Meta-analysis identifies multiple loci associated with kidney function??related traits in east Asian populations

Okada, Yukinori,Sim, Xueling,Go, Min Jin,Wu, Jer-Yuarn,Gu, Dongfeng,Takeuchi, Fumihiko,Takahashi, Atsushi,Maeda, Shiro,Tsunoda, Tatsuhiko,Chen, Peng,Lim, Su-Chi,Wong, Tien-Yin,Liu, Jianjun,Young, Terr Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.8

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function??related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function??related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 ? 10<SUP>??8</SUP>). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ??10,347 individuals. We identify pleiotropic associations among these loci with kidney function??related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Multiple Biomarkers Improved Prediction for the Risk of Type 2 Diabetes Mellitus in Singapore Chinese Men and Women

Yeli Wang,Woon-Puay Koh,Xueling Sim,Jian-Min Yuan,An Pan 대한당뇨병학회 2020 Diabetes and Metabolism Journal Vol.44 No.2

Background: Multiple biomarkers have performed well in predicting type 2 diabetes mellitus (T2DM) risk in Western populations. However, evidence is scarce among Asian populations. Methods: Plasma triglyceride-to-high density lipoprotein (TG-to-HDL) ratio, alanine transaminase (ALT), high-sensitivity Creactive protein (hs-CRP), ferritin, adiponectin, fetuin-A, and retinol-binding protein 4 were measured in 485 T2DM cases and 485 age-and-sex matched controls nested within the prospective Singapore Chinese Health Study cohort. Participants were free of T2DM at blood collection (1999 to 2004), and T2DM cases were identified at the subsequent follow-up interviews (2006 to 2010). A weighted biomarker score was created based on the strengths of associations between these biomarkers and T2DM risks. The predictive utility of the biomarker score was assessed by the area under receiver operating characteristics curve (AUC). Results: The biomarker score that comprised of four biomarkers (TG-to-HDL ratio, ALT, ferritin, and adiponectin) was positively associated with T2DM risk (P trend <0.001). Compared to the lowest quartile of the score, the odds ratio was 12.0 (95% confidence interval [CI], 5.43 to 26.6) for those in the highest quartile. Adding the biomarker score to a base model that included smoking, history of hypertension, body mass index, and levels of random glucose and insulin improved AUC significantly from 0.81 (95% CI, 0.78 to 0.83) to 0.83 (95% CI, 0.81 to 0.86; P=0.002). When substituting the random glucose levels with glycosylated hemoglobin in the base model, adding the biomarker score improved AUC from 0.85 (95% CI, 0.83 to 0.88) to 0.86 (95% CI, 0.84 to 0.89; P=0.032). Conclusion: A composite score of blood biomarkers improved T2DM risk prediction among Chinese.

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

Kato, Norihiro,Takeuchi, Fumihiko,Tabara, Yasuharu,Kelly, Tanika N,Go, Min Jin,Sim, Xueling,Tay, Wan Ting,Chen, Chien-Hsiun,Zhang, Yi,Yamamoto, Ken,Katsuya, Tomohiro,Yokota, Mitsuhiro,Kim, Young Jin,O Nature Publishing Group, a division of Macmillan P 2011 Nature genetics Vol.43 No.6

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 ? 10<SUP>??8</SUP>) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 ? 10<SUP>??31</SUP> and P = 1.3 ? 10<SUP>??35</SUP> for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Wheeler, Eleanor,Leong, Aaron,Liu, Ching-Ti,Hivert, Marie-France,Strawbridge, Rona J.,Podmore, Clara,Li, Man,Yao, Jie,Sim, Xueling,Hong, Jaeyoung,Chu, Audrey Y.,Zhang, Weihua,Wang, Xu,Chen, Peng,Marut Public Library of Science 2017 PLoS medicine Vol.14 No.9

<▼1><P><B>Background</B></P><P>Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.</P><P><B>Methods & findings</B></P><P>Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (<I>N</I> = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, <I>p</I> = 3 × 10<SUP>−29</SUP>); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, <I>p</I> = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked <I>G6PD</I> G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The <I>G6PD</I> variant may cause approximately 2% (<I>N</I> = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.</P><P><B>Conclusions</B></P><P>As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the <I>G6PD</I> genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where <I>G6PD</I> deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.</P></▼1><▼2><P>Ines Barroso and colleagues identify a genetic variant that leads to reduced levels of HbA1c in African American adults; 2% of this population are at risk of missed diagnosis for diabetes.</P></▼2><▼3><P><B>Author summary</B></P><P><B>Why was this study done?</B></P><P>Blood glucose binds in an irreversible manner to circulating hemoglobin in red blood cells (RBCs), generating “glycated hemoglobin,” called HbA1c. HbA1c is used to diagnose and monitor diabetes.</P><P>Previous large-scale human genetic studies have demonstrated that HbA1c is influenced by genetic variants. Some vari

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

Cho, Yoon Shin,Chen, Chien-Hsiun,Hu, Cheng,Long, Jirong,Hee Ong, Rick Twee,Sim, Xueling,Takeuchi, Fumihiko,Wu, Ying,Go, Min Jin,Yamauchi, Toshimasa,Chang, Yi-Cheng,Kwak, Soo Heon,Ma, Ronald C W,Yamamo Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.1

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

Horikoshi, Momoko,Pasquali, Lorenzo,Wiltshire, Steven,Huyghe, Jeroen R.,Mahajan, Anubha,Asimit, Jennifer L.,Ferreira, Teresa,Locke, Adam E.,Robertson, Neil R.,Wang, Xu,Sim, Xueling,Fujita, Hayato,Hara IRL Press 2016 Human molecular genetics Vol.25 No.10

<P>To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (<I>CDKAL1</I>, <I>CDKN2A-B</I>, <I>IGF2BP2</I> and <I>KCNQ1</I>) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.</P>