The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians

One thousand thirty-eight normal glucose-tolerant and 1031 type 2 diabetic subjects selected from the Chennai Urban Rural Epidemiology Study were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay to investigate the association of rs12255372(G/T) and rs7903146(C/T) polymorphisms of the transcription factor 7–like 2 (TCF7L2) gene with type 2 diabetes mellitus in Asian Indians. The frequency of the “T” allele of both rs12255372(G/T) and rs7903146(C/T) polymorphisms was significantly higher in diabetic subjects (23% and 33%) compared to that in normal glucose-tolerant subjects (19% and 28%; P = .001 and P = .0001, respectively). Logistic regression analysis of the rs12255372(G/T) polymorphism showed that the odds ratio (adjusted for age, sex, and body mass index) was 1.56 (95% confidence interval [CI], 1.03-2.37; P = .034) for the TT genotype and 1.29 (95% CI, 1.06-1.58; P = .011) for the TG genotype when compared with the GG genotype. Adjusted odds ratios for the TT and TC genotypes of the rs7903146(C/T) polymorphism were found to be 1.50 (95% CI, 1.08-2.08; P = .013) and 1.44 (95% CI, 1.18-1.76; P = .0003), respectively, compared with the CC genotype. Normal glucose-tolerant subjects with the TT genotype of rs12255372(G/T) had significantly higher 2-hour plasma glucose levels (mean ± SD, 6.1 ± 1.4 mmol/L) than those with the GG genotype (5.6 ± 1.0 mmol/L, P = .011). Normal glucose-tolerant subjects with the TT genotype of rs7903146(C/T) polymorphism had significantly higher 2-hour plasma glucose levels (mean ± SD, 6.0 ± 1.3 mmol/L) than those with the CC genotype (5.6 ± 1.0 mmol/L, P = .004). In conclusion, the T allele of the rs12255372(G/T) and rs7903146(C/T) polymorphisms of TCF7L2 gene confer susceptibility to type 2 diabetes mellitus in Asian Indians. © 2007 Elsevier Inc. All rights reserved

Association of CAPN10 SNPs and Haplotypes with Polycystic Ovary Syndrome among South Indian Women

Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007) with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37–4.61) as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13–3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR = 0.20, p = 0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS

Replication of TCF7L2 rs7903146 association with type 2 diabetes in an Iranian population

The transcription factor 7-like 2 gene (TCF7L2) rs7903146 T allele is constantly associated with Type 2 diabetes in various populations and ethnic groups. Nevertheless, this has not been observed in two studies involving Arab populations. The aim of the present study was to investigate the association between TCF7L2 rs7903146 in an Iranian population. Type 2 diabetes patients (N = 258) and normal healthy control subjects (N = 168) from the same area, were examined. The ARMS- PCR (Amplification Refractory Mutation System) technique, subsequently validated by direct sequencing, was used for genotyping. Allele and genotype frequencies were significantly different between patients and controls TT vs. CT + CC [p 0.0081 OR 3.4 95%CI (1.27-11.9)] and T vs. C allele [p 0.02 OR 1.4 95%CI (1.03-1.9)]. Our data thus confirm the association between the rs7903146 T allele and T2D in an Iranian population, contrary to previous reports in Arab populations. This can possibly be attributed to differences in ethnic background or the effects of environmental factors

Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population

<p>Abstract</p> <p>Background</p> <p>The rs7903146 and rs12255372 variants of <it>TCF7L2 </it>have been strongly associated with type 2 diabetes (T2D) risk in most populations studied to date. Meta-analysis of 27 different studies has resulted in a global OR of 1.46 [1.42–1.51] (rs7903146 variant). Thus far, despite a high incidence of T2D, the role of this variant in Arabs has not been established.</p> <p>Methods</p> <p>We performed a case-control association study using 522 Saudi T2D patients (WHO criteria), and 346 controls (age > 60; fasting plasma glucose < 7 mmol/L). Genotyping was performed by pyrosequencing. Statistical analyses were performed using SPSS version 13.0 for Windows (SPSS, Chicago, IL, USA).</p> <p>Results</p> <p>For rs7903146, the T allele frequency of the cases (0.415) was not different from that observed in the controls (0.405). The crude odds ratio (OR) was 1.04 with a 95% CI of 0.86–1.27 (P = 0.675). For rs12255372, the T allele frequency of the cases (0.368) was not different from that observed in the controls (0.355). Retrospective power calculations based upon an OR of 1.46 reported in a comprehensive meta-analysis of <it>TCF7L2 </it>risk, indicated this study was sufficiently powered (96.92%; α = 0.05) to detect an effect of similar magnitude to that reported for rs7903146.</p> <p>Conclusion</p> <p>Our study is consistent with weak or no association of T2D in Arabs with the two <it>TCF7L2 </it>variants, however it cannot rule out an effect of other SNPs in this gene. Future studies in this population are required to confirm our findings and may indicate the presence of yet to be defined genetic risk factors for T2D.</p

TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes

<p>Abstract</p> <p>Background</p> <p>Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to developing countries in tropical regions and one of its important features is invariable progression to diabetes, a condition called fibro-calculous pancreatic diabetes (FCPD), but the nature of diabetes in TCP is controversial. We analysed the recently reported type 2 diabetes (T2D) associated polymorphisms in the <it>TCF7L2 </it>gene using a case-control approach, under the hypothesis that <it>TCF7L2 </it>variants should show similar association if diabetes in FCPD is similar to T2D. We also investigated the interaction between the <it>TCF7L2 </it>variants and N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations, since they are strong predictors of risk for TCP.</p> <p>Methods</p> <p>Two polymorphisms rs7903146 and rs12255372 in the <it>TCF7L2 </it>gene were analyzed by direct sequencing in 478 well-characterized TCP patients and 661 healthy controls of Dravidian and Indo-European ethnicities. Their association with TCP with diabetes (FCPD) and without diabetes was tested in both populations independently using chi-square test. Finally, a meta analysis was performed on all the cases and controls for assessing the overall significance irrespective of ethnicity. We dichotomized the whole cohort based on the presence or absence of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations and further subdivided them into TCP and FCPD patients and compared the distribution of <it>TCF7L2 </it>variants between them.</p> <p>Results</p> <p>The allelic and genotypic frequencies for both <it>TCF7L2 </it>polymorphisms, did not differ significantly between TCP patients and controls belonging to either of the ethnic groups or taken together. No statistically significant association of the SNPs was observed with TCP or FCPD or between carriers and non-carriers of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations. The minor allele frequency for rs7903146 was different between TCP and FCPD patients carrying the N34S <it>SPINK1 </it>variant but did not reach statistical significance (OR = 1.59, 95% CI = 0.93–2.70, P = 0.09), while, <it>TCF7L2</it><it/>variant showed a statistically significant association between TCP and FCPD patients carrying the 26V allele (OR = 1.69, 95% CI = 1.11–2.56, P = 0.013).</p> <p>Conclusion</p> <p>Type 2 diabetes associated <it>TCF7L2 </it>variants are not associated with diabetes in TCP. Since, <it>TCF7L2 </it>is a major susceptibility gene for T2D, it may be hypothesized that the diabetes in TCP patients may not be similar to T2D. Our data also suggests that co-existence of <it>TCF7L2 </it>variants and the <it>SPINK1 </it>and <it>CTSB </it>mutations, that predict susceptibility to exocrine damage, may interact to determine the onset of diabetes in TCP patients.</p

Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (<it>PPARG2</it>; rs 1801282); insulin-like growth factor two binding protein 2 (<it>IGF2BP2</it>; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (<it>CDK5</it>; rs7754840); a zinc transporter and member of solute carrier family 30 (<it>SLC30A8</it>; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (<it>CDKN2A</it>; rs10811661); hematopoietically expressed homeobox (<it>HHEX</it>; rs 1111875); transcription factor-7-like 2 (<it>TCF7L2</it>; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(<it>KCNJ11</it>; rs 5219); and fat mass obesity-associated gene (<it>FTO</it>; rs 9939609)].</p> <p>Methods</p> <p>We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis.</p> <p>Results</p> <p>Four of the nine SNPs revealed a significant association with T2D; <it>PPARG2 </it>(Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03–0.52); p = 0.005], <it>IGF2BP2 </it>[OR 1.37; 95% CI (1.04–1.82); p = 0.027], <it>TCF7L2 </it>[OR 1.64; 95% CI (1.20–2.24); p = 0.001] and <it>FTO </it>[OR 1.46; 95% CI (1.11–1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of <it>CDK5 </it>(rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of <it>TCF7L2 </it>(rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort.</p> <p>Conclusion</p> <p>To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.</p

High fat diet modifies the association of lipoprotein lipase gene polymorphism with high density lipoprotein cholesterol in an Asian Indian population

Background Single nucleotide polymorphisms (SNPs) in lipoprotein lipase gene (LPL) have been shown to influence metabolism related to lipid phenotypes. Dietary factors have been shown to modify the association between LPL SNPs and lipids; however, to date, there are no studies in South Asians. Hence, we tested for the association of four common LPL SNPs with plasma lipids and examined the interactions between the SNPs and dietary factors on lipids in 1,845 Asian Indians. Methods The analysis was performed in 788 Type 2 diabetes cases and 1,057 controls randomly chosen from the cross-sectional Chennai Urban Rural Epidemiological Study. Serum triacylglycerol (TAG), serum total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured using a Hitachi-912 autoanalyzer (Roche Diagnostics GmbH, Mannheim, Germany). Dietary intake was assessed using a semi-quantitative food frequency questionnaire. The SNPs (rs1121923, rs328, rs4922115 and rs285) were genotyped by polymerase chain reaction followed by restriction enzyme digestion and 20% of samples were sequenced to validate the genotypes obtained. Statistical Package for Social Sciences for Windows version 22.0 (SPSS, Chicago, IL) was used for statistical analysis. Results After correction for multiple testing and adjusting for potential confounders, SNPs rs328 and rs285 showed association with HDL-C (P = 0.0004) and serum TAG (P = 1×10−5), respectively. The interaction between SNP rs1121923 and fat intake (energy %) on HDL-C (P = 0.003) was also significant, where, among those who consumed a high fat diet (28.4 ± 2.5%), the T allele carriers (TT + XT) had significantly higher HDL-C concentrations (P = 0.0002) and 30% reduced risk of low HDL-C levels compared to the CC homozygotes. None of the interactions on other lipid traits were statistically significant. Conclusion Our findings suggest that individuals carrying T allele of the SNP rs1121923 have increased HDL-C levels when consuming a high fat diet compared to CC homozygotes. Our finding warrants confirmation in prospective studies and randomized controlled trials

Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia

Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific

Interaction between FTO gene variants and lifestyle factors on metabolic traits in an Asian Indian population

Background Lifestyle factors such as diet and physical activity have been shown to modify the association between fat mass and obesity–associated (FTO) gene variants and metabolic traits in several populations; however, there are no gene-lifestyle interaction studies, to date, among Asian Indians living in India. In this study, we examined whether dietary factors and physical activity modified the association between two FTO single nucleotide polymorphisms (rs8050136 and rs11076023) (SNPs) and obesity traits and type 2 diabetes (T2D). Methods The study included 734 unrelated T2D and 884 normal glucose-tolerant (NGT) participants randomly selected from the urban component of the Chennai Urban Rural Epidemiology Study (CURES). Dietary intakes were assessed using a validated interviewer administered semi-quantitative food frequency questionnaire (FFQ). Physical activity was based upon the self-report. Interaction analyses were performed by including the interaction terms in the linear/logistic regression model. Results There was a significant interaction between SNP rs8050136 and carbohydrate intake (% energy) (Pinteraction = 0.04), where the ‘A’ allele carriers had 2.46 times increased risk of obesity than those with ‘CC’ genotype (P = 3.0 × 10−5) among individuals in the highest tertile of carbohydrate intake (% energy, 71 %). A significant interaction was also observed between SNP rs11076023 and dietary fibre intake (Pinteraction = 0.0008), where individuals with AA genotype who are in the 3rd tertile of dietary fibre intake had 1.62 cm lower waist circumference than those with ‘T’ allele carriers (P = 0.02). Furthermore, among those who were physically inactive, the ‘A’ allele carriers of the SNP rs8050136 had 1.89 times increased risk of obesity than those with ‘CC’ genotype (P = 4.0 × 10−5). Conclusions This is the first study to provide evidence for a gene-diet and gene-physical activity interaction on obesity and T2D in an Asian Indian population. Our findings suggest that the association between FTO SNPs and obesity might be influenced by carbohydrate and dietary fibre intake and physical inactivity. Further understanding of how FTO gene influences obesity and T2D through dietary and exercise interventions is warranted to advance the development of behavioral intervention and personalised lifestyle strategies, which could reduce the risk of metabolic diseases in this Asian Indian population