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Candidate gene analysis supports a role for polymorphisms at TCF7L2 as risk factors for type 2 diabetes in Sudan.

ABSTRACT: BACKGROUND:Genetic susceptibility to type 2 diabetes (T2D) is multifactorial. A growing number of genes have been identified as risk factors for T2D across multiple ethnicities in trans-ancestry meta-analysis of large-scale genome-wide association studies. Few studies have looked at these genes in Sub-Saharan African populations. This study was undertaken to look for associations between T2D and single nucleotide polymorphisms (SNPs) in a number of the top candidate genes in a selected Sudanese population. METHODS:A total 240 T2D cases and 128 unrelated healthy control subjects were included in this study. Age, sex, weight and height were recorded, blood pressure and biochemical profiles of glucose and lipids were analysed. Single nucleotide polymorphism (SNP) genotyping was performed using the Sequenom MassARRAY® system. Fourteen SNPs were selected across 7 genes: CAPN10 (rs2975760 and rs5030952), PPARG (rs17036314 and rs1801282), IGF2BP2 (rs4402960 and rs1470579), CDKAL1 (rs9465871), HHEX (rs1111875), TCF7L2 (rs7903146, rs11196205 and rs12255372), and KCNJ11 (rs5215, rs1800467 and rs5219). Allelic and haplotype association analyses were performed under additive models in PLINK. P???0.007 (=0.05/7 genes) was the P-value required to achieve correction for multiple testing. RESULTS:A significant genetic association between the SNPs rs7903146 (odds ratio 1.69, 95 % confidence interval 1.21-2.38, P?=?0.002) and rs12255372 (odds ratio 1.70, 95 % confidence interval 1.20-2.41, P?=?0.003) at TCF7L2 and T2D was found in Sudanese population. These associations were retained after adjusting for age, sex and BMI (e.g. rs7903146: odds ratio 1.70, P adj:age/sex/BMI?=?0.005). The strongest haplotype association (odds ratio 2.24; P adj:age/sex/BMI?=?0.0003) comprised the two point haplotype T_C across rs7903146 and rs11196205. Stepwise logistic regression demonstrated that SNP rs7903146 added significant main effects to rs11196205 or rs12255372, whereas the reverse was not true, indicating that the main effect for association with T2D in this population is most strongly tagged by SNP rs7903146. Adjusted analyses also provided support for protection from T2D associated with minor alleles at SNPs rs2975760 at CAPN10 (odds ratio 0.44, 95 % confidence interval 0.20-0.97, P adj:age/sex/BMI?=?0.042) and rs1111876 at HHEX (odds ratio 0.60, 95 % confidence interval 0.39- 0.93, P adj:age/sex/BMI?=?0.022). CONCLUSIONS:Multiethnic associations between T2D and SNPs at TCF7L2, CAPN10 and HHEX extend to Sub-Saharan Africa, specifically Sudan.

SUBMITTER: Ibrahim AT

PROVIDER: S-EPMC4774008 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Candidate gene analysis supports a role for polymorphisms at TCF7L2 as risk factors for type 2 diabetes in Sudan.

Ibrahim Amir T AT Hussain Ayman A Salih Mohamed A M MA Ibrahim Omima Abdeen OA Jamieson Sarra E SE Ibrahim Muntaser E ME Blackwell Jenefer M JM Mohamed Hiba S HS

Journal of diabetes and metabolic disorders 20150101

<h4>Background</h4>Genetic susceptibility to type 2 diabetes (T2D) is multifactorial. A growing number of genes have been identified as risk factors for T2D across multiple ethnicities in trans-ancestry meta-analysis of large-scale genome-wide association studies. Few studies have looked at these genes in Sub-Saharan African populations. This study was undertaken to look for associations between T2D and single nucleotide polymorphisms (SNPs) in a number of the top candidate genes in a selected S ...[more]

PMID: 26937418

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Project description:Aims/hypothesisThe T allele of transcription factor 7-like 2 gene variant, TCF7L2 rs7903146, increases the risk of type 2 diabetes by 40-50%. As TCF7L2 rs7903146 has been associated with diminished incretin effect we investigated whether interaction between dietary intake of carbohydrate, fat, protein or fibre and this variant affects the risk of type 2 diabetes.MethodsA cohort of 24,799 non-diabetic individuals from the Malmö Diet and Cancer Study (MDCS), with dietary data obtained by a modified diet history method, were followed up for 12 years, with 1,649 recordings of incident type 2 diabetes made. Risk of type 2 diabetes in strata of diet quintiles was analysed prospectively adjusting for potential confounders. Cross-sectional analyses were performed on baseline fasting glucose and HbA(1c) levels in a subset of 5,216 randomly selected individuals from the MDCS.ResultsThe elevated risk of type 2 diabetes with rs7903146 (OR 1.44, 95% CI 1.33, 1.56, p = 4.6 × 10(-19)) increased with higher intake of dietary fibre (OR 1.24, 95% CI 1.04, 1.47 to OR 1.56, 95% CI 1.31, 1.86 from the lowest to highest quintile; p (interaction) = 0.049). High intake of dietary fibre was inversely associated with diabetes incidence only among CC genotype carriers (OR 0.74, 95% CI 0.58, 0.94 per quintile, p = 0.025). The T allele was associated with 0.027% elevated HbA(1c) (p = 0.02) and this effect increased with higher intake of fibre (from -0.021% to 0.079% for the lowest to the highest quintile, p (interaction) = 0.02). Each quintile of higher fibre intake was associated with lower HbA(1c) levels among CC and CT but not among TT genotype carriers (-0.036%, p = 6.5 × 10(-7); -0.023%, p = 0.009; and 0.012%, p = 0.52, respectively).Conclusions/interpretationOur study suggests that dietary fibre intake may modify the association between TCF7L2 rs7903146 and incidence of type 2 diabetes, and that higher fibre intake may associate with protection from type 2 diabetes only among non-risk allele carriers.

Project description:BACKGROUND: Associations between transcription factor 7-like 2 (TCF7L2) polymorphisms and type 2 diabetes mellitus (T2DM) have been evaluated extensively in multiple ethnic groups. TCF7L2 has emerged as the strongest T2DM susceptibility gene in Europeans, but the findings have been inconsistent in the Chinese population. The purpose of this meta-analysis was to evaluate the associations between TCF7L2 single nucleotide polymorphisms (SNPs) and T2DM risk in the Chinese population. METHODS: We performed searches in the PubMed, EMBASE, Cochrane, and Chinese databases (CNKI, CQVIP and Wanfang databases) for literature published from January 2007 to February 2012. We reviewed all relevant articles on TCF7L2 polymorphisms and susceptibility to T2DM in the Chinese population written in English and Chinese. Two reviewers extracted data independently using a standardized protocol, and any discrepancies were adjudicated by a third reviewer. Fixed-effects and random-effects meta-analyses were performed to pool the odds ratios (ORs). Publication bias and heterogeneity were examined. RESULTS: A total of 21 articles were confirmed to be eligible for and included in this meta-analysis: 7 (with 3942 cases and 3502 controls) concerning rs11196218 (IVS-/+4G>A), 8 (with 3377 cases and 2975 controls) concerning rs290487 (IVS3-/+C>T), and 14 (with 7902 cases and 7436 controls) concerning rs7903146 (IVS3-/+C>T). Overall, the results showed a significant association between rs7903146 and T2DM risk. The pooled ORs were 1.54 for the comparison of T and C alleles (95% CI [confidence interval]: 1.37-1.74, p = 1.47 × 10-12, I2 = 25.20%) and 1.56 for TC heterozygotes and CC homozygotes (95% CI : 1.38-1.76, p = 8.25 × 10-9, I2 = 21.00%). The rs11196218(IVS4G>A) and rs290487 (IVS3C>T) SNPs were not associated with T2DM risk. CONCLUSIONS: The rs7903146 SNP of the TCF7L2 gene is associated with increased susceptibility to T2DM in the Chinese population as a whole as well as northern Chinese and southern Chinese as subgroups.

Project description:Several studies have shown that genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) are highly associated with the development of type 2 diabetes mellitus (T2DM) and its associated complications in several populations. The aim of our study was to investigate the association of the rs7903146 (C/T) and rs12255372 (G/T) polymorphism in the TCF7L2 gene with the risk of developing T2DM in the Moroccan population. A total of 150 T2DM patients and 100 healthy controls were recruited for various anthropometric, biochemical and genetic parameters. Genotyping was performed by using Real Time-PCR. The frequency of genotypes, alleles, anthropometric measures, glycemia, glycated hemoglobin (HbA1c) were evaluated in patients and control, while lipid profile was available only for T2DM group. Glycemia, HbA1c and body mass index (BMI) were significantly higher in T2DM group than control. Analysis of the distribution of the TCF7L2 rs7903146 genotype and allele revealed that the TT genotype was more frequent in T2DM group (24.0%) than in healthy controls (5%) (OR = 4.08, 95% confidence interval (CI = 1.95-11.80, p < 0.0001). The T allele was more frequent in diabetic patients (45.2%) than healthy control (34.5%) and it was associated with high risk of diabetes (OR = 2.13, 95% CI = 1.12-7.31, p = 0.005). The same results were found regarding rs12255372, TT genotype frequencies were 18,7% and 6.0% in T2DM and control group, respectively (OR = 3.11, 95% CI = 1.33-7.24, p = 0.004). The T allele was over-presented in diabetics compared to controls (45.3% and 38.0%, respectively) and increases the risk of T2DM (OR = 2.01, 95% CI = 1.04-3.10, p = 0.01). However, there was no significant difference between the three genotypes of rs7903146 and rs12255372 regarding age, BMI, glycemia, HbA1c and lipid profile. The present study confirmed a significant association of the TCF7L2 gene (rs7903146 (C/T) and rs12255372 (G/T) polymorphisms with a higher risk to T2DM in the Moroccan population. No significant difference in respect to anthropometric and metabolic parameters between different genotypes.

Project description:BackgroundThe emerging renal and cardiovascular complications of type 2 diabetes (T2DM) genetics involves differently assembled gene variants including transcription factor 7-like 2 (TCF7L2) and peroxisome proliferator-activated receptor gamma 2 (PPARG2) polymorphisms. However, the relevance of these genes for complication prediction has not been extensively tested.MethodsWe analyzed the SNP rs7903146 variants in TCF7L2 and PPARG2 gene polymorphisms for their contribution to the incidence of chronic kidney disease (CKD) and cardiovascular complications in a prospective cohort study. All T2DM patients were followed up to estimate the glomerular filtration rate and cardiovascular outcomes. Cox proportional hazards regression models were used to estimate the genotype effect on the incidence of CKD and vascular complications.ResultsA total of 422 patients were included. SNP rs7903146 variants in the TCF7L2 gene were classified into 3 groups: CC, 385 patients (91.2%), CT, 32 patients (7.6%), and TT, 5 patients (1.2%), while in the PPARG2 gene they were classified into 2 groups: Pro12Pro, 404 patients (95.7%) and Pro12Ala, 18 patients (4.3%). The prevalence of CKD, cardiovascular disease, and death at the end of the 5-year follow-up was 16.8, 29, and 7.9%, respectively. The Pro12Ala variant of the PPARG2 gene was significantly associated with increased CKD risk at the end of the study (adjusted HR 3.45, 95% CI 1.01-11.77, p = 0.046); it showed a significant association with increased cerebrovascular risk, but not cardiovascular disease and mortality. No genotype effect of rs7903146 in the TCF7L2 gene was apparent on renal and cardiovascular complications, except the TT variant of rs7903146 increased cardiovascular events when compared with the non-TT variant.ConclusionThe findings of our study were that the Pro12Ala variant in the PPARG2 gene was associated with risk of developing CKD and cerebrovascular disease in Asian T2DM subjects in a prospective cohort study. The TCF7L2 polymorphism was not associated with cardiovascular outcomes.

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Candidate gene analysis supports a role for polymorphisms at TCF7L2 as risk factors for type 2 diabetes in Sudan.

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Candidate gene analysis supports a role for polymorphisms at TCF7L2 as risk factors for type 2 diabetes in Sudan.

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