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1. Genome-wide association studies for pelvic organ prolapse in the Japanese population

Author

Masatoshi Matsunami, Minako Imamura, Asuka Ashikari, Xiaoxi Liu, Kohei Tomizuka, Keiko Hikino, Kosei Miwa, Katsumi Kadekawa, Tetsuji Suda, The Biobank Japan project, Koichi Matsuda, Minoru Miyazato, Chikashi Terao, and Shiro Maeda

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by the descent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wide association study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in the Japanese population. We identified a significant association of WT1 locus with POP in the Japanese population; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29–1.68, P = 6.72 × 10− 9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data and previously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2 locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04–1.08, P = 4.11 × 10− 8). We also observed consistent directions of the effects for 21 out of 24 European GWAS derived loci (binomial test P = 2.8 × 10− 4), indicating that most of susceptibility loci for POP are shared across the Japanese and European populations.

Published
2024
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2. Perspectives on genetic studies of type 2 diabetes from the genome‐wide association studies era to precision medicine

Author

Minako Imamura and Shiro Maeda

Subjects
Genome‐wide association studies, Polygenic risk scores, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Abstract Genome‐wide association studies (GWAS) have facilitated a substantial and rapid increase in the number of confirmed genetic susceptibility variants for complex diseases. Approximately 700 variants predisposing individuals to the risk for type 2 diabetes have been identified through GWAS until 2023. From 2018 to 2022, hundreds of type 2 diabetes susceptibility loci with smaller effect sizes were identified through large‐scale GWAS with sample sizes of 200,000 to >1 million. The clinical translation of genetic information for type 2 diabetes includes the development of novel therapeutics and risk predictions. Although drug discovery based on loci identified in GWAS remains challenging owing to the difficulty of functional annotation, global efforts have been made to identify novel biological mechanisms and therapeutic targets by applying multi‐omics approaches or searching for disease‐associated coding variants in isolated founder populations. Polygenic risk scores (PRSs), comprising up to millions of associated variants, can identify individuals with higher disease risk than those in the general population. In populations of European descent, PRSs constructed from base GWAS data with a sample size of approximately 450,000 have predicted the onset of diseases well. However, European GWAS‐derived PRSs have limited predictive performance in non‐European populations. The predictive accuracy of a PRS largely depends on the sample size of the base GWAS data. The results of GWAS meta‐analyses for multi‐ethnic groups as base GWAS data and cross‐population polygenic prediction methodology have been applied to establish a universal PRS applicable to small isolated ethnic populations.

Published
2024
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3. Profile of gut microbiota and serum metabolites associated with metabolic syndrome in a remote island most afflicted by obesity in Japan

Author

Tsugumi Uema, Jasmine F. Millman, Shiki Okamoto, Takehiro Nakamura, Kiyoto Yamashiro, Moriyuki Uehara, Ken-ichiro Honma, Minoru Miyazato, Asuka Ashikari, Seiichi Saito, Shiro Maeda, Minako Imamura, Hajime Ishida, Masayuki Matsushita, Koshi Nakamura, and Hiroaki Masuzaki

Subjects
Medicine, Science
Abstract

Abstract Numerous studies have revealed distinct differences in the profiles of gut microbiota between non-obese and obese individuals. To date, however, little is known if any disparities in the community of gut microbiota exist between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) subjects. We therefore aimed to comprehensively characterize the gut microbiota and circulating metabolites in serum from both MHO and MUO residing in the remote island, Kumejima, where the prevalence of obesity is one of the highest in Japan, and explored possible correlations between the gut microbiota profile and markers of metabolic syndrome. Results revealed that MUO showed significantly higher levels of genera such as g_Succinivibrio, g_Granulicatella, g_Brachyspira, g_Oribacterium and g_Atopobium in comparison to MHO. Moreover, abundance of g_Succinivibrio, g_Brachyspira and g_Atopobium were positively correlated with value of fasting insulin, HOMA-R, circulating triglycerides, diastolic blood pressure, BMI, body weight, waist circumference and HbA1c. In addition, MUO compared to MHO showed an imbalance of serum metabolites, with a significant elevation in 2-oxoisovaleric acid, pyruvic acid, 2-hydroxybutyric acid, and creatine. Our data highlight unmet needs in precision approaches for the treatment of obesity, targeting the gut microbiota profile and serum metabolites in a distinct population affected by obesity.

Published
2022
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4. Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Author

Kenichi Shikata, Masakazu Haneda, Toshiharu Ninomiya, Daisuke Koya, Yoshiki Suzuki, Daisuke Suzuki, Hitoshi Ishida, Hiroaki Akai, Yasuhiko Tomino, Takashi Uzu, Motonobu Nishimura, Shiro Maeda, Daisuke Ogawa, Satoshi Miyamoto, Hirofumi Makino, and the Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) collaborative group

Subjects
Diabetic kidney disease, Diabetic nephropathy, Diabetic Nephropathy Remission and Regression Team Trial in Japan, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Abstract Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P

Published
2021
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5. Impact of anti-diabetic sodium-glucose cotransporter 2 inhibitors on tumor growth of intractable hematological malignancy in humans

Author

Sawako Nakachi, Shiki Okamoto, Keita Tamaki, Ikumi Nomura, Mamiko Tomihama, Yukiko Nishi, Takuya Fukushima, Yuetsu Tanaka, Satoko Morishima, Minako Imamura, Shiro Maeda, Masato Tsutsui, Masayuki Matsushita, and Hiroaki Masuzaki

Subjects
Adult T cell leukemia (ATL), Hematological malignancy, Metabolic oncology, Sodium-glucose cotransporter-2 (SGLT2), Warburg effect, Therapeutics. Pharmacology, RM1-950
Abstract

Under the dysfunction of mitochondria, cancer cells preferentially utilize both glycolytic and pentose phosphate pathways rather than electron transport chains to desperately generate adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH), classically recognized as the Warburg effect. Based on this background, the present study tested the hypothesis that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors would exert a tumor-suppressive impact on intractable human hematological malignancies via the modulation of glucose metabolism within cells and cell cycles. The level of mRNA for SGLT2 was remarkably elevated in leukemic cells from patients with adult T-cell leukemia (ATL), one of the most intractable blood cancers in humans, and as well as in two kinds of ATL cell lines (MT-1 and MT-2). Two kinds of SGLT2 inhibitors, Luseogliflozin and Tofogliflozin substantially suppressed the proliferation of MT-1 and MT-2 cells in both adherent and anchorage-independent culture conditions. Such a suppressive effect on tumor cell growth was reproduced by Luseogliflozin in leukemic cells in peripheral blood from patients with ATL. In MT-2 cells, both of SGLT2 inhibitors considerably attenuated glucose uptake, intracellular ATP levels, and NADPH production, resultantly enhancing cell cycle arrest at the G0/G1 phase. From the standpoint of metabolic oncology, the present study suggests that SGLT2 inhibitors would be a promising adjunctive option for the treatment of the most intractable human hematological malignancies like ATL.

Published
2022
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6. Obesity and Voiding Parameters in a Community-Based Population of Okinawa, Japan: Kumejima Digital Health Project (KDHP)

Author

Asuka Ashikari, Minoru Miyazato, Koshi Nakamura, Kiyoto Yamashiro, Takehiro Nakamura, Tsugumi Uema, Moriyuki Uehara, Hiroaki Masuzaki, Seiichi Saito, Shiro Maeda, Hajime Ishida, and Masayuki Matsushita

Subjects
obesity, nocturia, polyuria, hours of undisturbed sleep, maximum bladder capacity, Microbiology, QR1-502
Abstract

(1) Background: Evidence has accumulated regarding the etiology of lower urinary tract symptoms associated with obesity and metabolic syndrome. Therefore, the present study aimed to identify which subjectively and objectively measured voiding parameters were associated with obesity in a community-based population. (2) Methods: Voiding parameters on a self-administered questionnaire and a digital self-health monitoring system for urine excretion (s-HMSU) were compared between participants with and without obesity, defined as a body mass index ≥ 25 kg/m2 (n = 30 and 29, respectively), from a community in Okinawa, Japan. Logistic regression analysis was employed to calculate the odds ratios of abnormalities in voiding parameters for the obese group, with the non-obese group serving as a reference. (3) Results: The obese group had odds ratios of 5.17 (95% confidence interval: 1.33–20.0) for shortened hours of undisturbed sleep (

Published
2022
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7. Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Author

Shinji Kume, Motoyuki Kondo, Shiro Maeda, Yoshihiko Nishio, Tsuyoshi Yanagimachi, Yukihiro Fujita, Masakazu Haneda, Keiko Kondo, Akihiro Sekine, Shin-ich Araki, Hisazumi Araki, Masami Chin-Kanasaki, Satoshi Ugi, Daisuke Koya, Sawako Kitahara, Kiyosumi Maeda, Atsunori Kashiwagi, Takashi Uzu, and Hiroshi Maegawa

Subjects
First-phase GSIS, Pancreatic β cell, Starvation, Diabetes, Insulin secretion, Medicine, Medicine (General), R5-920
Abstract

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes.

Published
2016
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8. Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

Author

Minako Imamura, Atsushi Takahashi, Toshimasa Yamauchi, Kazuo Hara, Kazuki Yasuda, Niels Grarup, Wei Zhao, Xu Wang, Alicia Huerta-Chagoya, Cheng Hu, Sanghoon Moon, Jirong Long, Soo Heon Kwak, Asif Rasheed, Richa Saxena, Ronald C. W. Ma, Yukinori Okada, Minoru Iwata, Jun Hosoe, Nobuhiro Shojima, Minaka Iwasaki, Hayato Fujita, Ken Suzuki, John Danesh, Torben Jørgensen, Marit E. Jørgensen, Daniel R. Witte, Ivan Brandslund, Cramer Christensen, Torben Hansen, Josep M. Mercader, Jason Flannick, Hortensia Moreno-Macías, Noël P. Burtt, Rong Zhang, Young Jin Kim, Wei Zheng, Jai Rup Singh, Claudia H. T. Tam, Hiroshi Hirose, Hiroshi Maegawa, Chikako Ito, Kohei Kaku, Hirotaka Watada, Yasushi Tanaka, Kazuyuki Tobe, Ryuzo Kawamori, Michiaki Kubo, Yoon Shin Cho, Juliana C. N. Chan, Dharambir Sanghera, Philippe Frossard, Kyong Soo Park, Xiao-Ou Shu, Bong-Jo Kim, Jose C. Florez, Teresa Tusié-Luna, Weiping Jia, E Shyong Tai, Oluf Pedersen, Danish Saleheen, Shiro Maeda, and Takashi Kadowaki

Subjects
Science
Abstract

Here, Imamuraet al. conduct meta-analysis of genome-wide association studies to identify novel susceptibility loci for type 2 diabetes (T2D) in the Japanese population. By doing so, this study shows that both ethnicity-specific and ethnically-shared genetic loci can contribute to T2D risk.

Published
2016
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9. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

Author

Makiko Taira, Minako Imamura, Atsushi Takahashi, Yoichiro Kamatani, Toshimasa Yamauchi, Shin-Ichi Araki, Nobue Tanaka, Natalie R van Zuydam, Emma Ahlqvist, Masao Toyoda, Tomoya Umezono, Koichi Kawai, Masahito Imanishi, Hirotaka Watada, Daisuke Suzuki, Hiroshi Maegawa, Tetsuya Babazono, Kohei Kaku, Ryuzo Kawamori, SUMMIT Consortium, Leif C Groop, Mark I McCarthy, Takashi Kadowaki, and Shiro Maeda

Subjects
Medicine, Science
Abstract

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

Published
2018
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10. Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies.

Author

Ren Matsuba, Minako Imamura, Yasushi Tanaka, Minoru Iwata, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Kazuyuki Tobe, Atsunori Kashiwagi, Ryuzo Kawamori, and Shiro Maeda

Subjects
Medicine, Science
Abstract

AIM:We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. METHODS:We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. RESULTS:Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019-1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026-1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. CONCLUSIONS:Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population.

Published
2016
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11. FTO Gene Polymorphism Is Associated with Type 2 Diabetes through Its Effect on Increasing the Maximum BMI in Japanese Men.

Author

Yutaka Kamura, Minoru Iwata, Shiro Maeda, Satomi Shinmura, Yukiko Koshimizu, Hisae Honoki, Kazuhito Fukuda, Manabu Ishiki, Isao Usui, Yasuo Fukushima, Atsuko Takano, Hiromi Kato, Shihou Murakami, Kiyohiro Higuchi, Chikaaki Kobashi, and Kazuyuki Tobe

Subjects
Medicine, Science
Abstract

Several studies have demonstrated that polymorphisms within the fat-mass and obesity-associated gene (FTO) are associated with type 2 diabetes (T2D). However, whether the effects of the FTO locus on T2D susceptibility are independent of fat-mass increases remains controversial. To investigate this issue, we examined the association of FTO variants with T2D and various aspects of BMI history during adult life in a Japanese population.We genotyped SNPs within FTO (rs1121980 and rs1558902) in 760 Japanese patients with T2D who had reached a lifetime maximum BMI (BMImax) before or at the time of diagnosis and 693 control individuals with information regarding their BMImax.The BMImax showed the strongest association with T2D risk among the BMIs evaluated in this study. In the sex-combined analysis, FTO SNPs were not associated with any of the BMI variables or with T2D, but in sex-stratified analyses, both SNPs were significantly associated with the BMImax and rs1558902 was associated with T2D in men. The association of the SNPs with T2D remained significant after adjustments for the current BMI and age, whereas the T2D association of the SNP was no longer significant after adjustments for BMImax and age.These results suggest that the effects of FTO polymorphisms on T2D susceptibility in Japanese men are mediated through their effect on increasing the BMImax before or at the time of diagnosis.

Published
2016
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12. Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes.

Author

Ren Matsuba, Kensuke Sakai, Minako Imamura, Yasushi Tanaka, Minoru Iwata, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Kazuyuki Tobe, Atsunori Kashiwagi, Ryuzo Kawamori, and Shiro Maeda

Subjects
Medicine, Science
Abstract

We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes.We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis.All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10(-4), binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037-1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10(-4), adjusted for sex, age and BMI).ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.

Published
2015
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14. Effect of a mobile digital intervention to enhance physical activity in individuals with metabolic disorders on voiding patterns measured by 24-h voided volume monitoring system: Kumejima Digital Health Project (KDHP)

Author

Kiyoto Yamashiro, Tsugumi Uema, Takehiro Nakamura, Seiichi Saito, Hiroaki Masuzaki, Minoru Miyazato, Moriyuki Uehara, Shiro Maeda, Asuka Ashikari, Hajime Ishida, Koshi Nakamura, and Masayuki Matsushita

Subjects
Adult, Male, medicine.medical_specialty, Urology, 030232 urology & nephrology, Urination, Urine, Excretion, 03 medical and health sciences, 0302 clinical medicine, Polyuria, Intervention (counseling), medicine, Blood test, Nocturia, Humans, Prospective Studies, Exercise, Monitoring, Physiologic, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, Urology - Original Paper, business.industry, Metabolic diseases, Middle Aged, Lifestyle, Digital health, Mobile Applications, Voided volume, Blood pressure, Nephrology, Physical therapy, Female, medicine.symptom, business
Abstract

Purpose:To evaluate the effect of a mobile digital intervention on voiding patterns, we performed 24-h voided volume monitoring in individuals with metabolic disorders.\nMethods:Participants with metabolic disorders were grouped into either the intervention group (n = 17), who had access to a smartphone app (CARADA), or the non-intervention group (n = 11), who did not. Urine monitoring was conducted for 24 h using a novel digital self-health monitoring system for urine excretion (s-HMSU). Body weight, abdominal circumference, blood pressure, and biomarkers were measured.\nResults:Physical findings and blood test results at baseline and 6 months indicated no significant between-group differences. Night-time frequency did not change between baseline and 6 months in the intervention group but significantly worsened at 6 months in the non-intervention group, as compared to baseline (1.0 ± 0.7 vs. 1.5 ± 0.5, p, 論文

Published
2021

16. Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes

Author

Minoru Iwata, Jeeyun Ahn, Masao Toyoda, Shin-ichi Araki, Lucia Sobrin, Momoko Horikoshi, M Imamura, Gayatri Susarla, Shiro Maeda, Sanghoon Moon, Atsushi Takahashi, Hiroshi Maegawa, Masatoshi Matsunami, Toshimasa Yamauchi, Jinhwa Kong, Takashi Kadowaki, Kazuyuki Tobe, and Kyu Hyung Park

Subjects
Genotype, Genome-wide association study, Single-nucleotide polymorphism, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Asian People, Gene Frequency, Japan, Meta-Analysis as Topic, Genetics, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Association Studies Article, Molecular Biology, Alleles, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Diabetic Retinopathy, 030305 genetics & heredity, Membrane Proteins, Correction, General Medicine, Diabetic retinopathy, Phosphoproteins, medicine.disease, Diabetes Mellitus, Type 2, Hexosyltransferases, Genetic Loci, Genome-Wide Association Study, Retinopathy
Abstract

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P

Published
2021

17. A unique profile of gut microbiota associated with metabolic syndrome: a remote island most afflicted by obesity in Japan

Author

Tsugumi Uema, Jasmine Frances Millman, Shiki Okamoto, Takehiro Nakamura, Kiyoto Yamashiro, Moriyuki Uehara, Ken-ichiro Honma, Minoru Miyazato, Asuka Ashikari, Seiichi Saito, Shiro Maeda, Minako Imamura, Hajime Ishida, Masayuki Matsushita, Koshi Nakamura, and Hiroaki Masuzaki

Abstract

Numerous studies have revealed distinct differences in the profiles of gut microbiota between non-obese (NO) and obese (OB) individuals. To date, however, little is known if any disparities in the community of gut microbiota exist between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) subjects. We therefore aimed to comprehensively characterize the gut microbiota and circulating metabolites in serum from both MHO and MUO residing in the remote island, Kumejima, where the prevalence of obesity is one of the highest in Japan, and explored possible correlations between the gut microbiota profile and markers of metabolic syndrome. In our data, MUO showed significantly higher levels of g_Paraprevotella, g_Cloacibacillus, g_Atopobium and g_Megasphaera in comparison to MHO. MUO also showed significantly lower levels of g_Holdemania, f_Ruminococcaceae;g_Ruminococcus, g_Eggerthella, g_Phascolarctobacterium and f_[Mogibacteraceae];g_ as compared to MHO, with a number of these genera negatively correlating with value of circulating triglyceride, total-cholesterol and LDL-cholesterol. In contrast to MHO, MUO showed an imbalance of serum metabolites, with a significant elevation in 2-oxoisovaleric acid, pyruvic acid, 2-hydroxybutyric acid, and creatine. Our data highlight unmet needs in precision approaches for the treatment of obesity, targeting the gut microbiota profile and serum metabolites in a distinct population affected by obesity.

Published
2022

18. Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Author

Kenichi Shikata, Masakazu Haneda, Toshiharu Ninomiya, Daisuke Koya, Yoshiki Suzuki, Daisuke Suzuki, Hitoshi Ishida, Hiroaki Akai, Yasuhiko Tomino, Takashi Uzu, Motonobu Nishimura, Shiro Maeda, Daisuke Ogawa, Satoshi Miyamoto, Hirofumi Makino, and the Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) collaborative group

Subjects
Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Type 2 diabetes, Diabetic nephropathy, 030204 cardiovascular system & hematology, Lower risk, Diseases of the endocrine glands. Clinical endocrinology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Diabetes mellitus, Internal medicine, Early Medical Intervention, Internal Medicine, Medicine, Humans, Diabetic Nephropathies, 030212 general & internal medicine, Prospective Studies, Diabetic kidney disease, education, Creatinine, education.field_of_study, business.industry, Hazard ratio, Remission Induction, General Medicine, Articles, Middle Aged, medicine.disease, RC648-665, Prognosis, Clinical Trial, Diabetic Nephropathy Remission and Regression Team Trial in Japan, Clinical Science and Care, chemistry, Diabetes Mellitus, Type 2, Female, business, Biomarkers, Follow-Up Studies
Abstract

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P, The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

Published
2020

20. Emergence of a multidrug-resistant plasmid encoding

Author

Kohei, Uechi, Mari, Tohya, Tatsuya, Tada, Takaaki, Tome, Ami, Takahashi, Takeshi, Kinjo, Shiro, Maeda, Teruo, Kirikae, and Jiro, Fujita

Subjects
Acinetobacter, Japan, Drug Resistance, Multiple, Bacterial, RNA, Ribosomal, 16S, Humans, Public Health Surveillance, Methyltransferases, Microbial Sensitivity Tests, Communicable Diseases, Emerging, beta-Lactamases, Acinetobacter Infections, Anti-Bacterial Agents
Published
2021

21. Emergence of a multidrug-resistant plasmid encoding bla NDM-1, bla OXA-420 and armA in a clinical isolate of Acinetobacter variabilis in Japan

Author

Ami Takahashi, Teruo Kirikae, Tatsuya Tada, Kohei Uechi, Takaaki Tome, Takeshi Kinjo, Mari Tohya, Shiro Maeda, and Jiro Fujita

Subjects
Microbiology (medical), Imipenem, Acinetobacter variabilis, General Medicine, Biology, medicine.disease_cause, Microbiology, Meropenem, Ciprofloxacin, Multiple drug resistance, Plasmid, Amikacin, medicine, Arbekacin, medicine.drug
Abstract

Acinetobacter variabilis (formerly genospecies 15 sensu Tjernberg and Ursing) has been isolated from humans and animals and was proposed to be a novel species in 2015. A multidrug-resistant A. variabilis isolate, RYU24, was obtained in 2012 from an inpatient in Okinawa, Japan, with no record of overseas travel. The isolate was resistant to carbapenems, aminoglycosides and ciprofloxacin, with minimum inhibitory concentrations (MICs) of 32 µg ml−1 for imipenem and meropenem; > 1024 µg ml−1 for amikacin, arbekacin, gentamicin and tobramycin; and 8 µg ml−1 for ciprofloxacin. The isolate was found to harbour a 68-kbp plasmid carrying bla NDM-1, which encodes New Delhi metallo-β-lactamase-1 (NDM-1); bla OXA-420, which encodes an OXA-58-like carbapenemase and; armA, which encodes ArmA 16S rRNA methylase conferring pan-aminoglycoside resistance. To our knowledge, this is the first report of a plasmid harbouring the three major drug-resistance genes, bla NDM-1, bla OXA-420 and armA.

Published
2021

22. CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes

Author

Nadja Vuori, M Imamura, Anmol Kumar, Niina Sandholm, Kustaa Hietala, Per-Henrik Groop, FinnDiane Study, Shiro Maeda, Paula Summanen, Markku Lehto, Heli Skottman, Anna Syreeni, Kati Juuti-Uusitalo, Carol Forsblom, Department of Medicine, Nefrologian yksikkö, University of Helsinki, HUS Abdominal Center, Faculty of Medicine, CAMM - Research Program for Clinical and Molecular Metabolism, Research Programs Unit, Clinicum, HUS Head and Neck Center, Department of Ophthalmology and Otorhinolaryngology, Per Henrik Groop / Principal Investigator, University Management, Endokrinologian yksikkö, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University

Subjects
0301 basic medicine, type 1 diabetes, Endocrinology, Diabetes and Metabolism, BETA(2) SUBUNIT, CUMULATIVE INCIDENCE, PROGRESSION, Genome-wide association study, L-tyypin kalsiumkanava, chemistry.chemical_compound, 0302 clinical medicine, CACNB2, linkage study, RISK, Sisätaudit - Internal medicine, Genetics/Genomes/Proteomics/Metabolomics, sequencing, Diabetic retinopathy, VEGF, Diabeettinen retinopatia, 3. Good health, Vascular endothelial growth factor, diabetic retinopathy, geneettinen assosiaatio, medicine.medical_specialty, Biolääketieteet - Biomedicine, 030209 endocrinology & metabolism, 03 medical and health sciences, Genetiikka, kehitysbiologia, fysiologia - Genetics, developmental biology, physiology, Diabetes mellitus, Internal medicine, LINKAGE, Internal Medicine, medicine, GENOME-WIDE ASSOCIATION, Genetic association, Diabetes Complication, Type 1 diabetes, CHANNELS, business.industry, Case-control study, tyyppi 1 diabetes, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, 3121 General medicine, internal medicine and other clinical medicine, ENDOTHELIAL GROWTH-FACTOR, CELLS, PROLIFERATIVE RETINOPATHY, business
Abstract

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 x 10(-4) for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the beta 2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.

Published
2019

23. Pseudomonas asiatica sp. nov., isolated from hospitalized patients in Japan and Myanmar

Author

Jiro Fujita, Mari Tohya, Kanae Teramoto, Tatsuya Tada, Ni Ni Zaw, Kohei Uechi, Htay Htay Tin, Takeshi Kinjo, Teruo Kirikae, Shiro Maeda, Kyoko Kuwahara-Arai, Isamu Nakasone, San Mya, Khin Nyein Zan, and Shin Watanabe

Subjects
DNA, Bacterial, Male, 0106 biological sciences, 0301 basic medicine, Pseudomonas monteilii, Myanmar, Biology, 010603 evolutionary biology, 01 natural sciences, Microbiology, Feces, 03 medical and health sciences, Japan, Pseudomonas, RNA, Ribosomal, 16S, Humans, Phylogeny, Ecology, Evolution, Behavior and Systematics, Base Composition, Phylogenetic tree, Strain (chemistry), Fatty Acids, Nucleic Acid Hybridization, Sequence Analysis, DNA, General Medicine, rpoB, biology.organism_classification, 16S ribosomal RNA, Pseudomonas putida, Bacterial Typing Techniques, Housekeeping gene, 030104 developmental biology, Genes, Bacterial, Female
Abstract

A novel Gram-negative, aerobic, rod-shaped, non-spore-forming bacterial strain, RYU5T, was isolated from a stool sample of an inpatient at a hospital in Okinawa, Japan. The optimal growth temperature of RYU5T was 30 °C. Phylogenetic analysis based on the sequences of housekeeping genes, including the 16S rRNA, rpoB, rpoD and gyrB genes, showed that RYU5T was a member of the Pseudomonas putida group and was located close to Pseudomonas monteilii and P. putida . Whole-genome comparisons, using average nucleotide identity and digital DNA–DNA hybridization, confirmed that strain RYU5T should be classified as a novel species of Pseudomonas . Phenotypic characterization tests showed that utilization of d-mannose, d-serine, l-arabinose and d-fructose could distinguish this strain from other related species of the genus Pseudomonas . Based on genetic and phenotypic evidence, strain RYU5T should be classified as a novel species, for which the name Pseudomonas asiatica sp. nov. is proposed. The type strain is RYU5T (=DSM 107182T, =JCM 32716T), with a DNA G+C content of 62.25 mol%.

Published
2019

24. Fine-Scale Genetic Structure and Demographic History in the Miyako Islands of the Ryukyu Archipelago

Author

M Imamura, Kae Koganebuchi, Masatoshi Matsunami, Hajime Ishida, Ryosuke Kimura, and Shiro Maeda

Subjects
Gene Flow, Ryukyu archipelago, Insular biogeography, Demographic history, Human Migration, Population structure, Population, Biology, AcademicSubjects/SCI01180, Polymorphism, Single Nucleotide, Coalescent theory, 03 medical and health sciences, 0302 clinical medicine, Japan, Genetics, Humans, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Discoveries, 030304 developmental biology, Islands, 0303 health sciences, geography, education.field_of_study, geography.geographical_feature_category, Genome, Human, Haplotype, AcademicSubjects/SCI01130, insular biogeography, population structure, demographic history, biobank, Evolutionary biology, Archipelago, Genetic structure, Japanese, 030217 neurology & neurosurgery
Abstract

The Ryukyu Archipelago is located in the southwest of the Japanese islands and is composed of dozens of islands, grouped into the Miyako Islands, Yaeyama Islands, and Okinawa Islands. Based on the results of principal component analysis on genome-wide single-nucleotide polymorphisms, genetic differentiation was observed among the island groups of the Ryukyu Archipelago. However, a detailed population structure analysis of the Ryukyu Archipelago has not yet been completed. We obtained genomic DNA samples from 1,240 individuals living in the Miyako Islands, and we genotyped 665,326 single-nucleotide polymorphisms to infer population history within the Miyako Islands, including Miyakojima, Irabu, and Ikema islands. The haplotype-based analysis showed that populations in the Miyako Islands were divided into three subpopulations located on Miyakojima northeast, Miyakojima southwest, and Irabu/Ikema. The results of haplotype sharing and the D statistics analyses showed that the Irabu/Ikema subpopulation received gene flows different from those of the Miyakojima subpopulations, which may be related with the historically attested immigration during the Gusuku period (900 − 500 BP). A coalescent-based demographic inference suggests that the Irabu/Ikema population firstly split away from the ancestral Ryukyu population about 41 generations ago, followed by a split of the Miyako southwest population from the ancestral Ryukyu population (about 16 generations ago), and the differentiation of the ancestral Ryukyu population into two populations (Miyako northeast and Okinawajima populations) about seven generations ago. Such genetic information is useful for explaining the population history of modern Miyako people and must be taken into account when performing disease association studies., 論文

Published
2021

25. Emergence of clinical isolates of

Author

Mari, Tohya, Kohei, Uechi, Tatsuya, Tada, Tomomi, Hishinuma, Takeshi, Kinjo, Takeya, Ohshiro, Shiro, Maeda, Teruo, Kirikae, and Jiro, Fujita

Subjects
Bacterial Proteins, Japan, Pseudomonas, Humans, Pseudomonas Infections, Microbial Sensitivity Tests, Communicable Diseases, Emerging, Phylogeny, beta-Lactamases, Anti-Bacterial Agents
Published
2020

26. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris

Subjects
0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Published
2020

27. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author

Mark I. McCarthy, Weihua Meng, Brian L. Yaspan, M Imamura, Mark W. Christiansen, Niina Sandholm, Yii-Der Ida Chen, Sharon G. Adler, Lucia Sobrin, Craig L. Hanis, Valeriya Lyssenko, Shiro Maeda, Yang Hai, Paul Mitchell, Roberta McKean-Cowdin, Xiuqing Guo, John R. Sedor, David S. Siscovick, Sudha K. Iyengar, Heather Hancock, Jane Z. Kuo, Barbara E.K. Klein, David-Alexandre Tregouet, Elisabet Agardh, Kent D. Taylor, Andrew D. Morris, S. Mohsen Hosseini, Andrew D. Paterson, I-Te Lee, Wayne Huey-Herng Sheu, Emma Ahlqvist, Kathryn P. Burdon, Leif Groop, Ayellet V. Segrè, Samy Hadjadj, Samaneh Davoudi, Lynn K. Stanwyck, Emily Y. Chew, Xiaohui Li, Michael A. Grassi, Jie Jin Wang, Samuela Pollack, Albert V. Smith, Kyu Hyung Park, Michiaki Kubo, Mary Frances Cotch, Yucheng Jia, Ching J. Chen, Colin N. A. Palmer, Helen M. Colhoun, Alan D. Penman, R. Varma, Per-Henrik Groop, Tien Yin Wong, Barry I. Freedman, Eli Ipp, Alex S. F. Doney, Gavin Tan, Ronald Klein, Kaanan P. Shah, Jamie E Craig, Donald W. Bowden, Jerome I. Rotter, Robert P. Igo, Darryl Nousome, Ching-Yu Cheng, Michel Marre, Maggie C.Y. Ng, Latchezar Dimitrov, Jeeyun Ahn, Atsushi Takahashi, Richard A. Jensen, Aaron Leong, Jihye Kim, Iiro Toppila, Elizabeth J. Rossin, Alkes L. Price, Diabetes and Obesity Research Program, University of Helsinki, Department of Medicine, Nefrologian yksikkö, Research Programs Unit, Clinicum, HUS Abdominal Center, and Per Henrik Groop / Principal Investigator

Subjects
Blood Glucose, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, LOCI, 030209 endocrinology & metabolism, Genome-wide association study, VARIANTS, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, RESOURCE, Internal medicine, Diabetes mellitus, REVEALS, Genetic variation, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, CHINESE PATIENTS, Allele, METAANALYSIS, POLYMORPHISMS, Glycemic, Glycated Hemoglobin, Diabetic Retinopathy, business.industry, Diabetic retinopathy, medicine.disease, PREVALENCE, 3. Good health, SEVERITY, 030104 developmental biology, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, Multiple comparisons problem, RISK-FACTORS, Medical genetics, Erratum, business, Genome-Wide Association Study, Protein Binding
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2018

28. Universal inverter driver and its technologies

Author

Koji Kubo, Shiro Maeda, Makoto Yoshida, Satoshi Komukai, Atsushi Yamada, and Koji Hamaoka

Subjects
business.industry, Computer science, Electrical engineering, Inverter, business
Published
2018

29. アシネトバクター属菌およびシュードモナス属菌におけるカルバペネマーゼ検出法、カルバペネム不活化法、CIMTrisの考案

Author

Tatsuya Tada, Teruo Kirikae, Kayo Shimada, Shiro Maeda, Takaaki Tome, Kyoko Kuwahara-Arai, Jiro Fujita, Kohei Uechi, Momoko Arakaki, and Isamu Nakasone

Subjects
0301 basic medicine, Microbiology (medical), Bacteriological Techniques, Carbapenem, Acinetobacter, Diagnostic Tests, Routine, 030106 microbiology, Bacteriology, Biology, biology.organism_classification, Sensitivity and Specificity, beta-Lactamases, Microbiology, 03 medical and health sciences, Bacterial Proteins, Pseudomonas species, Pseudomonas, medicine, Acinetobacter species, Bacteria, medicine.drug, Carbapenem resistance
Abstract

The carbapenem inactivation method (CIM) and modified CIM (mCIM) are simple and economical phenotypic screening methods for detecting carbapenemase production in Gram-negative bacteria. Although the mCIM has been recommended by the Clinical and Laboratory Standards Institute, both the CIM and mCIM have limitations. This study describes another modified CIM, called CIMTris, in which carbapenemase was extracted from bacteria with 0.5 M Tris-HCl (pH 7.6) buffer. The ability of the CIMTris to detect carbapenemase production was examined in Acinetobacter and Pseudomonas species. The CIMTris had an overall sensitivity of 97.6% and an overall specificity of 92.6%, whereas the mCIM had a sensitivity of 45.1% and a specificity of 100% for the isolates tested. These findings indicate that the CIMTris is useful for detecting carbapenemase production in Acinetobacter and Pseudomonas species.

Published
2017

30. Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice

Author

Akihide Tanimoto, Taro Uchida, Shiro Maeda, Tadashi Kaname, Yuji Taira, Akira Arasaki, Hiroaki Masuzaki, Katsuhiko Noguchi, Kimio Satoh, Masayuki Matsushita, Yuichi Totsuka, Chisayo Kozuka, Toshihiro Matsuzaki, Junichi Omura, Masato Tsutsui, Haruaki Kubota, Shin ichiro Kina, Nobuyuki Yanagihara, Junko Nakasone, Mika Kina-Tanada, Mayuko Sakanashi, Hiroaki Shimokawa, Hajime Sunakawa, Masayoshi Ishida, and Yusuke Ohya

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Nitric Oxide, Endothelial NOS, Cardiovascular System, Nitric oxide, Mice, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, Nitrate, Internal medicine, Internal Medicine, Animals, Medicine, Endothelial dysfunction, Nitrite, Nitrites, Metabolic Syndrome, Nitrates, business.industry, medicine.disease, Dietary Nitrite, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, Biochemistry, Metabolic syndrome, business
Abstract

Nitric oxide (NO) is synthesised not only from l-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of l-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

Published
2017

31. Identification of type 2 diabetes loci in 433,540 East Asian individuals

Author

Chien-Hsiun Chen, Anna L. Gloyn, Atsushi Takahashi, Sohee Han, Ken Suzuki, Mark A Pereira, Shi Jinxiu, Fiona Bragg, Yii-Der Ida Chen, Robin G. Walters, Takashi Kadowaki, Charumathi Sabanayagam, Annie-Green Howard, Mark I. McCarthy, Zheng Bian, Zhengming Chen, E-Shyong Tai, Chii-Min Hwu, Cassandra N. Spracklen, Yuan-Tsong Chen, Linda S. Adair, Momoko Horikoshi, Guozhi Jiang, Ching-Yu Cheng, Mi Yeong Hwang, Andrew P. Morris, Karen L. Mohlke, John C. Chambers, Jian-Min Yuan, Woon-Puay Koh, Hyeok Sun Choi, Ju Young Lee, Bong-Jo Kim, Masato Akiyama, Sahoko Ichihara, Xueling Sim, Norihiro Kato, Kuang Lin, Jirong Long, Xiuqing Guo, Fumihiko Takeuchi, Penny Gordon-Larsen, Hannah J Perrin, Young Jin Kim, Lee-Ming Chuang, Weihua Zhang, Rob M. van Dam, Andrea O.Y. Luk, Masahiro Nakatochi, Yukinori Okada, Katsuhiko Kohara, Yoichiro Kamatani, Jerome I. Rotter, Iona Y Millwood, Jer-Yuarn Wu, Canqing Yu, Wayne Huey-Herng Sheu, Shiro Maeda, Jost B. Jonas, Yasuharu Tabara, Mitsuhiro Yokota, Li-Ching Chang, Toshimasa Yamauchi, Shufa Du, Yu Guo, Yoon Shin Cho, Yi-Jen Hung, Jie Yao, Soo Heon Kwak, Hye-Mi Jang, Maggie C.Y. Ng, Xiao-Ou Shu, Myung-Shik Lee, Kyungheon Yoon, Sarah M Brotman, Sanghoon Moon, Tien Yin Wong, Martijn van de Bunt, Michiya Igase, Claudia H. T. Tam, Fumihiko Matsuda, Wei Zheng, Liang Zhang, Yong-Bing Xiang, Victor Jun Yu Lim, Ronald Cw Ma, Liming Li, Tomohiro Katsuya, Jianjun Liu, Jun Lv, Jennifer E. Below, Anubha Mahajan, Kyong-Soo Park, Masato Isono, Wing-Yee So, Nanette R. Lee, Brian Tomlinson, Juliana C.N. Chan, Lauren E. Petty, Chiea Chuen Khor, Miao-Li Chee, Ken Yamamoto, Wei Huang, Michael Boehnke, Jin-Fang Chai, Donald W. Bowden, Apoorva K Iyengar, Dong Mun Shin, Myron D. Gross, Takahisa Kawaguchi, Ya Xing Wang, and Fuu Jen Tsai

Subjects
Ankyrins, Male, 0301 basic medicine, Transcription, Genetic, endocrine system diseases, Nerve Tissue Proteins, 030209 endocrinology & metabolism, Locus (genetics), Genome-wide association study, Type 2 diabetes, Biology, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Asian People, ANK1, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Allele, Eye Proteins, Gene, Alleles, 030304 developmental biology, ALDH2, Genetic association, 2. Zero hunger, Homeodomain Proteins, Genetics, 0303 health sciences, Multidisciplinary, Asia, Eastern, Aldehyde Dehydrogenase, Mitochondrial, Case-control study, nutritional and metabolic diseases, medicine.disease, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, Meta-analysis, Expression quantitative trait loci, Female, Body mass index, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Published
2019
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32. Genome-Wide Association Study for Type 2 Diabetes

Author

Shiro Maeda, Momoko Horikoshi, and M Imamura

Subjects
Missing heritability problem, business.industry, Diabetes mellitus, Pharmacogenomics, medicine, Genetic predisposition, Genome-wide association study, Type 2 diabetes, medicine.disease, Bioinformatics, business, Glycemic, Genetic association
Abstract

Genome-wide association studies (GWAS) have facilitated a substantial and rapid rise in the number of confirmed genetic susceptibility variants for type 2 diabetes (T2D) and glycemic traits. Approximately 90 variants for conferring susceptibility to T2D and 80 variants for glycemic traits have been identified until the end of 2016. This success has led to widespread hope that the findings will translate into improved clinical care for the increasing numbers of patients with diabetes. Potential areas or clinical translation include risk prediction and subsequent disease prevention, pharmacogenomics, and the development of novel therapeutics. In contrast, worldwide efforts to identify susceptibility loci to diabetic nephropathy have not been successful so far, and most of heritability for diabetic nephropathy remains to be elucidated. Uncovering the missing heritability is essential to the progress of T2D genetic studies and to the translation of genetic information into clinical practice.

Published
2019

33. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes

Author

Takashi Kadowaki, Hirotaka Watada, Kohei Kaku, Mark I. McCarthy, Masao Toyoda, Hiroshi Maegawa, Tetsuya Babazono, Tomoya Umezono, Masahito Imanishi, Nobue Tanaka, Ryuzo Kawamori, Shin-ichi Araki, Koichi Kawai, Shiro Maeda, Daisuke Suzuki, Leif Groop, Natalie R. van Zuydam, Atsushi Takahashi, Makiko Taira, Yoichiro Kamatani, Toshimasa Yamauchi, M Imamura, Emma Ahlqvist, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, and HUS Abdominal Center

Subjects
Male, 0301 basic medicine, Physiology, Genome-wide association study, Type 2 diabetes, Gastroenterology, Diabetic nephropathy, MELLITUS, Endocrinology, Mathematical and Statistical Techniques, Japan, Chronic Kidney Disease, Medicine and Health Sciences, Diabetic Nephropathies, COMPLICATIONS, Multidisciplinary, Statistics, Genomics, Metaanalysis, Middle Aged, Type 2 Diabetes, 3. Good health, Physiological Parameters, Nephrology, OBESITY, Physical Sciences, Medicine, Female, Research Article, medicine.medical_specialty, Endocrine Disorders, Science, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Single-nucleotide polymorphism, Research and Analysis Methods, Polymorphism, Single Nucleotide, Nephropathy, Molecular Genetics, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Genome-Wide Association Studies, Genetics, medicine, Humans, Genetic Predisposition to Disease, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology, Aged, Genetic association, business.industry, Body Weight, Case-control study, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, medicine.disease, GENE, POLYMORPHISM, RENAL-DISEASE, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Metabolic Disorders, Case-Control Studies, 3111 Biomedicine, business, Mathematics, Genome-Wide Association Study
Abstract

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 x 10^) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 x 10^. We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 x 10^). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes., 論文

Published
2018

34. An improved carbapenem inactivation method, CIMTrisII, for carbapenemase production by Gram-negative pathogens

Author

Tatsuya Tada, Jun-ichiro Sekiguchi, Khin Nyein Zan, Takaaki Tome, Kohei Uechi, Teruo Kirikae, San Mya, Jiro Fujita, Kyoko Kuwahara-Arai, Izumi Yanagisawa, Isamu Nakasone, Shiro Maeda, and Htay Htay Tin

Subjects
0301 basic medicine, Microbiology (medical), DNA, Bacterial, Carbapenem, Time Factors, 030106 microbiology, Microbial Sensitivity Tests, medicine.disease_cause, Microbiology, Meropenem, Sensitivity and Specificity, beta-Lactamases, Incubation period, 03 medical and health sciences, Bacterial Proteins, Enterobacteriaceae, Japan, Nepal, Pseudomonas, medicine, Humans, Asia, Southeastern, Gram, biology, Acinetobacter, Pseudomonas aeruginosa, General Medicine, Bacterial Infections, Sequence Analysis, DNA, biology.organism_classification, Anti-Bacterial Agents, Imipenem, 030104 developmental biology, Carbapenems, Bacteria, medicine.drug
Abstract

The modified carbapenem inactivation method (mCIM) is a simple phenotypic screening method for detecting carbapenemase production by Enterobacteriaceae and Pseudomonas aeruginosa. We recently developed another modified carbapenem inactivation method (CIMTris), in which carbapenemase is extracted from bacteria with Tris-HCl buffer, to detect carbapenemase production by Acinetobacter and Pseudomonas species. This study describes an improved carbapenem inactivation method, CIMTrisII, for detecting carbapenemase production by Gram-negative pathogens, including Enterobacteriaceae, Acinetobacter and Pseudomonas species. CIMTrisII was different from CIMTris in the concentration of Meropenem disks (5-µg MEM disks vs. 10-µg MEM disks), the inoculum volume of the bacteria (a 5-µl loopful vs. a 10 µl loopful) and the incubation time (1 vs. 2 h). CIMTrisII showed an overall sensitivity of 99.3 % and an overall specificity of 95.0 % for tested isolates. In comparison, CIMTris showed a sensitivity of 96.1 % and a specificity of 96.3 %, and mCIM showed a sensitivity of 67.1 % and a specificity of 100 %. CIMTrisII is thus deemed useful for detecting carbapenemase production by Gram-negative pathogens.

Published
2018

35. Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Author

Masakazu Haneda, Masami Chin-Kanasaki, Satoshi Ugi, Yukihiro Fujita, Tsuyoshi Yanagimachi, Shinji Kume, Keiko Kondo, Takashi Uzu, Sawako Kitahara, Shin-ich Araki, Hisazumi Araki, Shiro Maeda, Daisuke Koya, Akihiro Sekine, Atsunori Kashiwagi, Motoyuki Kondo, Hiroshi Maegawa, Kiyosumi Maeda, and Yoshihiko Nishio

Subjects
0301 basic medicine, SNS, sympathetic nervous system, Male, Sympathetic Nervous System, Time Factors, 18F-FDG, 2-[fluorine-18]-2-deoxy-d-glucose, OGTT, oral glucose tolerance test, Insulins, lcsh:Medicine, Type 2 diabetes, AMP-Activated Protein Kinases, ACC, acetyl CoA carboxylase, IPITT, intraperitoneal insulin tolerance test, chemistry.chemical_compound, 0302 clinical medicine, AMP-activated protein kinase, Insulin-Secreting Cells, Pancreatic β cell, Kg, glucose disappearance rate, lcsh:R5-920, biology, Insulin secretion, Diabetes, GIP, glucose-dependent insulinotropic polypeptide, LETO, Long-Evans Tokushima Otsuka, Brain, GLP-1, glucagon-like peptide-1, General Medicine, Fasting, Glucagon-like peptide-1, Denervation, CT, computed tomography, Organ Specificity, OLETF, Otsuka Long-Evans Tokushima Fatty, SNPs, single nucleotide polymorphisms, First-phase GSIS, lcsh:Medicine (General), Research Paper, Cell physiology, HOMA-β, homeostasis model assessment beta-cell function index, medicine.medical_specialty, endocrine system, FSIVGTT, frequently sampled intravenous glucose tolerance test, SUV, standardized uptake value, Hypothalamus, 2-DG, 2-deoxy-d-glucose, General Biochemistry, Genetics and Molecular Biology, PET, positron emission tomography, AIR, acute insulin response, GSIS, glucose-stimulated insulin secretion, 03 medical and health sciences, Fluorodeoxyglucose F18, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Secretion, Protein kinase A, Pancreas, ICV, intracerebroventricular, business.industry, lcsh:R, SD, Sprague-Dawley, AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, PNx, pancreatic denervation, Glucose Tolerance Test, medicine.disease, Rats, AMPK, AMP-activated protein kinase, Disease Models, Animal, 030104 developmental biology, Endocrinology, Glucose, chemistry, Diabetes Mellitus, Type 2, Starvation, Positron-Emission Tomography, biology.protein, business, 2-Deoxy-D-glucose, Tomography, X-Ray Computed, 030217 neurology & neurosurgery
Abstract

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes., Highlights • Fasting-induced hypothalamic AMPK activation inhibited first-phase GSIS by stimulating the α-adrenergic nerve. • The brain-pancreas neural axis was involved in β cell dysfunction and glucose intolerance in diabetes. • Pancreatic denervation improved first-phase GSIS, glucose tolerance and β cell survival in type 2 diabetic animals. Glucose-stimulated insulin secretion (GSIS) from pancreatic β cells is biphasic. Furthermore, first-phase GSIS is inhibited in type 2 diabetes. This study revealed that fasting reduced first-phase GSIS by signaling via the brain-pancreatic β cell neural axis, which is essential for maintaining glucose supply to the brain at re-feeding after fasting. Abnormal excitability of this neural axis was also associated with impaired first-phase GSIS in type 2 diabetes. Surgical pancreatic denervation improved diabetes in an animal study. The present data reveal that diabetic β cells exist under conditions that mimic starvation and provide a therapeutic potency of pancreatic denervation against diabetes., Graphical Abstract Image 2

Published
2016

36. Erratum. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2019;68:441—456

Author

Aaron Leong, Yii-Der Ida Chen, Iiro Toppila, Elizabeth J. Rossin, Alan D. Penman, I-Te Lee, Kathryn P. Burdon, Yucheng Jia, Sudha K. Iyengar, Helen M. Colhoun, Michael A. Grassi, Jie Jin Wang, Tien Yin Wong, Barry I. Freedman, Kaanan P. Shah, Ching J. Chen, Weihua Meng, Brian L. Yaspan, Samaneh Davoudi, David S. Siscovick, Per-Henrik Groop, Samy Hadjadj, Michel Marre, Ching-Yu Cheng, John R. Sedor, Xiuqing Guo, Albert V. Smith, Robert P. Igo, Kyu Hyung Park, Jerome I. Rotter, Andrew D. Paterson, Samuela Pollack, Sharon G. Adler, Alkes L. Price, Emily Y. Chew, Emma Ahlqvist, Eli Ipp, Jamie E Craig, Richard A. Jensen, Barbara E.K. Klein, Maggie C.Y. Ng, Leif Groop, Craig L. Hanis, Xiaohui Li, Atsushi Takahashi, Roberta McKean-Cowdin, Mark P. Christiansen, Lynn K. Stanwyck, Paul Mitchell, Shiro Maeda, Alex S. F. Doney, Darryl Nousome, Ronald Klein, Yang Hai, Mark I. McCarthy, Niina Sandholm, Kent D. Taylor, Andrew D. Morris, Rohit Varma, David-Alexandre Trégouët, Jihye Kim, Valeriya Lyssenko, Colin N. A. Palmer, Mary Frances Cotch, Jane Z. Kuo, Elisabet Agardh, S. Mohsen Hosseini, Michiaki Kubo, Jeeyun Ahn, Gavin Tan, Minako Imamura, Lucia Sobrin, Heather Hancock, Wayne Huey-Herng Sheu, Donald W. Bowden, Ayellet V. Segrè, and Latchezar Dimitrov

Subjects
Pediatrics, medicine.medical_specialty, Complications, business.industry, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Diabetic retinopathy, medicine.disease, Diabetes mellitus, Internal Medicine, medicine, Duration (project management), business, Glycemic
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2020

37. LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins

Author

Jonathan D. Mosley, Yukihide Momozawa, George Hripcsak, Dan M. Roden, Shiro Maeda, Peggy L. Peissig, Eric B. Larson, David Cronkite, Ming Ta Michael Lee, Michiaki Kubo, Jerome I. Rotter, Sarah T. Bland, Gail P. Jarvik, Jennifer A. Pacheco, Todd L. Edwards, David R. Crosslin, Christian M. Shaffer, Eric A Larson, Ning Shang, Marc S. Williams, Xiaohui Li, Momoko Horikoshi, QiPing Feng, Laura J. Rasmussen-Torvik, Iftikhar J. Kullo, Joshua C. Denny, Wei-Qi Wei, C. Michael Stein, Nancy J. Cox, Ronald M. Krauss, Elizabeth W. Karlson, Marylyn D. Ritchie, and Russell A. Wilke

Subjects
0301 basic medicine, Time Factors, Hydroxymethylglutaryl-CoA, Coronary Disease, 030204 cardiovascular system & hematology, hydroxymethylglutaryl-CoA, Cardiorespiratory Medicine and Haematology, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Risk Factors, Lysophosphatidic acid, Databases, Genetic, Medicine, Electronic Health Records, 2.1 Biological and endogenous factors, Aetiology, Lipoprotein cholesterol, Cause of death, Incidence (epidemiology), Single Nucleotide, Treatment Outcome, Phenotype, Heart Disease, Cardiology, Public Health and Health Services, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Clinical Sciences, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Databases, Genetic, Clinical Research, Physiology (medical), Internal medicine, Genetics, Humans, In patient, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, Heart Disease - Coronary Heart Disease, Dyslipidemias, Cholesterol, business.industry, Human Genome, cholesterol, Atherosclerosis, Coronary heart disease, LDL reductase inhibitors, 030104 developmental biology, chemistry, Cardiovascular System & Hematology, Case-Control Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, lysophosphatidic acid, Lipoprotein(a), Genome-Wide Association Study
Abstract

Background: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Published
2018

38. ALDH2 Polymorphism rs671, but Not ADH1B Polymorphism rs1229984, Increases Risk for Hypo-HDL-Cholesterolemia in a/a Carriers Compared to the G/G Carriers

Author

Ghislain Rocheleau, Loic Yengo, Takuya Imatoh, Motonobu Miyazaki, Shiro Maeda, Philippe Froguel, and Seiichiro Kamimura

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Longitudinal study, Heterozygote, Hypercholesterolemia, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Logistic regression, Biochemistry, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Japan, Risk Factors, Internal medicine, medicine, Humans, Longitudinal Studies, Allele, ALDH2, Aged, medicine.diagnostic_test, Aldehyde Dehydrogenase, Mitochondrial, Organic Chemistry, Confounding, Cholesterol, HDL, Alcohol Dehydrogenase, ADH1B, Cell Biology, Middle Aged, Healthy Volunteers, 030104 developmental biology, Endocrinology, lipids (amino acids, peptides, and proteins), Lipid profile
Abstract

It has been reported that polymorphisms within the gene-encoding enzymes related to alcohol metabolism are associated with levels of serum HDL-cholesterol (HDL-C) in East Asian populations. We evaluated the effects of genetic variants within the aldehyde dehydrogenase-2 (ALDH2) gene and the alcohol dehydrogenase-1B (ADH1B) gene on changes in the lipid profile in an 11-year longitudinal study. We genotyped rs1229984 within ADH1B and rs671 within ALDH2. We combined the genetic data with longitudinal clinical and biochemical data from 2002 to 2013 and designed a retrospective longitudinal study of 1436 Japanese males. There were significant negative relationships between rs671 within ALDH2 and HDL-C levels according to multiple linear regression analysis. Next, we assessed the association between the development of hypo-HDL cholesterolemia and rs1229984 within ADH1B or rs671 within ALDH2. In logistic regression analysis, rs671 A allele homozygote carriers have 2.65 times higher risk of developing hypo-HDL cholesterolemia than G allele homozygote carriers. Even after adjusting for possible confounding factors, a significant association was observed. However, no association between rs1229984 within ADH1B and the development of hypo-HDL cholesterolemia was observed. Rs671 within ALDH2 but not rs1229984 within ADH1B was associated with lower HDL-C levels in Japanese males.

Published
2018

39. Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population

Author

Ken, Suzuki, Masato, Akiyama, Kazuyoshi, Ishigaki, Masahiro, Kanai, Jun, Hosoe, Nobuhiro, Shojima, Atsushi, Hozawa, Aya, Kadota, Kiyonori, Kuriki, Mariko, Naito, Kozo, Tanno, Yasushi, Ishigaki, Makoto, Hirata, Koichi, Matsuda, Nakao, Iwata, Masashi, Ikeda, Norie, Sawada, Taiki, Yamaji, Motoki, Iwasaki, Shiro, Ikegawa, Shiro, Maeda, Yoshinori, Murakami, Kenji, Wakai, Shoichiro, Tsugane, Makoto, Sasaki, Masayuki, Yamamoto, Yukinori, Okada, Michiaki, Kubo, Yoichiro, Kamatani, Momoko, Horikoshi, Toshimasa, Yamauchi, and Takashi, Kadowaki

Subjects
Adult, Male, Genotype, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Asian People, Diabetes Mellitus, Type 2, Gene Frequency, Genetic Loci, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P 5.0 × 10

Published
2018

40. Replication study of the association of rs7578597 in THADA, rs10886471 in GRK5, and rs7403531 in RASGRP1 with susceptibility to type 2 diabetes among a Japanese population

Author

Kazuyuki Tobe, Shiro Maeda, Hirotaka Watada, Kensuke Sakai, Kohei Kaku, Minoru Iwata, Yasushi Tanaka, Hiroshi Maegawa, Ryuzo Kawamori, Hiroshi Hirose, Atsunori Kashiwagi, and Minako Imamura

Subjects
Genetics, business.industry, Endocrinology, Diabetes and Metabolism, Type 2 Diabetes Mellitus, Single-nucleotide polymorphism, Type 2 diabetes, Japanese population, medicine.disease, Diabetes mellitus, Replication (statistics), Internal Medicine, Medicine, SNP, business
Abstract

Aims To evaluate the association of rs7578597 in THADA, rs10886471 in GRK5, rs7403531 in RASGRP1, and rs6723108 in TMEM163 with type 2 diabetes among the Japanese we performed a replication study of the association of these single nucleotide polymorphism (SNP) loci.

Published
2015

41. Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice

Author

Naoko Takeda, Shinji Kume, Masami Chin-Kanasaki, Keiji Isshiki, Shin-ichi Araki, Itsuki Oshima, Takashi Uzu, Satoshi Ugi, Yuki Tanaka, Shiro Maeda, Hiroshi Maegawa, and Norihisa Osawa

Subjects
0301 basic medicine, medicine.medical_specialty, 030232 urology & nephrology, Biophysics, Mice, Transgenic, Biochemistry, Gene Expression Regulation, Enzymologic, Podocyte, Diabetic nephropathy, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, medicine, Animals, Diabetic Nephropathies, Molecular Biology, Cells, Cultured, ACACB, biology, Chemistry, Podocytes, Acetyl-CoA carboxylase, AMPK, Cell Biology, Streptozotocin, medicine.disease, Up-Regulation, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Podocin, biology.protein, Synaptopodin, medicine.drug, Acetyl-CoA Carboxylase
Abstract

A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) β gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCβ in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCβ on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCβ might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCβ pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.

Published
2017

42. A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin

Author

Kathleen M. Giacomini, Fei Xu, Dan M. Roden, Shiro Maeda, Sook Wah Yee, Jonathan Jd Mosley, Michiaki Kubo, Atsushi Takahashi, Monique M. Hedderson, Radojka M. Savic, Sneha B. Sridhar, Robert L. Davis, and Srijib Goswami

Subjects
0301 basic medicine, Male, Candidate gene, Glycated Hemoglobin A, Pharmacogenomic Variants, Bioinformatics, Polymorphism (computer science), 80 and over, 2.1 Biological and endogenous factors, Pharmacology (medical), Longitudinal Studies, Pharmacology & Pharmacy, Aetiology, Aged, 80 and over, Diabetes, Organic Cation Transporter 2, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, Middle Aged, Metformin, Disease Progression, Female, Type 2, medicine.drug, Adult, Organic Cation Transport Proteins, Single-nucleotide polymorphism, and over, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Clinical Research, Diabetes mellitus, medicine, Diabetes Mellitus, Genetics, SNP, Humans, Hypoglycemic Agents, Allele, Polymorphism, Aged, Pharmacology, Glycated Hemoglobin, Tumor Suppressor Proteins, Prevention, Membrane Proteins, medicine.disease, 030104 developmental biology, Good Health and Well Being, Diabetes Mellitus, Type 2, Nonlinear Dynamics
Abstract

© 2016 American Society for Clinical Pharmacology and Therapeutics One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

Published
2016

43. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Author

Kathleen M. Giacomini, Adriaan Kooy, Coen D.A. Stehouwer, MetGen Investigators, Valdis Pirags, Daniel M. Rotroff, Ivan Tkáč, Huan-Chieh Chien, Michael J. Wagner, Shiro Maeda, Federico Innocenti, Joline W.J. Beulens, Monique M. Hedderson, Eric L. Seiser, Sook Wah Yee, Bruno H. Stricker, Accord Investigators, Jozef Židzik, Leen M 't Hart, Rury R. Holman, Alison A. Motsinger-Reif, Jose C. Florez, Albert Hofman, Mattijs Out, Albert M. Levin, Christopher J. Groves, Michiaki Kubo, Longyang Wu, Catherine E. de Keyser, Ewan R. Pearson, Lisa Logie, Calum Sutherland, Sabina Semiz, Tanja Dujic, John S. Witte, Amanda J. Bennett, Kathleen A. Jablonski, Linda Zaharenko, Nienke van Leeuwen, Ling Chen, Dpp Investigators, Roger Tavendale, Ruth L. Coleman, Amber A. van der Heijden, Colin N. A. Palmer, Janis Klovins, Martin Javorský, Ron H.N. van Schaik, Mark I. McCarthy, L. Keoki Williams, Kaixin Zhou, Epidemiology, Clinical Chemistry, General practice, EMGO - Lifestyle, overweight and diabetes, Epidemiology and Data Science, MUMC+: HVC Pieken Maastricht Studie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Interne Geneeskunde, and MUMC+: MA Interne Geneeskunde (3)

Subjects
Blood Glucose, 0301 basic medicine, medicine.medical_specialty, endocrine system diseases, Genome-wide association study, Type 2 diabetes, Polymorphism, Single Nucleotide, White People, Body Mass Index, 03 medical and health sciences, Quantitative Trait, Heritable, Internal medicine, Diabetes mellitus, Genetics, medicine, Humans, Hypoglycemic Agents, Allele, Glycemic, Glucose Transporter Type 2, Glycated Hemoglobin, biology, Glucose transporter, nutritional and metabolic diseases, medicine.disease, Metformin, 3. Good health, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, GLUT2, Genome-Wide Association Study, medicine.drug
Abstract

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear(1). Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 x 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Published
2016

45. Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies

Author

Atsunori Kashiwagi, Minako Imamura, Hiroshi Hirose, Hirotaka Watada, Minoru Iwata, Ryuzo Kawamori, Kohei Kaku, Kazuyuki Tobe, Hiroshi Maegawa, Shiro Maeda, Yasushi Tanaka, and Ren Matsuba

Subjects
0301 basic medicine, Male, Heredity, Epidemiology, lcsh:Medicine, Genome-wide association study, Type 2 diabetes, 0302 clinical medicine, Endocrinology, Mathematical and Statistical Techniques, Japan, Medicine and Health Sciences, lcsh:Science, Genetics, education.field_of_study, Multidisciplinary, Genomics, Middle Aged, Type 2 Diabetes, Genetic Mapping, Physical Sciences, Regression Analysis, Female, Statistics (Mathematics), Research Article, Genotype, Endocrine Disorders, Population, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Variant Genotypes, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, Ethnic Epidemiology, 03 medical and health sciences, Asian People, medicine, Diabetes Mellitus, Genome-Wide Association Studies, SNP, Humans, Genetic Predisposition to Disease, Statistical Methods, education, Genetic association, Aged, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, Odds ratio, medicine.disease, Genome Analysis, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Metabolic Disorders, lcsh:Q, Octamer Transcription Factor-3, Mathematics, Meta-Analysis, Genome-Wide Association Study
Abstract

Aim We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. Methods We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. Results Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019–1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026–1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. Conclusions Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population.

Published
2016

46. [Genome-Wide Association Studies for life-style related diseases]

Author

Shiro, Maeda

Subjects
Asian People, Diabetes Mellitus, Type 2, Animals, Humans, Genetic Predisposition to Disease, Life Style, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study
Abstract

After the completion of human genome project, development of single nucleotide polymorphism (SNP) typing technology and collation of information regarding linkage disequilibrium in the human genome have facilitated genome-wide association studies (GWAS) for investigating genes associated with disease susceptibility across the entire human genome. In case of type 2 diabetes, approximately 100 genetic loci have been identified and confirmed as susceptibility to the disease through GWAS in different ethnic groups, including Japanese, European, East Asian and South Asian populations. However, integration of these information accounts for less than 20% of the disease heritability, and thus most of the heritability of type 2 diabetes remain to be identified. Since the rationale of GWAS is based on the hypothesis that common variants contribute to the susceptibility to common diseases, common disease-common variant hypothesis, GWAS have selectively identified common susceptibility variants (allele frequency=0.05) with lower effect size (odds ratio1.5), that is a limitation of the GWAS approach. Although GWAS have brought a significant breakthrough in the field of genetic study for life-style related diseases, new approaches other than GWAS, such as whole genome sequencing to identify rare variants with greater effect size or integration of genetic and environmental information, will be required to elucidate a heritability of life-style related diseases completely.

Published
2016

47. Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

Author

Danish Saleheen, John Danesh, Claudia H. T. Tam, Josep M. Mercader, Torben Hansen, Sanghoon Moon, Noël P. Burtt, Ivan Brandslund, Rong Zhang, Minaka Iwasaki, Kazuyuki Tobe, Takashi Kadowaki, Daniel R. Witte, Young-Jin Kim, Hiroshi Hirose, Bong-Jo Kim, Jai Rup Singh, Jason Flannick, Hortensia Moreno-Macías, Jun Hosoe, Minako Imamura, Torben Jørgensen, Kazuki Yasuda, Toshimasa Yamauchi, Jose C. Florez, Hirotaka Watada, Richa Saxena, Teresa Tusié-Luna, Atsushi Takahashi, Cramer Christensen, Kyong Soo Park, Juliana C.N. Chan, Niels Grarup, Cheng Hu, Ryuzo Kawamori, Yasushi Tanaka, Asif Rasheed, Kazuo Hara, Kohei Kaku, Ronald C.W. Ma, Jirong Long, Yoon Shin Cho, Dharambir K. Sanghera, E. Shyong Tai, Soo Heon Kwak, Xu Wang, Chikako Ito, Alicia Huerta-Chagoya, Yukinori Okada, Wei Zheng, Wei Zhao, Shiro Maeda, Hayato Fujita, Ken Suzuki, Xiao-Ou Shu, Weiping Jia, Philippe M. Frossard, Oluf Pedersen, Marit E. Jørgensen, Hiroshi Maegawa, Michiaki Kubo, Nobuhiro Shojima, and Minoru Iwata

Subjects
0301 basic medicine, Asian Continental Ancestry Group, Suppressor of Cytokine Signaling Proteins/genetics, endocrine system diseases, Science, Transcription Factors/genetics, General Physics and Astronomy, Single-nucleotide polymorphism, Genome-wide association study, Suppressor of Cytokine Signaling Proteins, Biology, Genetic analysis, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Asian People, Japan, Polymorphism (computer science), Genotype, Genetic predisposition, Humans, Asian Continental Ancestry Group/genetics, Genetic Predisposition to Disease, Genetic association, Genetics, Multidisciplinary, Penicillium, nutritional and metabolic diseases, Genomics, General Chemistry, Heritability, 3. Good health, DNA-Binding Proteins, Genome variation, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, Diabetes Mellitus, Type 2/genetics, Genètica, DNA-Binding Proteins/genetics, Genome-Wide Association Study, Transcription Factors
Abstract

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P, 論文

Published
2016

48. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. 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L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

49. Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes

Author

Kensuke Sakai, Kazuyuki Tobe, Hirotaka Watada, Minako Imamura, Atsunori Kashiwagi, Ryuzo Kawamori, Shiro Maeda, Yasushi Tanaka, Kohei Kaku, Hiroshi Maegawa, Hiroshi Hirose, Ren Matsuba, and Minoru Iwata

Subjects
Male, lcsh:Medicine, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Japan, medicine, SNP, Humans, lcsh:Science, Aged, Genetics, Multidisciplinary, lcsh:R, Case-control study, Odds ratio, Middle Aged, medicine.disease, Europe, Diabetes Mellitus, Type 2, Case-Control Studies, lcsh:Q, Female, Body mass index, Research Article, Genome-Wide Association Study
Abstract

Aim We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes. Methods We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis. Results All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10-4, binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037–1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10-4, adjusted for sex, age and BMI). Conclusions ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.

Published
2015

50. Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

Author

Takashi Higuchi, Jin Ogata, Eiko Kaneshiro, Yoshikatsu Eto, Hiroshi Kobayashi, Hiroyuki Ida, Toya Ohashi, Masahisa Kobayashi, Yohta Shimada, Shiro Maeda, and Akira Ohtake

Subjects
0301 basic medicine, Genetics, Point mutation, Intron, nutritional and metabolic diseases, 030204 cardiovascular system & hematology, Biology, Gene mutation, Article, 03 medical and health sciences, Exon, 030104 developmental biology, 0302 clinical medicine, RNA splicing, Multiplex ligation-dependent probe amplification, Insertion, Enhancer
Abstract

Anderson-Fabry (FD) disease is an inborn error of metabolism caused by a deficiency of α-galactosidase A (GLA), a lysosomal enzyme. Many male FD patients display a classic FD phenotype; however, some female patients have neither reduced leukocyte GLA enzyme activity level nor FD symptoms. Thus, GLA gene analysis is especially important for diagnosing suspected FD in female subjects. In this study, we revealed 4 novel GLA gene mutations in 5 independent families using GLA cDNA analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. These distinct mutations included a large deletion mutation from intron 1 to exon 5 (c.195-471_c.691del5.5k, corresponding to g.8508_g.14069del5.5k), an insertion mutation of splicing enhancer sequence in intron 4 (c.639+329_c.639+330ins113, corresponding to g.12627_g.12628ins113), an insertion mutation of retrotransposon L1 in exon 4 (c.634_c.635, corresponding to g.12293_g.12294), and a non-SNP deep intronic point mutation in intron 3 (c.547+395G>C, corresponding to g.11727G>C). It is difficult to detect these mutations with direct sequencing of only the exonic element. When exonic mutations are not found in the GLA gene from suspected FD patients, GLA cDNA and MLPA analyses should be performed to detect large deletion/insertion and intronic mutations including transcription abnormalities.

Published
2015

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