Claudia H. T. Tam

Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians

OBJECTIVE— Recent genome-wide association studies have identified six novel genes for type 2 diabetes and obesity and confirmed TCF7L2 as the major type 2 diabetes gene to date in Europeans. However, the implications of these genes in Asians are unclear. RESEARCH DESIGN AND METHODS— We studied 13 associated single nucleotide polymorphisms from these genes in 3,041 patients with type 2 diabetes and 3,678 control subjects of Asian ancestry from Hong Kong and Korea. RESULTS— We confirmed the associations of TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, and FTO with risk for type 2 diabetes, with odds ratios ranging from 1.13 to 1.35 (1.3 × 10−12 < Punadjusted < 0.016). In addition, the A allele of rs8050136 at FTO was associated with increased BMI in the control subjects (Punadjusted = 0.008). However, we did not observe significant association of any genetic variants with surrogate measures of insulin secretion or insulin sensitivity indexes in a subset of 2,662 control subjects. Compared with subjects carrying zero, one, or two risk alleles, each additional risk allele was associated with 17% increased risk, and there was an up to 3.3-fold increased risk for type 2 diabetes in those carrying eight or more risk alleles. Despite most of the effect sizes being similar between Asians and Europeans in the meta-analyses, the ethnic differences in risk allele frequencies in most of these genes lead to variable attributable risks in these two populations. CONCLUSIONS— Our findings support the important but differential contribution of these genetic variants to type 2 diabetes and obesity in Asians compared with Europeans.

Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese.

OBJECTIVE Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity and type 2 diabetes (T2D) in Chinese. RESEARCH DESIGN AND METHODS We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong. RESULTS The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 x 10(-8) < P < 0.024), and/or obesity risk (odds ratio 1.14-1.22, 2.0 x 10(-5) < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09-1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m(2) in BMI with each additional copy of at-risk allele (P(trend) = 4.2 x 10(-12)). CONCLUSIONS Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

Aims/hypothesisMost genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.MethodsWe performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.ResultsWe identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.Conclusions/interpretationOur study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects.

Background Previous studies identified melatonin receptor 1B (MTNR1B), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2), glucokinase (GCK) and glucokinase regulatory protein (GCKR) as candidate genes for type 2 diabetes (T2D) acting through elevated fasting plasma glucose (FPG). We examined the associations of the reported common variants of these genes with T2D and glucose homeostasis in three independent Chinese cohorts. Methodology/Principal Findings Five single nucleotide polymorphisms (SNPs), MTNR1B rs10830963, G6PC2 rs16856187 and rs478333, GCK rs1799884 and GCKR rs780094, were genotyped in 1644 controls (583 adults and 1061 adolescents) and 1342 T2D patients. The G-allele of MTNR1B rs10830963 and the C-alleles of both G6PC2 rs16856187 and rs478333 were associated with higher FPG (0.0034<P<6.6×10−5) in healthy controls. In addition to our previous report for association with FPG, the A-allele of GCK rs1799884 was also associated with reduced homeostasis model assessment of beta-cell function (HOMA-B) (P = 0.0015). Together with GCKR rs780094, the risk alleles of these SNPs exhibited dosage effect in their associations with increased FPG (P = 2.9×10−9) and reduced HOMA-B (P = 1.1×10−3). Meta-analyses strongly supported additive effects of MTNR1B rs10830963 and G6PC2 rs16856187 on FPG. Conclusions/Significance Common variants of MTNR1B, G6PC2 and GCK are associated with elevated FPG and impaired insulin secretion, both individually and jointly, suggesting that these risk alleles may precipitate or perpetuate hyperglycemia in predisposed individuals.

Interaction Effect of Genetic Polymorphisms in Glucokinase (GCK) and Glucokinase Regulatory Protein (GCKR) on Metabolic Traits in Healthy Chinese Adults and Adolescents

OBJECTIVE— Recent studies in European populations have reported a reciprocal association of glucokinase regulatory protein (GCKR) gene with triglyceride versus fasting plasma glucose (FPG) levels and type 2 diabetes risk. GCKR is a rate-limiting factor of glucokinase (GCK), which functions as a key glycolytic enzyme for maintaining glucose homeostasis. We examined the associations of two common genetic polymorphisms of GCKR and GCK with metabolic traits in healthy Chinese adults and adolescents. RESEARCH DESIGN AND METHODS— Two single nucleotide polymorphisms (SNPs), rs780094 at GCKR and rs1799884 at GCK, were genotyped in 600 healthy adults and 986 healthy adolescents. The associations of these SNPs with metabolic traits were assessed by linear regression adjusted for age, sex, and/or BMI. We also tested for the epistasis between these two SNPs and performed a meta-analysis among European and Asian populations. RESULTS— The T-allele of GCKR rs780094 was associated with increased triglycerides (P = 5.4 × 10−7), while the A-allele of GCK rs1799884 was associated with higher FPG (P = 3.1 × 10−7). A novel interaction effect between the two SNPs on FPG was also observed (P = 0.0025). Meta-analyses strongly supported the additive effects of the two SNPs on FPG and triglycerides, respectively. CONCLUSIONS— In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase FPG in healthy adults and adolescents. These risk alleles may contribute to increased diabetes risk in subjects who harbor other genetic or environmental/lifestyle risk factors.

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

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<5 × 10−8), 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<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.

Genetic Variants of the Protein Kinase C-β 1 Gene and Development of End-Stage Renal Disease in Patients With Type 2 Diabetes

CONTEXT Protein kinase C-beta (PKC-beta) is a cell-signaling intermediate implicated in development of diabetic complications. OBJECTIVE To examine the risk association of PKC-beta 1 gene (PRKCB1) polymorphisms and end-stage renal disease (ESRD) in an 8-year prospective cohort of Chinese patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS We genotyped 18 common tag single-nucleotide polymorphisms (SNPs) that span the PRKCB1 gene (r(2) = 0.80) in 1172 Chinese patients (recruited 1995-1998) without renal disease at baseline. A validation cohort included an additional 1049 patients with early-onset diabetes who were free of renal disease at baseline and were recruited after 1998. MAIN OUTCOME MEASURES Associations of PRKCB1 polymorphisms under additive, dominant, and recessive genetic models with new onset of ESRD (defined as estimated glomerular filtration rate <15 mL/min/1.73 m(2) or dialysis or renal-related death) were assessed by Cox proportional hazard regression, adjusted for all conventional risk factors including use of medications. RESULTS After a mean (SD) of 7.9 (1.9) years, 90 patients (7.7%) progressed to ESRD. Four common SNPs were associated with ESRD (P < .05). The closely linked T allele at rs3760106 and G allele rs2575390 (r(2) = 0.98) showed the strongest association with ESRD (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.31-3.87; P = .003, and HR, 2.26; 95% CI, 1.31-3.88; P = .003, respectively). Four common variants predicted ESRD in separate models. The HR for ESRD increased with increasing number of risk alleles (P < .001) in the joint effect analysis. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for patients with 4 risk alleles compared with patients with 0 or 1 risk allele. Incidence was 4.4 per 1000 person-years (95% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 8.8-31.1) in those carrying 4 risk alleles (6.9% of the cohort). These results were validated in a separate prospective cohort of young-onset diabetic patients. Of 1049 patients in the validation cohort, 151 (14.3%) developed chronic kidney disease (CKD) during follow-up, and there were significant associations between both the T allele of rs3760106 and the G allele of rs2575390 and development of CKD (HR, 1.68; 95% CI, 1.10-2.57; P = .02, and HR, 1.62; 95% CI, 1.07-2.47; P = .02, respectively). CONCLUSION Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes.

Use of Net Reclassification Improvement (NRI) Method Confirms The Utility of Combined Genetic Risk Score to Predict Type 2 Diabetes

Background Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we investigated their individual and combined effects on T2D in a Chinese population. Methodology We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI). Results We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10−18<P<8.5×10−3), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09. The 8 significant SNPs exhibited joint effect on increasing T2D risk, fasting plasma glucose and use of insulin therapy as well as reducing HOMA-β, BMI, waist circumference and younger age of diagnosis of T2D. The addition of CGS marginally increased AUC (2%) but significantly improved the predictive ability on T2D risk by 11.2% and 11.3% for unweighted and weighted CGS, respectively using the NRI approach (P<0.001). Conclusion In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).

Genome-Wide Association Meta-analysis Identifies Novel Variants Associated With Fasting Plasma Glucose in East Asians

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Evaluation of erectile dysfunction and associated cardiovascular risk using structured questionnaires in Chinese type 2 diabetic men.

Erectile dysfunction (ED) is not uncommon, but frequently underdiagnosed in type 2 diabetic men. In this study, we aimed to explore the frequency and severity of ED in Chinese type 2 diabetic men using a structured questionnaire. We furthermore sought to investigate the associations of ED with diabetes-related complications and metabolic indices. A consecutive cohort of 313 Chinese type 2 diabetic men aged between 25 and 76 years attending a diabetic centre were recruited between October 2006 and June 2007. Of the study population, the frequency of ED was 39.3% according to the National Institutes of Health (NIH) Consensus Conference criteria, compared with 84.3% (41.7% of them having moderate to severe ED) as diagnosed by International Index of Erectile Function (IIEF-5) questionnaire. After adjusting for potential confounding factors by multivariable logistic regression, ED defined by NIH criterion was associated with advanced age [OR = 1.05 (95% CI 1.01-1.09), p = 0.012], the presence of diabetic retinopathy [OR = 2.43 (95% CI 1.27-4.66), p = 0.008] and coronary heart disease [OR = 2.63 (95% CI 1.21-5.70), p = 0.015]. ED defined by IIEF-5 was associated with advanced age [OR = 1.12 (95% CI 1.06-1.17), p < 0.0001], use of insulin therapy [OR = 2.94 (95% CI 1.12-7.73), p = 0.029] and urinary albumin-creatinine ratio [OR = 2.29 (95% CI 1.05-5.01), p = 0.037]. In conclusion, ED was highly prevalent in Chinese type 2 diabetic men and was associated with multiple cardiovascular risk factors and complications. Advanced age, use of insulin therapy, the existence of microvascular complications such as retinopathy, albuminuria and coronary heart disease were associated with ED. NIH criteria diagnosed a much lower rate of ED compared with IIEF-5. Overall, structured questionnaires are useful and objective tools to detect ED, which should prompt a comprehensive risk assessment in these subjects.