Lihua, Wang, Ya X., Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K., Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Chen, Yii-Der Ida, de Faire, Ulf, Deary, Ian J., Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost B., Kato, Norihiro, Kooner, Jaspal S., Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K. E., Newman, Anne B., Oldehinkel, Albertine J., Pereira, Alexandre C., Redline, Susan, Rettig, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Kamatani, Yoichiro, Laurie, Cathy C., Bouchard, Claude, Cooper, Richard S., Evans, Michele K., Gudnason, Vilmundur, Kardia, Sharon L. R., Kritchevsky, Stephen B., Levy, Daniel, O'Connell, Jeff R., Psaty, Bruce M., van Dam, Rob M., Sims, Mario, Arnett, Donna K., Mook-Kanamori, Dennis O., Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Fornage, Myriam, Rotimi, Charles N., Province, Michael A., van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Loos, Ruth J. F., Reiner, Alex P., Rotter, Jerome I., Zhu, Xiaofeng, Bierut, Laura J., Gauderman, W. Jame, Caulfield, Mark J., Elliott, Paul, Rice, Kenneth, Munroe, Patricia B., Morrison, Alanna C., Cupples, L. Adrienne, Rao, Dabeeru C., Chasman, Daniel I., Marten, Jonathan [0000-0001-6916-2014], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Epidemiology, Internal Medicine, Gastroenterology & Hepatology, Clinicum, Department of Medicine, Endokrinologian yksikkö, HUS Internal Medicine and Rehabilitation, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, multi-ancestry, Smoking/genetics, Genome-wide association study, Continental Population Groups/genetics, INTIMA-MEDIA THICKNESS, Cohort Studies, Diastole, Polymorphism (computer science), GWAS, TRANSTORNOS RELACIONADOS AO USO DE ÁLCOOL, GENE-ENVIRONMENT INTERACTION, Genetics (clinical), ddc:616, INSULIN-RESISTANCE, Multi-ancestry, Smoking, 1184 Genetics, developmental biology, physiology, blood pressure, GxE interaction, Diastole/genetics, 3. Good health, FALSE DISCOVERY RATE, Blood pressure, Medical genetics, CORONARY-ARTERY-DISEASE, Female, Single Nucleotide/genetics, Systole/genetics, BODY-MASS INDEX, ASSOCIATION ANALYSIS, COMMON VARIANTS, METAANALYSIS, DISEASE, OBESITY, JOINT, medicine.medical_specialty, lifestyle, SUSCEPTIBILITY LOCI, Blood Pressure/genetics, Systole, Quantitative Trait Loci, Single-nucleotide polymorphism, Accounting, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, GxE interactions, Article, smoking, 03 medical and health sciences, Genetic, medicine, Genetics, Journal Article, Humans, Polymorphism, Genetic association, ALCOHOL DEPENDENCE, business.industry, Racial Groups, Reproducibility of Results, Epistasis, Genetic, ta3121, Lifestyle, Genetic architecture, NICOTINE DEPENDENCE, 030104 developmental biology, Genetic Loci, Epistasis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, business, Quantitative Trait Loci/genetics, Genome-Wide Association Study
Abstract

The authors declare no competing financial interests except for the following. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health); L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; P.S. has received research awards from Pfizer Inc., is a consultant for Mundipharma Co. (Cambridge, UK), is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and has a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15 000 771.4); P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project; M.A.N.’s participation is supported by a consulting contract between Data Tecnica Internation and the National Institute on Aging (NIH, Bethesda, MD, USA), and he also consults for Illumina, Inc., the Michael J. Fox Foundation, and University of California Healthcare among others; and M.J.C. is Chief Scientist for Genomics England, a UK government company.; International audience; Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined approximately 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Published
2018
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44. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)

Published
2018
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45. Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Author

Lorenz Risch, Anne-Claire Vergnaud, Nguyen Quang Tri, Rona J. Strawbridge, Alan F. Wright, Francesco Cucca, Evan Tzanis, Caterina Barbieri, Jaakko Tuomilehto, Louise V. Wain, Jonathan Marten, James F. Wilson, Christopher Newton-Cheh, Reedik Mägi, Olli T. Raitakari, Peter W.F. Wilson, Joris Deelen, Morris Brown, Anna Morgan, Nabi Shah, Weihua Zhang, Ganesh Chauhan, Gail Davies, Peter S. Braund, Bram P. Prins, Alison Pattie, Marcus Dörr, Zoltán Kutalik, Marco Brumat, Franco Giulianini, Rainer Rettig, Uwe Völker, Georgios Ntritsos, Teresa Nutile, Todd L. Edwards, Albertine J. Oldehinkel, Christopher J. O'Donnell, Jaume Marrugat, Evangelos Evangelou, Nilesh J. Samani, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Francis S. Collins, Tim D. Spector, Simon Thom, Sarah E. Harris, Heather J. Cordell, Helen R. Warren, Cinzia Sala, Peter P. Pramstaller, Seppo Koskinen, Paul F. O'Reilly, Aravinda Chakravarti, Joshua C. Bis, Archie Campbell, Bernard Keavney, Sébastien Thériault, Gonneke Willemsen, Lynda M. Rose, Massimiliano Cocca, Jennifer E. Huffman, Meixia Ren, Massimo Mangino, Markus Perola, Joanna M. M. Howson, David Mosen-Ansorena, Harriëtte Riese, Martin Farrall, Albert V. Smith, Lenore J. Launer, Marina Ciullo, Antti-Pekka Sarin, Veikko Salomaa, Ilaria Gandin, Kent D. Taylor, Peter S. Sever, Markku Laakso, André G. Uitterlinden, Yan V. Sun, Raymond Noordam, Renée de Mutsert, Alan L. James, Jing Hua Zhao, Stefan Enroth, Andrew D. Morris, David S. Siscovick, Andrew D. Johnson, Igor Rudan, Tõnu Esko, Jun Ding, David P. Strachan, Martin D. Tobin, Christopher P. Nelson, Daniela Toniolo, J. Wouter Jukema, Vilmundur Gudnason, Borbala Mifsud, Marty Larson, Andrew A. Hicks, Adriana M. Hung, Antonietta Robino, Ruifang Li-Gao, Paul Elliott, Anne U. Jackson, Michela Traglia, Martin H. de Borst, Germaine C. Verwoert, Rheinhold Schmidt, Fabiola M Del Greco, Åsa Johansson, Anders Hamsten, Csaba P. Kovesdy, Mark J. Caulfield, Cumhur Y Demirkale, John M. C. Connell, Jian'an Luan, K. Witkowska, Georg Ehret, Cecilia M. Lindgren, Oscar H. Franco, Yongmei Liu, Ioanna Tzoulaki, Eric Boerwinkle, Catharina A. Hartman, Muralidharan Sargurupremraj, Claudia Langenberg, J. Michael Gaziano, Peter K. Joshi, Cornelia M. van Duijn, Maris Laan, Nick Shrine, Peter J. van der Most, Michael Boehnke, Leo-Pekka Lyytikäinen, Samuli Ripatti, Ben A. Oostra, Robert A. Scott, Lingchan Lu, Edward G. Lakatta, Yasaman Saba, Daniel Levy, Li Lin, Harold Schneider, Alex S. F. Doney, Michael R. Barnes, Najaf Amin, Hugh Watkins, Paul M. Ridker, Janina S Reid, Ayush Giri, Sekar Kathiresan, Lorna M. Lopez, Mike A. Nalls, Marina Evangelou, Erik Ingelsson, Lili Milani, Alice Stanton, Ozren Polasek, Sara M. Willems, Colin N. A. Palmer, Stéphanie Debette, Dan E. Arking, Helena Schmidt, Paul Knekt, John M. Starr, Yong Qian, Cristina Menni, Yuri Milaneschi, Christophe Tzourio, Tamara B. Harris, Kristin L. Ayers, Peter Vollenweider, Paolo Gasparini, Dennis O. Mook-Kanamori, Rodney J. Scott, Sandosh Padmanabhan, Anubha Mahajan, Peter Almgren, Jacklyn N. Hellwege, Teemu J. Niiranen, Mika Kähönen, Shih-Jen Hwang, Elizabeth G. Holliday, Edith Hofer, Priyanka Nandakumar, Peter J. Munson, Rick Jansen, Andrew P. Morris, Walter Palmas, Ilja M. Nolte, Siim Sõber, Thibaud Boutin, Ahmad Vaez, Albert Hofman, He Gao, Brenda W.J.H. Penninx, Neil Poulter, Alan J. Gow, Caroline Hayward, Nicholas J. Wareham, Elin Org, Philip S. Tsao, Claudia P. Cabrera, Aki S. Havulinna, Dragana Vuckovic, Kelly Cho, Jie Yao, Lars Lind, Jerome I. Rotter, David J. Stott, Ivana Kolcic, Wei-Yu Lin, Tatijana Zemunik, Tineka Blake, Kenneth Rice, Veronique Vitart, Alanna C. Morrison, Kay-Tee Khaw, Marjo-Riitta Järvelin, Guillaume Paré, Jouke-Jan Hottenga, Giorgia Girotto, Chiara Batini, Niki Dimou, Stella Trompet, John Danesh, Annette Peters, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Morris A. Swertz, Jaspal S. Kooner, Niek Verweij, Ibrahim Karaman, Murielle Bochud, Christian Gieger, Ruth J. F. Loos, Daniella Ruggiero, Arno Palotie, David Conen, Raha Pazoki, Denis C. Shields, Rossella Sorice, Philippe Amouyel, Gonçalo R. Abecasis, Andres Metspalu, John Attia, Bruce M. Psaty, Sarah H. Wild, Patricia B. Munroe, Daniel I. Chasman, Ollie Melander, John C. Chambers, Roby Joehanes, Eleftheria Zeggini, Johan Sundström, Chrysovalanto Mamasoula, Benjamin Lehne, Kati Kristiansson, Christopher Oldmeadow, Eco J. C. de Geus, A. Mesut Erzurumluoglu, Anuj Goel, Adam S. Butterworth, Digna R. Velez Edwards, Xiuqing Guo, Antti Jula, Praveen Surendran, Terho Lehtimäki, Mattias Frånberg, Teresa Ferreira, Ian J. Deary, David C. Liewald, Pim van der Harst, Erwin P. Bottinger, Roberto Elosua, and Fu Liang Ng

Subjects
Genetics, 0303 health sciences, Diastole, Disease, 030204 cardiovascular system & hematology, Biology, Precision medicine, Genetic analysis, 3. Good health, Pulse pressure, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Disease prevention, 030304 developmental biology, Genetic association
Abstract

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

Published
2017
Full Text
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46. Corrigendum: Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Author

Neil R Poulter, Barnes, Danish Saleheen, Borbala Mifsud, Tobin, Aravinda Chakravarti, Ioanna Tzoulaki, Meixia Ren, Ching-Ti Liu, MA Said, Char Genome, Ron T. Gansevoort, Simon A. McG. Thom, Claudia P. Cabrera, Niek Verweij, Norihiro Kato, Evangelos Evangelou, Patricia B. Munroe, Igb Pressure, John M. C. Connell, Paul F. O'Reilly, R Magi, Peter S. Sever, Paul Elliott, Icbp Icbp, John C. Chambers, Morris J. Brown, J. Marten, Mps Lepe, Alice Stanton, Sandosh Padmanabhan, Daniel Levy, He Gao, Denis C. Shields, Marie Loh, Jmm Howson, Mark J. Caulfield, James P. Cook, Helen R. Warren, E-Shyong Tai, David J. Porteous, Fotios Drenos, Jaspal S. Kooner, Bernard Keavney, P. van der Harst, Maris Alver, Christopher Newton-Cheh, A. Metspalu, Martin Farrall, Praveen Surendran, Caroline Hayward, Joanne Knight, Maciej Tomaszewski, Jiang He, Ioanna Ntalla, C M Lindgren, Daniel I. Chasman, T Esko, Harold Snieder, Sjl Bakker, Ibrahim Karaman, Louise V. Wain, G. Ehret, Aldi T. Kraja, Rajiv Chowdhury, Nilesh J. Samani, and Pfizer Inc

Subjects
International Consortium of Blood Pressure (ICBP) 1000G Analyses, The CHD Exome+ Consortium, The ExomeBP Consortium, The T2D-GENES Consortium, The GoT2DGenes Consortium, The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium, The International Genomics of Blood Pressure (iGEN-BP) Consortium, College health, medicine.medical_specialty, media_common.quotation_subject, UK Biobank CardioMetabolic Consortium BP working group, Library science, Translational research, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Excellence, Health care, Genetics, medicine, Genome-Wide Association Analysis, media_common, business.industry, Public health, 11 Medical And Health Sciences, 06 Biological Sciences, Medical research, Biobank, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

HRW, CPC, MR, MRB, PBM, MB and MJC were funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. HG was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. MR was a recipient from China Scholarship Council (No. 2011632047). BM holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. JMMH was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), European Commission Framework Programme 7 (HEALTH-F2-2012-279233). BK holds a British Heart Foundation Personal Chair (CH/13/2/30154). NJS holds a chair funded by the British Heart Foundation and is a NIHR Senior Investigator. FD was funded by the MRC Unit at the University of Bristol (MC_UU_12013/1-9). PSu was funded by the UK Medical Research Council (G0800270). CL and AK were funded by the NHLBI intramural funding. CNC was funded by the National Institutes of Health (HL113933, HL124262). PVDH was funded by the ZonMw grant 90.700.441, Marie Sklodowska-Curie GF (call: H2020- MSCA-IF-2014, Project ID: 661395). NV was supported by Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. NP received funding from the UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and also from his Senior Investigator Award. PS was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. ST was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. PFO received funding from the UK Medical Research Council (MR/N015746/1) and the Wellcome Trust (109863/Z/15/Z). IK was supported by the EU PhenoMeNal project (Horizon 2020, 654241). AC was funded by the National Institutes of Health (HL128782, HL086694). MF was supported by the Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). CH was funded by an MRC core grant for QTL in Health and Disease programme. Some of this work used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. MJC is a National Institute for Health Research (NIHR) senior investigator. PE is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). As director of the MRC-PHE Centre for Environment and Health, PE acknowledges support from the Medical Research Council and Public Health England (MR/L01341X/1). This work used the computing resources of the UK MEDical BIOinformatics partnership - aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO) which is supported by the Medical Research Council (MR/L01632X/1). This research was supported by the British Heart Foundation (grant SP/13/2/30111). Project title: Large-scale comprehensive genotyping of UK Biobank for cardiometabolic traits and diseases: UK CardioMetabolic Consortium (UKCMC).

Published
2017

47. Bacterial conjugated linoleic acid production and their applications

Author

Yong Q. Chen, Catherine Stanton, R. Paul Ross, Wei Chen, Hao Zhang, He Gao, Bo Yang, Haiqin Chen, National Natural Science Foundation of China, National Natural Science Foundation of Jiangsu Province, Fundamental Research Funds for the Central Universities, Jiangsu Province 'Collaborative Innovation Center for Food Safety and Quality Control', BK20150141, JUSRP51702A, and JUSRP11733

Subjects
0301 basic medicine, Conjugated linoleic acid, Linoleic acid, 030106 microbiology, CLA bioconversion mechanism, Biochemistry, 03 medical and health sciences, Propionibacterium acnes, chemistry.chemical_compound, Microbial cell factories, Biosynthesis, Animals, Humans, Linoleic Acids, Conjugated, biology, Bacteria, integumentary system, Fungi, food and beverages, Cell Biology, Bacterial CLA-producers, biology.organism_classification, Food supplement, chemistry, lipids (amino acids, peptides, and proteins), Heterologous expression, Lactobacillus plantarum
Abstract

peer-reviewed Conjugated linoleic acid (CLA) has been shown to exert various potential physiological properties including anti-carcinogenic, anti-obesity, anti-cardiovascular and anti-diabetic activities, and consequently has been considered as a promising food supplement. Bacterial biosynthesis of CLA is an attractive approach for commercial production due to its high isomer-selectivity and convenient purification process. Many bacterial species have been reported to convert free linoleic acid (LA) to CLA, hitherto only the precise CLA-producing mechanisms in Propionibacterium acnes and Lactobacillus plantarum have been illustrated completely, prompting the development of recombinant technology used in CLA production. The purpose of the article is to review the bacterial CLA producers as well as the recent progress on describing the mechanism of microbial CLA-production. Furthermore, the advances and potential in the heterologous expression of CLA genetic determinants will be presented.

Published
2017

48. Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

Author

Nancy L. Pedersen, John M. Starr, Kjetil Sundet, Qiong Yang, Nicole A. Kochan, Beverly Gwen Windham, Ida K. Karlsson, Daniel E. Gustavson, Jerome I. Rotter, Antony Payton, M. Arfan Ikram, Alison D. Murray, Edith Hofer, Ozren Polasek, Markus Leber, Will Longstreth, Stephanie Le Hellard, Peter W. Schofield, Raha Pazoki, Janie Corley, Max Lam, Deborah K. Attix, Hieab H.H. Adams, Tobias Luck, Ian J. Deary, Panos Roussos, Amelia A. Assareh, Katja Petrovic, Dwight Dickinson, Elizabeth T. Cirulli, Thomas Espeseth, Richard J. Rose, Annette L. Fitzpatrick, Robert M. Bilder, Rodney J. Scott, Katherine E. Burdick, William S. Kremen, Christophe Tzourio, Richard E. Straub, Thomas H. Mosley, Michael Griswold, Ulman Lindenberger, Peter R. Schofield, Riccardo E. Marioni, Stéphanie Debette, Jennifer A. Smith, M. Kamran Ikram, Pamela DeRosse, Russell A. Poldrack, Teemu Palviainen, Panos Bitsios, Nikos C. Stefanis, Anu Loukola, Nikolaos Smyrnis, Todd Lencz, Michelle Luciano, Robert Karlsson, Bettina Konte, Dan Rujescu, Mika Kähönen, James F. Wilson, Steven T. Turner, David A. Bennett, Jingyun Yang, Cornelia M. van Duijn, David S. Knopman, Harry Campbell, R. F. Gottesman, Vidar M. Steen, Nicola J. Armstrong, Alfredo Ramirez, Ina Giegling, Jari Lahti, Marisa Koini, Tyrone D. Cannon, Gerardo Heiss, Ian Ford, Vilmundur Gudnason, Alex Hatzimanolis, Joshua C. Bis, Albert V. Smith, David Ames, Jan Bressler, Catriona L. K. Barnes, Emily Drabant Conley, Raymond Noordam, Ornit Chiba-Falek, Michael Gill, Simone Reppermund, Katri Räikkönen, Christopher Oldmeadow, Kent D. Taylor, Holger Wagner, Claudia L. Satizabal, Chandra A. Reynolds, Tian Liu, Daniel R. Weinberger, Neil Pendleton, Scott D. Gordon, Eric Boerwinkle, Saskia P. Hagenaars, Andrew M. McIntosh, Igor Rudan, Joey W. Trampush, John Attia, Michael Wagner, K. Hoyan Wen, Judith A. Okely, Aristotle N. Voineskos, Patricia A. Boyle, Danielle M. Dick, Anna C. Need, Markus Scholz, Luca Kleineidam, Aiden Corvin, Ingrid Melle, Margaret J. Wright, Helena Schmidt, Leo-Pekka Lyytikäinen, Natalie Terzikhan, Stuart J. Ritchie, He Gao, Anne C. Böhmer, Dan E. Arking, Narelle K. Hansell, Nicholas G. Martin, Fred W. Sabb, Nathan A. Gillespie, Evangelos Evangelou, Bruce M. Psaty, Anders Lundquist, Oscar L. Lopez, Emma Knowles, Matthew C. Keller, Henry Brodaty, Julian N. Trollor, Gary Donohoe, Ivar Reinvang, Ari Ahola-Olli, Tamara B. Harris, André G. Uitterlinden, David R. Weir, Abbas Dehghan, Sarah E. Harris, P. Eline Slagboom, Chloe Fawns-Ritchie, Paul Elliott, William Ollier, Edythe D. London, Anders M. Dale, Jaakko Kaprio, Catharine R. Gale, Karen A. Mather, Aarno Palotie, Stella G. Giakoumaki, Sven J. van der Lee, Jeannette Simino, Elisabeth Widen, Teresa Lee, Sudheer Giddaluru, Anil K. Malhotra, Philippe Amouyel, Caroline Hayward, Shuo Li, Goran Papenberg, Steffi G. Riedel-Heller, Wei Zhao, Nelson A. Freimer, Simon R. Cox, Yasaman Saba, Andrea Christoforou, Johan G. Eriksson, Eliza Congdon, David J. Porteous, Matthew A. Scult, Eero Vuoksimaa, Veronique Vitart, Derek W. Morris, Sharon L.R. Kardia, Elizabeth G. Holliday, Peter K. Joshi, Suvi P. Rovio, Astri J. Lundervold, J. Wouter Jukema, Aicha Soumare, Stella Trompet, Annette M. Hartmann, Ole A. Andreassen, Erin B. Ware, Matthias Schmid, Perminder S. Sachdev, Grant W. Montgomery, Lars Bertram, Philip L. De Jager, Olli T. Raitakari, Terho Lehtimäki, Arno Villringer, Srdjan Djurovic, David C. Liewald, Sudha Seshadri, Gail Davies, Ahmad R. Hariri, Sara Hägg, Lars Nyberg, Dimitrios Avramopoulos, Muralidharan Sargurupremraj, W. David Hill, Shu-Chen Li, Leonie Weinhold, David J. Stott, David C. Glahn, John B.J. Kwok, Ioanna Tzoulaki, Reinhold Schmidt, Najaf Amin, Lenore J. Launer, Jin Yu, Jessica D. Faul, Adele M. Taylor, Anbupalam Thalamuthu, and Alison Pattie

Subjects
Genetics, 0303 health sciences, media_common.quotation_subject, Longevity, Genetic data, Cognition, Heritability, Significant snps, Biology, Biobank, 03 medical and health sciences, 0302 clinical medicine, Trait, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract

General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P−8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function wereSGCZ,ATXN1,MAPT,AUTS2, andP2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

Published
2017
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49. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney

Author

Peter Vollenweider, Christophe Tzourio, Stefan Enroth, Cinzia Sala, Mark J. Caulfield, Murielle Bochud, Peter P. Pramstaller, Ozren Polasek, Paul Elliott, Dennis O. Mook-Kanamori, Daniel I. Chasman, Christian Gieger, Harriëtte Riese, Rodney J. Scott, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Priyanka Nandakumar, Tatijana Zemunik, Dragana Vuckovic, Tõnu Esko, Franco Giulianini, Michael Boehnke, Antonietta Robino, Anne U. Jackson, Roby Joehanes, Alanna C. Morrison, Kay-Tee Khaw, Alison Pattie, Peter J. van der Most, Mika Kähönen, Rick Jansen, Andrew D. Johnson, John M. Starr, Marcus Dörr, Anders Hamsten, Kenneth Rice, Alice Stanton, James F. Wilson, Nabi Shah, Weihua Zhang, Andrew A. Hicks, Jeffrey Damman, Jing Hua Zhao, Aarno Palotie, Veronique Vitart, Alan J. Gow, Caroline Hayward, Alan James, Ben A. Oostra, Janina S. Ried, John Beilby, David P. Strachan, Martin D. Tobin, Eco J. C. de Geus, Vilmundur Gudnason, Bruce M. Psaty, Zoltán Kutalik, Neil Poulter, Paul M. Ridker, Johan Sundström, Cornelia M. van Duijn, Eleftheria Zeggini, Christopher Oldmeadow, Borbala Mifsud, Giorgia Girotto, Aravinda Chakravarti, Jonathan Marten, Alexander Teumer, Joanne Knight, Robert A. Scott, Vilmantas Giedraitis, Paul F. O'Reilly, Marco Brumat, Brenda W.J.H. Penninx, Peter J. Munson, Olli T. Raitakari, Leo-Pekka Lyytikäinen, He Gao, Massimo Mangino, Benjamin Lehne, J. Wouter Jukema, Paul Knekt, Catharina A. Hartman, Rona J. Strawbridge, Jouke-Jan Hottenga, Jaspal S. Kooner, Nilesh J. Samani, Kristin L. Ayers, A. Mesut Erzurumluoglu, Joshua C. Bis, Archie Campbell, Dan E. Arking, Germaine C. Verwoert, John Attia, Samuli Ripatti, Yuri Milaneschi, Caterina Barbieri, Fabiola M. Del Greco, C M Lindgren, Peter K. Joshi, Helen R. Warren, Nicholas J. Wareham, Simon Thom, Seppo Koskinen, Tamara B. Harris, Ilaria Gandin, Kent D. Taylor, Andrew D. Morris, Anna Morgan, Chiara Batini, Terho Lehtimäki, Walter Palmas, David Conen, Harold Snieder, Martin H. de Borst, Sarah E. Harris, Igor Rudan, Ruth J. F. Loos, Claudia Langenberg, Anuj Goel, Christopher P. Nelson, Peter S. Braund, Rossella Sorice, Yasaman Saba, Oscar H. Franco, Yongmei Liu, Mattias Frånberg, David S. Siscovick, Patricia B. Munroe, Rainer Rettig, Michela Traglia, Daniel Levy, Li Lin, Michael R. Barnes, Elin Org, Anne-Claire Vergnaud, Andres Metspalu, Stéphanie Debette, Yusuf Demirkale, John M. C. Connell, Jian'an Luan, Paolo Gasparini, Tim D. Spector, Marina Ciullo, Antti-Pekka Sarin, Ian J. Deary, Teemu J. Niiranen, Marty Larson, Heather J. Cordell, Jerome I. Rotter, Sekar Kathiresan, Teresa Nutile, Andrew P. Morris, Denis C. Shields, Alan F. Wright, Lorna M. Lopez, Aki S. Havulinna, Gonçalo R. Abecasis, Edith Hofer, Siim Sõber, Sébastien Thériault, Ahmad Vaez, Albert Hofman, Gonneke Willemsen, Lynda M. Rose, John C. Chambers, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, François Mach, Massimiliano Cocca, Sarah H Wild, Reinhold Schmidt, Jaume Marrugat, Marc A. Seelen, Maris Laan, Aude Saint Pierre, David C. Liewald, Pim van der Harst, Sandosh Padmanabhan, Martin Farrall, Georg Ehret, Albert V. Smith, Quang Tri Nguyen, Ulf Gyllensten, Helena Schmidt, Ganesh Chauhan, Jennifer E. Huffman, Morris A. Swertz, Jaakko Tuomilehto, Louise V. Wain, Meixia Ren, Erwin P. Bottinger, Roberto Elosua, Ivana Kolcic, Veikko Salomaa, Stella Trompet, Bernard Keavney, Claudia P. Cabrera, Bram P. Prins, Jennie Hui, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Shih-Jen Hwang, Jie Yao, Francis S. Collins, Chrysovalanto Mamasoula, Kati Kristiansson, Markus Perola, Renée de Mutsert, Xiuqing Guo, Antti Jula, Daniela Toniolo, Ruifang Li-Gao, Åsa Johansson, Nick Shrine, Teresa Ferreira, Lars Lind, David J. Stott, Tineka Blake, Daniela Ruggiero, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Christopher Newton-Cheh, Marjo-Riitta Järvelin, Guillaume Paré, Joris Deelen, Morris Brown, Gail Davies, Annette Peters, Ioanna Tzoulaki, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Yingchang Lu, Wain, Lv, Vaez, A, Jansen, R, Joehanes, R, van der Most, Pj, Erzurumluoglu, Am, O'Reilly, Pf, Cabrera, Cp, Warren, Hr, Rose, Lm, Verwoert, Gc, Hottenga, Jj, Strawbridge, Rj, Esko, T, Arking, De, Hwang, Sj, Guo, X, Kutalik, Z, Trompet, S, Shrine, N, Teumer, A, Ried, J, Bis, Jc, Smith, Av, Amin, N, Nolte, Im, Lyytikäinen, Lp, Mahajan, A, Wareham, Nj, Hofer, E, Joshi, Pk, Kristiansson, K, Traglia, M, Havulinna, A, Goel, A, Nalls, Ma, Sõber, S, Vuckovic, Dragana, Luan, J, Del Greco, M. F, Ayers, Kl, Marrugat, J, Ruggiero, D, Lopez, Lm, Niiranen, T, Enroth, S, Jackson, Au, Nelson, Cp, Huffman, Je, Zhang, W, Marten, J, Gandin, I, Harris, Se, Zemunik, T, Lu, Y, Evangelou, E, Shah, N, de Borst, Mh, Mangino, M, Prins, Bp, Campbell, A, Li Gao, R, Chauhan, G, Oldmeadow, C, Abecasis, G, Abedi, M, Barbieri, Cm, Barnes, Mr, Batini, C, Beilby, J, Blake, T, Boehnke, M, Bottinger, Ep, Braund, P, Brown, M, Brumat, M, Campbell, H, Chambers, Jc, Cocca, M, Collins, F, Connell, J, Cordell, Hj, Damman, Jj, Davies, G, de Geus, Ej, de Mutsert, R, Deelen, J, Demirkale, Y, Doney, Asf, Dörr, M, Farrall, M, Ferreira, T, Frånberg, M, Gao, H, Giedraitis, V, Gieger, C, Giulianini, F, Gow, Aj, Hamsten, A, Harris, Tb, Hofman, A, Holliday, Eg, Hui, J, Jarvelin, Mr, Johansson, Å, Johnson, Ad, Jousilahti, P, Jula, A, Kähönen, M, Kathiresan, S, Khaw, Kt, Kolcic, I, Koskinen, S, Langenberg, C, Larson, M, Launer, Lj, Lehne, B, Liewald, Dcm, Lin, L, Lind, L, Mach, F, Mamasoula, C, Menni, C, Mifsud, B, Milaneschi, Y, Morgan, Anna, Morris, Ad, Morrison, Ac, Munson, Pj, Nandakumar, P, Nguyen, Qt, Nutile, T, Oldehinkel, Aj, Oostra, Ba, Org, E, Padmanabhan, S, Palotie, A, Paré, G, Pattie, A, Penninx, Bwjh, Poulter, N, Pramstaller, Pp, Raitakari, Ot, Ren, M, Rice, K, Ridker, Pm, Riese, H, Ripatti, S, Robino, A, Rotter, Ji, Rudan, I, Saba, Y, Saint Pierre, A, Sala, Cf, Sarin, Ap, Schmidt, R, Scott, R, Seelen, Ma, Shields, Dc, Siscovick, D, Sorice, R, Stanton, A, Stott, Dj, Sundström, J, Swertz, M, Taylor, Kd, Thom, S, Tzoulaki, I, Tzourio, C, Uitterlinden, Ag, Völker, U, Vollenweider, P, Wild, S, Willemsen, G, Wright, Af, Yao, J, Thériault, S, Conen, D, Attia, J, Sever, P, Debette, S, Mook Kanamori, Do, Zeggini, E, Spector, Td, van der Harst, P, Palmer, Cna, Vergnaud, Ac, Loos, Rjf, Polasek, O, Starr, Jm, Girotto, Giorgia, Hayward, C, Kooner, J, Lindgren, Cm, Vitart, V, Samani, Nj, Tuomilehto, J, Gyllensten, U, Knekt, P, Deary, Ij, Ciullo, M, Elosua, R, Keavney, Bd, Hicks, Aa, Scott, Ra, Gasparini, Paolo, Laan, M, Liu, Y, Watkins, H, Hartman, Ca, Salomaa, V, Toniolo, D, Perola, M, Wilson, Jf, Schmidt, H, Zhao, Jh, Lehtimäki, T, van Duijn, Cm, Gudnason, V, Psaty, Bm, Peters, A, Rettig, R, James, A, Jukema, Jw, Strachan, Dp, Palmas, W, Metspalu, A, Ingelsson, E, Boomsma, Di, Franco, Oh, Bochud, M, Newton Cheh, C, Munroe, Pb, Elliott, P, Chasman, Di, Chakravarti, A, Knight, J, Morris, Ap, Levy, D, Tobin, Md, Snieder, H, Caulfield, Mj, Ehret, G. b., Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Organ Transplantation (GIOT), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Epidemiology, Gastroenterology & Hepatology, Clinical Genetics, Internal Medicine, Erasmus MC other, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, Division 6, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology

Subjects
0301 basic medicine, cardiovascular risk, Netherlands Twin Register (NTR), hypertension, NETHERLANDS, Sistema cardiovascular -- Malalties, GWAS, blood pressure, complex traits, eSNP, Locus (genetics), Genome-wide association study, Disease, Biology, PERIPHERAL-BLOOD, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Internal Medicine, Journal Article, Cardiac and Cardiovascular Systems, 1000 Genomes Project, Gene, CENTRIC ARRAY, METAANALYSIS, Genetics, ddc:616, Kardiologi, PULSE PRESSURE, COMMON VARIANTS, 1103 Clinical Sciences, ta3121, 3. Good health, INDIVIDUALS, 030104 developmental biology, Blood pressure, TARGET, Cardiovascular System & Hematology, complex trait, GWAS, blood pressure, cardiovascular risk, complex traits, eSNP, hypertension, Hipertensió, Imputation (genetics), TRAITS
Abstract

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Published
2017
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50. Transcriptional Regulation of the Type VI Secretion System 1 Genes by Quorum Sensing and ToxR in

Author

Yin Zhe, Wenhui Yang, Dongsheng Zhou, Ying Zhang, Yiquan Zhang, George Osei-Adjei, Xinxiang Huang, He Gao, and Huiying Yang

Subjects
0301 basic medicine, Microbiology (medical), AphA, Operon, 030106 microbiology, lcsh:QR1-502, ToxR, Microbiology, lcsh:Microbiology, 03 medical and health sciences, Transcriptional regulation, Type VI secretion system, Original Research, Regulation of gene expression, Genetics, T6SS1, biology, Vibrio parahaemolyticus, Correction, quorum sensing, Promoter, biology.organism_classification, OpaR, Vibrio, Quorum sensing
Abstract

Vibrio parahaemolyticus, the leading cause of seafood-associated gastroenteritis, harbors two separate T6SSs on chromosomes 1 and 2, i.e., T6SS1 (VP1386-1420) and T6SS2 (VPA1025-1046). T6SS1 contains at least 7 putative operons: VP1386-1387, VP1388-1390, VP1392-1391, VP1393-1406, VP1400-1406, VP1409-1407, and VP1410-1420. V. parahaemolyticus AphA and OpaR are the two master regulators of quorum sensing (QS) system that are highly expressed at low cell density and high cell density, respectively. ToxR is a membrane-bound virulence regulatory protein conserved across the Vibrio family. In the present work, we show that ToxR coordinates with AphA and OpaR to repress T6SS1 expression in V. parahaemolyticus. OpaR binds to the promoters of VP1388-1390, VP1400-1406, and VP1409-1407 to repress their transcription, but it appears to negatively regulate VP1393-1406 transcription in an indirect manner. By contrast, AphA negatively regulated the above four T6SS1 operons in an indirect manner. In addition, ToxR binds to the promoters of VP1400-1406 and VP1409-1407 to inhibit their transcription, but it presents an indirect interaction with VP1388-1390 and VP1393-1406 promoters. Notably, the expression of ToxR also manifested in a QS-dependent manner and the highest expression occurred at LCD. Meanwhile, the highest expression of T6SS1 occurred at an OD600 value of 0.6 to 0.8 due to the tight regulation of ToxR and QS, suggesting T6SS1 functions only during the mid-logarithmic growth phase. These observations provide significant insight into the molecular mechanism of T6SS1 gene regulation by QS and ToxR in V. parahaemolyticus.

Published
2017

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