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Acute disseminated encephalomyelitis (ADEM) is a common phenotype in children with myelin oligodendrocyte glycoprotein IgG (MOG-IgG)-associated disease. We aimed to identify novel genetic variants that distinguish children with MOG-IgG-positive ADEM (MOG-IgG+ ADEM) from children with MOG-IgG-negative ADEM (MOG-IgG− ADEM) using whole exome sequencing (WES) analysis. We conducted a two-stage study design. First, we performed WES on five patients with MOG-IgG+ ADEM and five patients with MOG-IgG− ADEM. Following bioinformatics analysis, the candidate variant list was constructed. Second, 29 children with MOG-IgG+ ADEM and 27 children with MOG-IgG− ADEM, together with discovery cohort, were genotyped to identify the novel variants. WES resulted in 33,999 variants, and 5388 nonsynonymous variants were selected for downstream analysis. In total, 118 protein-affecting variants that were significantly different between the two groups were identified. Together with the five variants extracted from the literature, 49 variants were selected as the candidate variant list for genotyping in the replication cohort. Finally, we identified three variants: rs11171951 in NACα , rs231775 in CTLA4, and rs11171951 in GOLGA5 , which were significantly different between MOG-IgG+ ADEM and MOG-IgG− ADEM. Only rs12440118 in NACα remained significant after Bonferroni correction for multiple testing (P adj < 0.001). We identified strong associations between NACα, CTLA4, and GOLGA5 variants and MOG-IgG+ ADEM in a Han Chinese population of Northern China, which may present novel genetic risk factor distinguishing patients with MOG-IgG+ ADEM from those with MOG-IgG− ADEM. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed a disruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone. [ABSTRACT FROM AUTHOR]

Introduction: About half of adults aged ≥80 years suffer from frailty. Exercise is considered effective in preventing frailty but may be inapplicable to adults aged ≥80 years due to physical limitations. As an alternative, we aimed to explore the association of leisure activities with frailty and identify potential interaction with established polygenic risk score (PRS) among adults aged ≥80 years. Methods: Analyses were performed in a prospective cohort study of 7,471 community-living older adults aged ≥80 years who were recruited between 2002 and 2014 from 23 provinces in China. Leisure activity was assessed using a seven-question leisure activity index and frailty was defined as a frailty index ≥0.25 using a validated 39-item health-related scale. The PRS was constructed using 59 single-nucleotide polymorphisms associated with frailty in a subsample of 2,541 older adults. Cox proportional hazards models were used to explore the associations of leisure activities, PRS with frailty. Results: The mean age of participants was 89.4 ± 6.6 years (range: 80–116). In total, 2,930 cases of frailty were identified during 42,216 person-years of follow-up. Each 1 unit increase in the leisure activity index was associated with 12% lower risk of frailty (hazard ratio: 0.88 [95% confidence interval, 0.85–0.91]). Participants with high genetic risk (PRS >2.47 × 10−4) suffered from 26% higher risk of frailty. Interaction between leisure activity and genetic risk was not observed. Conclusion: Evidence is presented for the independent association of leisure activities and genetic risk with frailty. Engagement in leisure activities is suggested to be associated with lower risk of frailty across all levels of genetic risk among adults aged ≥80 years. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an autoimmune small bowel disease. Genetic susceptibility for CD is mainly determined by the human leukocyte antigen (HLA)-DQ haplotypes. The risk of CD conferred by HLA genotypes varies geographically and across populations, however, this has not yet been documented in Chinese patients with CD. To investigate the distribution of HLA-DQ and the related risks of CD development in Northwest China. A total of 75 CD patients and 300 healthy individuals were genotyped for HLA-DQ using the Illumina NextSeq, and the relative risks of the different genotypes were evaluated. In total, 68.00% of CD patients and 21.00% of controls carried HLA-DQ2.5 heterodimers (p < 0.001). We identified four CD risk gradients. Individuals carrying a double dose of DQB1*02 had the highest risk of developing CD (1:16); however, with heterozygosis (DQB1*02:02/DQB1*02:01) having the highest risk (1:9). HLA-DQ2.5 individuals with a single copy of HLA-DQB1*02, in either the cis or trans configuration, were at a medium risk (1:38). Non-DQ2.5 carriers of DQ8 or DQ2.2 were at low risk, while only carriers of DQ7.5 or DQX.5 were at very low risk. Patients with the HLA-DQ2.5 genotype had more severe mucosal damage compared with the HLA-DQ2.5 genotype negative CD patients (70.59% vs. 41.67%, p = 0.016). Genetic susceptibility to CD is highly prevalent in the Northwest Chinese population and the highest risk of developing CD was associated with the DQ2.5/DQ2.2 genotype. The DQ2.5 allele is involved in the severity of mucosal injury. [ABSTRACT FROM AUTHOR]

We investigated the prevalence and clinical metabolic characteristics of lean nonalcoholic fatty liver disease (NAFLD) in an elderly Chinese population and assessed the relevance of lipid markers and genetic variation. All 5,338 community subjects underwent detailed clinical and laboratory examinations and were divided into three groups: lean (Body mass index (BMI) < 23 kg/m2, n = 2,012), overweight (BMI = 23–24.9 kg/m2, n = 1,354), and obese (BMI ≥ 25 kg/m2, n = 1,972). Single nucleotide polymorphisms were selected based on those reported in previous NAFLD or obesity genome-wide association studies. The frequencies of alleles and genotypes were calculated and statistically analyzed with Pearson's χ2 tests. One-way ANCOVA was used to test the association between positive SNPs and metabolic parameters in lean NAFLD individuals. Our results showed that the C allele frequency of rs2279026, the G allele of rs2279028, the C allele of rs780093, and the C allele frequency of rs1260326 were higher in obese NAFLD than in lean NAFLD (P < 0.05). In addition, we observed an association between the CC of rs1421085, TT of rs3751812, AA of rs8050136, and AA of rs9939609 genotypes in the FTO gene and low-density lipoprotein levels (P < 0.05). In conclusion, our findings provide a unique perspective on the prevalence, genetic characteristics, and metabolic profile of NAFLD in older lean individuals in China. This is the first study to examine the association between genetic variants in the FTO, TFAP2B and GCKR genes and NAFLD in a cohort of lean individuals. [ABSTRACT FROM AUTHOR]

Limited research has reported the association between MTNR1B gene polymorphisms and ischemic stroke (IS), and there is insufficient evidence on whether adopting a healthy lifestyle can mitigate genetic risks in this context. This study aimed to investigate the associations between MTNR1B gene variants (rs10830963 and rs1387153) and IS, examining the potential effect of gene-lifestyle interactions on IS risk. Conducted in northern China, this family-based cohort study involved 5116 initially IS-free subjects. Genotype data for rs10830963 and rs1387153 in MTNR1B were collected. Eight modifiable lifestyle factors, including body mass index (BMI), smoking, alcohol consumption, dietary habits, physical activity, sedentary time, sleep duration, and chronotype, were considered in calculating healthy lifestyle scores. Multilevel Cox models were used to examine the associations between MTNR1B variants and IS. Participants carrying the rs10830963-G and rs1387153-T alleles exhibited an elevated IS risk. Each additional rs10830963-G allele and rs1387153-T allele increased the IS risk by 36% (HR = 1.36, 95% CI, 1.12-1.65) and 32% (HR = 1.32, 95% CI, 1.09-1.60), respectively. Participants were stratified into low, medium, and high healthy lifestyle score groups (1537, 2188, and 1391 participants, respectively). Genetic-lifestyle interactions were observed for rs10830963 and rs1387153 (p for interaction < 0.001). Notably, as the healthy lifestyle score increased, the effect of MTNR1B gene variants on IS risk diminished (p for trend < 0.001). This study underscores the association between the MTNR1B gene and IS, emphasizing that adherence to a healthy lifestyle can mitigate the genetic predisposition to IS., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital., Methods: A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD., Results: Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10 - 8 . Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%., Conclusions: Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation., (© 2024. The Author(s).)

aimed to identify whether two key genes (CYP21A2 and CYP19A1) involved in the synthesis and metabolism of androgens were associated with Pillsbury III-IV severe acne vulgaris. Methods: We carried out a standard questionnaire survey about acne and enlisted 600 Pillsbury III-IV severe acne vulgaris patients and 652 healthy controls of Han Chinese descent from Yunnan, China in the study. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot assay and analyzed for association with severe acne. Results: There was no significant difference in gender between the two groups (P = 0.085), and the age of the acne case group was significantly lower than that of the control group (P < 0.001). Our results revealed that only two SNPs, rs6474 (p.Arg102Lys) (P = 0.001) and rs6465 (P = 0.025) of the CYP21A2 gene were significantly associated with severe acne among the Han Chinese. When subjects were divided into males and females, significant associations were observed only in male patients with severe acne vulgaris for four variants: CYP21A2 rs6474 (p.Arg102Lys) (P = 0.002); CYP21A2 rs6465 (P = 0.012); CYP19A1 rs8023263 (P = 0.037); and CYP19A1 rs2470152 (P = 0.007). Haplotype analyses showed that the distribution of CYP21A2 haplotypes was significantly associated with male patients, while no association of CYP19A1 haplotypes was observed. The structure of the human CYP21A2 consists of two substrate binding sites and one substrate access channel. Conclusion: This study shed a light on a potentially important effect of CYP21A2 and CYP19A1 genes in severe acne vulgaris in the Han Chinese, especially for male patients. Future studies using independently verified datasets from a broader geographical spectrum will be valuable in identifying the causal and functional variants responsible for severe acne vulgaris within the CYP19A1 and CYP21A2 genes. [ABSTRACT FROM AUTHOR]

[Display omitted] • It is still unclear whether genetics modifies the effect of PM 2.5 exposure on CAD. • Exposure to PM 2.5 increases CAD risk, especially in population at high genetic risk. • Interaction effect is identified between PM 2.5 exposure and genetic risk on CAD. • It is important to consider both air pollution and genetic risk for CAD prevention. Although both environmental and genetic factors were linked to coronary artery disease (CAD), the extent to which the association of air pollution exposure with CAD can be influenced by genetic risk was not well understood. A total of 41,149 participants recruited from the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) were included. Genetic risk scores of CAD were constructed based on 540 genetic variants. Long-term PM 2.5 exposures were assessed by adopting satellite-based PM 2.5 estimations at 1-km resolution. We used stratified Cox proportional hazards regression model to examine the impact of PM 2.5 exposure and genetic risk on CAD risk, and further analyzed modification effect of genetic predisposition on association between PM 2.5 exposure and CAD risk. During a median of 13.01 years of follow-up, 1,373 incident CAD events were observed. Long-term PM 2.5 exposure significantly increased CAD risk, and the hazard ratios (HRs) [95% confidence intervals (CIs)] were 1.27 (1.05–1.54) and 1.95 (1.57–2.42) among intermediate and high PM 2.5 exposure groups compared to low PM 2.5 exposure group. The relative risks of CAD were 40% (HR: 1.40, 95%CI: 1.18–1.66) and 133% (HR: 2.33, 95%CI: 1.94–2.79) higher among individuals at intermediate and high genetic risk than those at low genetic risk. Compared with individuals with both low genetic risk and low PM 2.5 exposure, those with high genetic risk and high PM 2.5 exposure had highest CAD risk, with HR of 4.37 (95%CI: 3.13–6.11). We observed significant multiplicative (P < 0.001) and additive interaction [relative excess risk due to interaction (95%CI): 2.75 (1.32–4.20); attributable proportion due to interaction (95%CI): 0.56 (0.42–0.70)] between genetic risk and PM 2.5 exposure on CAD. This study provided evidence that long-term PM 2.5 exposure might increase CAD risk, especially among people at high genetic risk. Our findings highlighted the importance of taking strategies on air quality improvement to cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Background: The efficiency of human brain depends on the integrity of both long- and short-range connections, but the long-range connections need to be “penalized” to reduce overall wiring costs. This principle, termed as the anatomical distance function (ADF), refers to the presence of an inverse relationship between anatomical distance and connectivity. A crucial developmental feature that occurs in normal adolescence is the weakening of ADF, which is characterized by a selective strengthening of long-distance connections. Schizophrenia is associated with widespread dysconnectivity that is linked to aberrant cortical development. Methods: We studied the ADF in adults with schizophrenia (n = 28), their age-matched siblings (n = 28), and healthy controls (n = 60). We investigated the proportional abnormalities in the long-range connections involving interhemispheric, subcortical, frontal, and salience network regions and localized the connections showing most significant changes in schizophrenia. The groups were discriminated on the basis of short- and long-range connectivity using a machine-learning algorithm. Results: Both patients and their siblings showed abnormally pronounced ADF. This was associated with a disproportionate reduction in the number of long-range connections, affecting the subcortical, interhemispheric, and the salience network connections. The abnormalities in long-range connections had superior ability to accurately identify group membership. Conclusions: A crucial organizing principle of the brain architecture that becomes apparent during normal adolescence is disturbed in schizophrenia. While siblings show some evidence of compensating for this deficit, patients lack putative compensatory changes. Age-related shift in ADF provides an explanatory framework for the developmental emergence of widespread dysconnectivity that is influenced by genetic risk in schizophrenia. [ABSTRACT FROM PUBLISHER]

Despite the similar clinical and pathological features between Niemann-Pick type C (NPC) disease and Alzheimer's disease (AD), few studies have investigated the role of NPC genes in AD. To elucidate the role of NPC genes in AD, we sequenced NPC1 and NPC2 in 1192 AD patients and 2412 controls. Variants were divided into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF≥0.01) based association analysis was conducted by PLINK 1.9. Gene-based aggregation testing of rare variants was performed by Sequence Kernel Association Test-Optimal (SKAT-O test), respectively. Age at onset (AAO) and mini-mental state examination (MMSE) association studies were also performed with PLINK 1.9. Six common variants were identified and exhibited no association with AD. Gene-based aggregation testing revealed that both NPC1 and NPC2 were not associated with AD risk. Additionally, AAO and MMSE association studies revealed that no common variants were linked with AD endophenotypes. Taken together, our study indicated that NPC1 and NPC2 may not be implicated in AD pathogenesis in the Chinese population., (Copyright © 2022. Published by Elsevier Inc.)

Alzheimer's disease (AD) and frontotemporal dementia (FTD) overlap clinically and pathologically. However, the role of FTD-associated genes in patients with AD remained unclear. To explore the relationship between FTD-associated genes and AD risk, we investigated 14 FTD-associated genes via targeted next-generation sequencing panel or whole-genome sequencing in a total of 721 AD patients and 1391 controls. Common variant-based association analysis and gene-based association test of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal (SKAT-O test) respectively. As a result, 2 common variants, UBQLN1 rs1044175 (p value = 2.76 × 10 -4 ) and MAPT rs2258689 (p value = 5.71 × 10 -4 ), differed significantly between AD patients and controls. Additionally, gene-based analysis aggregating rare variants demonstrated that HNRNPA1 reached statistical significance in the SKAT-O test (p value = 2.24 × 10 -3 ). Protein-protein interaction analysis showed that UBQLN1, MAPT, and HNRNPA1 interacted with proteins encoded by well-recognized AD-associated genes. Our study indicated that UBQLN1, MAPT, and HNRNPA1 are implicated in the pathogenesis of AD in the mainland Chinese population., (Copyright © 2021. Published by Elsevier Inc.)

Background: Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear., Objectives: To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations., Methods: An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline., Results: During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [-0.22, 0.33] in CKB and 0.04 [-0.14, 0.22] in UKB)., Conclusions: In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk., (© 2021. The Author(s).)

• SSR labeled-release-recapture routines were established to evaluate stock enhancement. • Silver carps were facing population depression and genetic structure homogeny. • Potential genetic risk existed between recaptured populations by constant SE. • Urgent scientific SE breeding programs and traceability system should be constructed. Hatchery release of silver carp (Hypophthalmichthys molitrix) is an efficient strategy that has been carried out for years, and its scales expand year by year in the lower reaches of the Yangtze River (LRYR) in China. As the cultured juveniles are released into self-recruiting wild population to increase fisheries resources yields, they may potentially come along with negative impacts such as intra-inter specific completion, loss of genetic diversity and fitness, even causing genetic risk. To assess the relationship between genetic risk and stock enhancement (SE) of the silver carp in the Yangtze River (YR); microsatellite loci amplification, parentage assignment, genetic diversity, genetic differentiation and structure were conducted and testified by the help of eleven fluorescence-labeled microsatellite markers method. Results showed that silver carp populations in the YR had relatively higher genetic diversity (UHe), inbreeding coefficient (Fis), and effective population size (Ne) than breeding stock populations from eight hatcheries. By using the analysis of molecular variance (AMOVA), results showed that the percentage of variance among populations and within populations were 4.15 % and 95.85 %, respectively, which indicated that genetic structure of YR populations possibly had been changed by SE. Therefore, the present study suggests that the large-scale SE possibly resulted in negative genetic impact on silver carp population. Most importantly, an evaluation system in fisheries resource recruitment and genetic risks was established for SE and management. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the role of endothelial nitric oxide synthase (eNOS), matrix metalloproteinases (MMP)-9, and Bcl2-associated oncogene 6 (BAG-6) gene polymorphisms, as well as the combined role of single nucleotide polymorphisms (SNPs) in hypertensive disorders of pregnancy (HDP) patients. This case-control study consisted of women with 326 HDP and 312 healthy pregnant controls. Multiplex PCR combined with next-generation sequencing method was used for determination of gene polymorphisms. Nine SNPs were analyzed, and we classified these case samples in depth by preeclampsia (PE) non-PE or blood pressure stages. We undertook allele and genotype haplotype association studies in all the cases and in the subgroups, as well as adjust age by binary logistic regression. Furthermore, the distribution of the haplotypes formed by the nine SNPs mentioned between the HDP patients and healthy pregnant controls were analyzed. There were no statistically significant differences in the nine SNPs of eNOS, MMP-9, and BAG-6 gene allele and genotype frequencies between HDP or subtypes and controls. However, for haplotype analyses, we found that the frequencies of AGACGCCGA ( p  = 3.67 e-005 ), AGACGCGCA ( p  = 0.03127), and GAACACCGA ( p  = 0.02449) were significantly lower in the cases than in the controls. However, the haplotype of GGACGCCGA ( p  = 0.000686) was higher in the cases than in the controls. Our results suggested protective effect of the haplotypes AGACGCCGA, AGACGCGCA, and GAACACCGA against the development of HDP, and the haplotype GGACGCCGA was the risk factor of HDP.

Objective: The objective of this study is to examine the association of olfactory function and genetic predisposition of Alzheimer's disease (AD) with cognitive performance in adults., Methods: A total of 2049 Chinese adults from Rugao Longevity and Ageing Study (RuLAS, n=1460, mean age 78 years) and Central China Cohort (CCC, n=589, mean age 48 years) were included in this study. A standard interview-based survey, clinical information, and blood samples were collected in both cohorts. Olfactory function in terms of olfactory identification was measured by the brief version of the Chinese Smell Identification Test consisted of 18 full points. Cognitive performance was measured by the Chinese version of the Mini-mental State Examination. A genetic risk score (GRS) was calculated from 5 single nucleotide polymorphisms, which were robustly related to Alzheimer's disease in Caucasians and cognitive performance in our Chinese population., Results: In the pooled analyses, participants at the lowest quartile of olfactory function had significantly higher odds of cognitive impairment (adjusted odds ratio [95% CI] =1.45 [1.00 to 2.09], Ptrend =0.005), and such association was stronger among participants with a stronger genetic predisposition of Alzheimer's disease (β coefficient±SE, -0.06±0.03 in participants with a lower GRS vs. -0.19±0.05 in those with a higher GRS, respectively, P interaction =0.01). Similar associations were observed in RuLAS (P-trend=0.06) and in CCC (P-trend<0.001)., Conclusion: In this study, a decreased olfactory function was associated with worse cognitive performance in adults, especially among participants with a higher genetic risk of Alzheimer's disease. Further studies are warranted to evaluate the causal relationship between olfaction and cognitive performance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Carotid intima-media thickness (cIMT) has been associated with an elevated risk of ischemic stroke (IS) in several studies, but the results are inconsistent. We investigated whether the association between cIMT and IS varied across different IS subtypes, and further assessed gene-cIMT interactions' association with IS risk., Methods: A total of 1048 IS cases (795 large-artery atherosclerosis (LAA) cases, 103 small-vessel occlusion (SVO) cases, and 150 other subtypes) and 2696 IS-free controls across 2179 families were included in the analysis. Self-reported IS cases were confirmed through medical records' review and head imaging by computed tomography and/or magnetic resonance imaging. The mean values of the common cIMT obtained in bilateral distal and proximal carotid artery segments were used. The genotype information of rs2910164 polymorphism in microRNA-146a (miR-146a) was also collected., Results: We found that cIMT was significantly associated with a higher risk of IS and LAA subtype but not SVO subtype in the multivariate-adjusted models. The odds ratio (OR) and 95% confidence interval (CI) in the highest quartile versus the lowest quartile of cIMT was 2.48 (1.92-3.20) for IS and 2.75 (2.08-3.64) for LAA (both p trend <0.001). The results also showed that there was a significant interaction between cIMT and rs2910164 genotype with the risk of IS ( p interaction = 0.03) and LAA ( p interaction = 0.02). The associations of cIMT with IS and LAA were strengthened among participants carried rs2910164&#95;GG genotype compared with those with rs2910164&#95;CC genotype., Conclusions: Our results indicate that higher cIMT levels were significantly associated with IS and LAA subtype but not SVO subtype, and the relations were modified by rs2910164 polymorphism in miR-146a.

Context: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases., Objects: To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT., Design: In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age., Results: We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10-8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed., Conclusion: Our findings suggested that the pathogenesis of HT and GD was different., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Both genetic and lifestyle factors contribute to the incidence of type 2 diabetes. It yet remains controversial whether and how alcohol consumption, one of the most prevalent lifestyle habits, influences type 2 diabetes. Moreover, whether alcohol consumption interacts with genetic risk is inconclusive. Thus, we aimed to explore the effects of alcohol, genetic risk and their potential interactions on type 2 diabetes risk. Methods: The Shanghai Diabetes study (SHDS) had a total of 2546 participants with 611 incident cases of combined type 2 diabetes and impaired glucose regulation (IGR). We constructed weighted genetic risk score (GRS) for type 2 diabetes and categorized the GRS into three strata. And the homeostatic model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated. Then we used logistic regression models and multiple linear regression models to examine the influence of both baseline alcohol consumption and genetic risk on blood glucose deterioration, insulin resistance (IR) and beta cell function (BC), respectively. Moreover, we investigated the interactions of alcohol intake with: (1) GRSs for type 2 diabetes, IR, BC, body mass index (BMI) and waist-to-hip ratio (WHR); and (2) each of the single nucleotide polymorphisms (SNPs) used to establish the GRSs mentioned above. Results: Alcohol consumption and higher T2D-GRS both contributed to a higher incidence rate of blood glucose deterioration [odds ratio (OR), 2.24, 95% confidence interval (CI), 1.76–2.87; OR, 1.25, 95% CI, 1.11–1.42; respectively]. Alcohol reduced insulin sensitivity and compensated by enhancing beta cell function (β = 1.98, P <.0001 and β = − 1.97, P <.0001 for HOMA-IR and inverse HOMA-β, respectively). T2D-GRS deteriorated insulin secretion (β = 0.10, P = 0.0069 for inverse HOMA-B) but not insulin sensitivity (P = 0.0856). Moreover, there was a significant interaction between alcohol and T2D-GRS (Pinteraction = 0.0318), suggesting the association between alcohol and type 2 diabetes was much stronger in the lower T2D-GRS group than in the higher T2D-GRS group. And this interaction was more pronounced in men (Pinteraction = 0.0176) than in women (Pinteraction = 0.3285). No single SNP interacted strongly with alcohol intake. Conclusions/interpretation: Alcohol consumption strongly increased the risk of type 2 diabetes by increasing IR, especially in men with low T2D-GRS, highlighting the importance of refraining from drinking alcohol when making recommendations for healthy lifestyle habits to prevent diabetes. [ABSTRACT FROM AUTHOR]

The isolated type of orofacial cleft, termed non-syndromic cleft lip with or without cleft palate (NSCL/P), is the second most common birth defect in China, with Asians having the highest incidence in the world. NSCL/P involves multiple genes and complex interactions between genetic and environmental factors, imposing difficulty for the genetic assessment of the unborn fetus carrying multiple NSCL/P-susceptible variants. Although genome-wide association studies (GWAS) have uncovered dozens of single nucleotide polymorphism (SNP) loci in different ethnic populations, the genetic diagnostic effectiveness of these SNPs requires further experimental validation in Chinese populations before a diagnostic panel or a predictive model covering multiple SNPs can be built. In this study, we collected blood samples from control and NSCL/P infants in Han and Uyghur Chinese populations to validate the diagnostic effectiveness of 43 candidate SNPs previously detected using GWAS. We then built predictive models with the validated SNPs using different machine learning algorithms and evaluated their prediction performance. Our results showed that logistic regression had the best performance for risk assessment according to the area under curve. Notably, defective variants in MTHFR and RBP4, two genes involved in folic acid and vitamin A biosynthesis, were found to have high contributions to NSCL/P incidence based on feature importance evaluation with logistic regression. This is consistent with the notion that folic acid and vitamin A are both essential nutritional supplements for pregnant women to reduce the risk of conceiving an NSCL/P baby. Moreover, we observed a lower predictive power in Uyghur than in Han cases, likely due to differences in genetic background between these two ethnic populations. Thus, our study highlights the urgency to generate the HapMap for Uyghur population and perform resequencing-based screening of Uyghur-specific NSCL/P markers., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status., Methods: We utilized the genome-wide methylation data of psoriatic skin (PP, N  = 114) and unaffected control skin (NN, N  = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility., Results: We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P  < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106 , the TSS1500 promoter region of DMBX1 and the body of SIK3 ., Conclusions: This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis.

Unlabelled: Severe adverse drug reactions (ADR) of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some patients receiving strontium ranelate have been reported, but the risk factors are unclear. We show that HLA-A*33:03 and B*58:01 are significantly associated with patients who developed SJS/TEN; and provide the first evidence that genetic risk factors are involved in strontium ranelate-associated SJS/TEN., Introduction: In this study, HLA as a genetic risk factor was assessed among osteoporotic patients prescribed with strontium ranelate that developed severe cutaneous adverse drug reactions (SCARs) compared with those who were tolerant., Methods: Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) of patients was HLA typed using sequencing-based typing method to determine their HLA profiles., Results: Osteoporotic patients who are currently on strontium ranelate were enrolled in the study (n = 76). Tolerant controls were defined as patients who received strontium ranelate for a minimum of 3 months (range 3 months to 8 years) with no reports of any cutaneous reactions as these reactions usually occur within the first 12 weeks after starting treatment. Retrospective cases of SJS/TEN were also identified (n = 5). The majority of the accrued samples were of Han Chinese descent: controls (n = 72) and cases (n = 4). All cases and controls were genotyped at four HLA genes, namely HLA-A, HLA-B, HLA-C, and HLA-DRB1. In comparing the samples of Han Chinese descent (72 controls and 4 cases), we found significant associations with HLA-A*33:03 (p = 0.002) and HLA-B*58:01 (p = 0.023). There was no significant association with any HLA-C or HLA-DRB1 alleles., Conclusions: This study reveals that the occurrence of SJS/TEN in Han Chinese patients receiving strontium ranelate is HLA associated. This has important clinical implications for understanding the underlying mechanisms for this ADR as well as evaluating the potential role of genetic pre-screening for osteoporotic patients who may be prescribed strontium ranelate.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer., Competing Interests: The authors declare no conflicts of interest.

Background and Objective: Genetic markers associated with disease are often non-functional and generally tag one or more functional "causative" variants in linkage disequilibrium. Markers may not show tight linkage to the causative variants across multiple ethnicities due to evolutionary divergence, and therefore may not be informative across different population groups. Validated markers of disease suggest causative variants exist in the gene and, if the causative variants can be identified, it is reasonable to hypothesize that such variants will be informative across diverse populations. The aim of this study was to test that hypothesis using functional Interleukin-1 (IL-1) gene variations across multiple ethnic populations to replace the non-functional markers originally associated with chronic adult periodontitis in Caucasians., Material and Methods: Adult chronic periodontitis cases and controls from four ethnic groups (Caucasians, African Americans, Hispanics and Asians) were recruited in the USA, Chile and China. Genotypes of IL1B gene single nucleotide polymorphisms (SNPs), including three functional SNPs (rs16944, rs1143623, rs4848306) in the promoter and one intronic SNP (rs1143633), were determined using a single base extension method or TaqMan 5' nuclease assay. Logistic regression and other statistical analyses were used to examine the association between moderate to severe periodontitis and IL1B gene variations, including SNPs, haplotypes and composite genotypes. Genotype patterns associated with disease in the discovery study were then evaluated in independent validation studies., Results: Significant associations were identified in the discovery study, consisting of Caucasians and African Americans, between moderate to severe adult chronic periodontitis and functional variations in the IL1B gene, including a pattern of four IL1B SNPs (OR = 1.87, p < 0.0001). The association between the disease and this IL1B composite genotype pattern was validated in two additional studies consisting of Hispanics (OR = 1.95, p = 0.04) or Asians (OR = 3.27, p = 0.01). A meta-analysis of the three populations supported the association between the IL-1 genotype pattern and moderate to severe periodontitis (OR 1.95; p < 0.001). Our analysis also demonstrated that IL1B gene variations had added value to conventional risk factors in predicting chronic periodontitis., Conclusion: This study validated the influence of IL-1 genetic factors on the severity of chronic periodontitis in four different ethnicities., (© 2014 Interleukin Genetics, Inc. Journal of Periodontal Research published by John Wiley & Sons Ltd.)

Abstract: Extracts of the leaves of the stevia plant (Stevia rebaudiana Bertoni) are used to sweeten food and beverages in South America, Japan and China. The components responsible for the sweet properties of the plant are glycosides of steviol, primary stevioside (ent-13-hydroxykaur-16-en-18-oic acid), which is 250–300 times sweeter than sucrose and rebaudiosides A and C. Stevioside and steviol have been subjected to extensive genetic testing. The majority of the findings show no evidence of genotoxic activity. Neither stevioside nor its aglycone steviol have been shown to react directly with DNA or demonstrate genotoxic damage in assays relevant to human risk. The mutagenic activity of steviol and some of its derivatives, exhibited in strain TM677, was not reproduced in the same bacteria having normal DNA repair processes. The single positive in vivo study measuring single-strand DNA breaks in Wistar rat tissues by stevioside, was not confirmed in experiments in mice and appears to be measuring processes other than direct DNA damage. Neither stevioside nor steviol-induced clastogenic effects at extremely high dose levels in vivo. Application of a Weight-of-Evidence approach to assess the genetic toxicology database concludes that these substances do not pose a risk of genetic damage following human consumption. [Copyright &y& Elsevier]