Venkatesan Radha

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10−4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10−8 to P = 1.9 × 10−11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10−4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) gene polymorphisms and their relationship to Type 2 diabetes in Asian Indians.

Aims  The objective of the present investigation was to examine the relationship of three polymorphisms, Thr394Thr, Gly482Ser and +A2962G, of the peroxisome proliferator activated receptor‐γ co‐activator‐1 alpha (PGC‐1α) gene with Type 2 diabetes in Asian Indians.

Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10−3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10−4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10−8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10−3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10−4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10−5 to < 10−7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.

Role of Genetic Polymorphism Peroxisome Proliferator–Activated Receptor-γ2 Pro12Ala on Ethnic Susceptibility to Diabetes in South-Asian and Caucasian Subjects

OBJECTIVE—To determine whether the peroxisome proliferator–activated receptor (PPAR)-γ Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS—South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-γ Pro12Ala was determined using restriction fragment–length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS—The Caucasian diabetic subjects had significantly lower prevalence of PPAR-γ 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-γ Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 ± 68 and 54 ± 33 μU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-γ Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS—Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-γ Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

Effect of polymorphisms in the PPARGC1A gene on body fat in Asian Indians

Objective:To evaluate whether polymorphisms in the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A) gene were related to body fat in Asian Indians.Methods:Three polymorphisms of PPARGC1A gene, the Thr394Thr, Gly482Ser and +A2962G, were genotyped on 82 type 2 diabetic and 82 normal glucose tolerant (NGT) subjects randomly chosen from the Chennai Urban Rural Epidemiology Study using PCR-RFLP, and the nature of the variants were confirmed using direct sequencing. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies using an expectation–maximization algorithm. Visceral, subcutaneous and total abdominal fat were measured using computed tomography, whereas dual X-ray absorptiometry was used to measure central abdominal and total body fat.Results:None of the three polymorphisms studied were in LD. The genotype (0.59 vs 0.32, P=0.001) and allele (0.30 vs 0.17, P=0.007) frequencies of Thr394Thr polymorphism were significantly higher in type 2 diabetic subjects compared to those in NGT subjects. The odds ratio for diabetes (adjusted for age, sex and body mass index) for the susceptible genotype, XA (GA+AA) of Thr394Thr polymorphism, was 2.53 (95% confidence intervals: 1.30–5.04, P=0.009). Visceral and subcutaneous fat were significantly higher in NGT subjects with XA genotype of the Thr394Thr polymorphism compared to those with GG genotype (visceral fat: XA 148.2±46.9 vs GG 106.5±51.9 cm2, P=0.001; subcutaneous fat: XA 271.8±167.1 vs GG 181.5±78.5 cm2, P=0.001). Abdominal (XA 4521.9±1749.6 vs GG 3445.2±1443.4 g, P=0.004), central abdominal (XA 1689.0±524.0 vs GG 1228.5±438.7 g, P<0.0001) and non-abdominal fat (XA 18763.8±8789.4 vs GG 13160.4±4255.3 g, P<0.0001) were also significantly higher in the NGT subjects with XA genotype compared to those with GG genotype. The Gly482Ser and +A2962G polymorphisms were not associated with any of the body fat measures.Conclusion:Among Asian Indians, the Thr394Thr (G → A) polymorphism is associated with increased total, visceral and subcutaneous body fat.

Rage gene promoter polymorphisms and diabetic retinopathy in a clinic-based population from South India

PurposeThe main objective of this study was to evaluate if the −429T/C, −374T/A and 63 bp deletion polymorphisms in the RAGE gene are associated with diabetic retinopathy (DR) among Type 2 diabetic subjects in a clinic-based population from South India.MethodsWe screened 149 normal glucose tolerant subjects (NGT), 189 Type 2 diabetes subjects without retinopathy (DM) and 190 subjects with DR for these polymorphisms using the PCR-RFLP method. DR was diagnosed by grading color fundus photography. Logistic regression models were used to evaluate the association of individual polymorphisms with DR. Expectation–maximization algorithms were implemented in haplotype tests of association to examine the combined effects of −429T/C and −374T/A polymorphisms on DR.ResultsThe allelic frequencies of −429T are 0.83 in NGT, 0.84 in DM and 0.85 in DR subjects, and that of −374T are 0.93 in NGT, 0.92 in DM and 0.88 in DR subjects. The −374 polymorphism was found to be associated with non-proliferative retinopathy when this subgroup was compared to the DM group (OR=1.814, 95% CI=1.005–3.273). However, this association was not obvious when both the subphenotypes of DR (the nonproliferative and proliferative DR groups) were studied jointly. We found no evidence for associations between the −429T/C polymorphism and the DR phenotype. Finally, extension to a 2-SNP haplotype did not reveal any significant statistical difference between the groups (P=0.668).ConclusionIn this study, we found a modest association with the −374T/A polymorphism in the nonproliferative DR subgroup.

Replication of recently described type 2 diabetes gene variants in a South Indian population

Recent genomewide association studies have identified several new gene variants associated with type 2 diabetes mellitus (T2D) mostly in European populations. These need to be replicated in other populations. We studied 926 unrelated T2D and 812 normal glucose-tolerant subjects randomly selected from the Chennai Urban Rural Epidemiology Study in Southern India. A total of 45 single nucleotide polymorphisms (SNPs) from 15 genes and 13 unannotated loci identified from recent genomewide association T2D studies were genotyped. Only 6 of 45 SNPs studied were replicated in this South Indian population. Three SNPs-rs7756992 (P = .007), rs7754840 (P = .015), and rs6931514 (P = .029)-of the CDKAL1, rs7020996 (P = .003) of the CDKN2A/B gene, rs7923837 (P = .038) of the HHEX gene, and rs12056034 (P = .033) of the BAZ1B gene were associated with T2D in our population. Large-scale studies are needed in our population to validate our findings.

Identification of Novel Variants in the Hepatocyte Nuclear Factor-1α Gene in South Indian Patients with Maturity Onset Diabetes of Young

CONTEXT Mutations in the HNF 1A gene are the most common cause of maturity-onset diabetes of the young (MODY) in most populations. India currently has the largest number of people with diabetes in the world, and onset of type 2 diabetes occurs at a younger age with possible overlap with MODY. There are very few data on MODY mutations from India. OBJECTIVE The objective was to screen coding and promoter regions of HNF1A gene for mutations in unrelated South Indian subjects in whom a clinical diagnosis of MODY was made. DESIGN This was an observational cross-sectional study. SETTING The study was conducted at a diabetes specialties centre in Chennai in southern India. PATIENTS Ninety-six unrelated south Indian subjects in whom clinical diagnosis of MODY was made were included in the study. The control population comprised of 57 unrelated nondiabetic subjects selected from the Chennai Urban Rural Epidemiology Study, a study conducted on a representative population (aged > or =20 yr) of Chennai. RESULTS We identified nine novel variants comprising seven mutations (one novel mutation -538G>C at promoter region and six novel coding region mutations) and two polymorphisms in the HNF1A gene. Functional studies revealed reduced transcriptional activity of the HNF1A promoter for two promoter variants. We also observed cosegregation with diabetes of the Arg263His coding region mutation in eight members of one MODY family, whereas it was absent in nondiabetic subjects of this family. CONCLUSION This study suggests that mutations in the HNF1A gene comprise about 9% of clinically diagnosed MODY subjects in southern India and a novel Arg263His mutation cosegregates with MODY in one family.

The G1057D polymorphism of IRS-2 gene and its relationship with obesity in conferring susceptibility to type 2 diabetes in Asian Indians.

Objective:To investigate the association of insulin receptor substrate-2 (IRS-2) G1057D polymorphism with type 2 diabetes and obesity in Asian Indians.Methods:The study comprised of 1193 normal glucose tolerant (NGT) subjects and 1018 subjects with type 2 diabetes, aged ⩾20 years with an average body mass index of 23.7±4.6 and 25.3±4.2 kg/m2, respectively. The subjects were unrelated and randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai in southern India. The G1057D polymorphism of the IRS-2 gene was genotyped using PCR-RFLP assay.Results:The genotype frequency of the IRS-2 G1057D polymorphism was significantly different between the NGT and type 2 diabetic groups (P=0.0007) in the total study subjects and among the obese subjects (P=0.00007). Logistic regression analysis showed that the DD genotype showed an increased susceptibility to diabetes with an odds ratio (adjusted for age and sex) of 2.19 (95% CI: 1.34–3.57, P=0.002) when compared to the GG+GD genotype, among the obese subjects, but not in non obese subjects. In order to explore possible interaction with obesity, logistic regression analysis was performed and the coefficient corresponding to the interaction parameter (genotype × obesity) was significant (P=0.0001).Conclusion:In Asian Indians, the DD genotype increases susceptibility to type 2 diabetes by interacting with obesity.

Association of novel variants in the hepatocyte nuclear factor 4A gene with maturity onset diabetes of the young and early onset type 2 diabetes.

Anuradha S, Radha V, Mohan V. Association of novel variants in the hepatocyte nuclear factor 4A gene with maturity onset diabetes of the young and early onset type 2 diabetes.