Evidence for Association between Measures of Insulin Secretion and Insulin Sensitivity and Type 2 Diabetes Susceptibility Variants Identified through Genome-Wide Association Studies

Department of Preventive Medicine, Laval University, Quebec City, QC, Canada.
Acta Diabetologica (Impact Factor: 2.4). 12/2008; 46(3):217-26. DOI: 10.1007/s00592-008-0080-5
Source: PubMed


Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 <or= P <or= 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R (2) was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0-8.5% of the variance of T2DM-related traits.

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Available from: Stephanie-May Ruchat, Nov 06, 2015
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    • "IGF2BP2 is encoded by the IGF2BP2 gene which is located on chromosome 3q27. Its strong association with β cell function is established by regulating IGF2 post-translation [4]. Several variants of the IGF2BP2 gene were investigated for relationship with T2DM, of which rs4402960 was the most extensively studied. "
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    ABSTRACT: Background The objective of this study was to systematically evaluate the contribution of the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to type 2 diabetes mellitus (T2DM) and its interaction with obesity to T2DM susceptibility. Methods To clarify whether IGF2BP2 is an independent risk factor for T2DM in Chinese population, we conducted a study with a total of 2,301 Chinese Han subjects, including 1,166 T2DM patients and 1,135 controls, for the genotype of a most common and widely studied polymorphism—rs4402960 of IGF2BP2. Genotyping was performed by iPLEX technology. Gene and environment interaction analysis was performed by using multiple logistic regression models. Results The repeatedly confirmed association between IGF2BP2 (rs4402960) and T2DM had not been replicated in this cohort (P = 0.182). Interestingly, we found that obese subjects (body mass index (BMI) ≥ 28.0 kg/m2) bearing the minor A allele had an increased risk to develop T2DM (P = 0.008 for allele analysis and P < 0.001 for genotype analysis). Conclusions The present study provided data suggesting that the wild C allele of IGF2BP2 (rs4402960) had a protective effect against T2DM in obese subjects of Chinese Han population.
    Full-text · Article · Jul 2014 · European journal of medical research
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    • "Genome-wide studies identify diabetes susceptibility loci on chromosomes 3q27 and 10q25.3, where adiponectin genes (ADIPOQ or APM1) and TCF7L2 are located, respectively [3]. Human adiponectin, encoded by ADIPOQ gene, is an adipose-specific secretory protein involved in many metabolic processes: for example, glucose modulation and fatty acid oxidation [4]. "
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    ABSTRACT: Diabetes is a serious global health problem. Large-scale genome-wide association studies identified loci for type 2 diabetes mellitus (T2DM), including adiponectin (ADIPOQ) gene and transcription factor 7-like 2 (TCF7L2), but few studies clarified the effect of genetic polymorphisms of ADIPOQ and TCF7L2 on risk of T2DM. We attempted to elucidate association between T2DM and polymorphic variations of both in Taiwan's Chinese Han population, with our retrospective case-control study genotyping single nucleotide polymorphisms (SNPs) in ADIPOQ and TCF7L2 genes both in 149 T2DM patients and in 139 healthy controls from Taiwan. Statistical analysis gauged association of these polymorphisms with risk of T2DM to show ADIPOQ rs1501299 polymorphism variations strongly correlated with T2DM risk (P = 0.042), with rs2241766 polymorphism being not associated with T2DM (P = 0.967). However, both polymorphisms rs7903146 and rs12255372 of TCF7L2 were rarely detected in Taiwanese people. This study avers that ADIPOQ rs1501299 polymorphism contributes to risk of T2DM in the Taiwanese population.
    Full-text · Article · Jul 2014
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    • "The CDKAL1 gene is one of the most reproducible risk genes for diabetes across different ethnic populations (Dehwah et al. 2010). Variations in this gene have been associated with impaired insulin secretion and increased risk of diabetes (Groenewoud et al. 2008; Ruchat et al. 2009). The molecular function of CDKAL1 is unknown, but recently, Wei et al. (2011) reported that CDKAL1 is a unique enzyme that catalyzes the ms2t6A modification in tRNALys (UUU) in mammalian cells, and the functional loss of CDKAL1 affects the accuracy of protein translation, causing the synthesis of abnormal insulin, which triggers endoplasmic reticulum stress in b-cells. "
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    ABSTRACT: Associations with type 2 diabetes mellitus have been identified for variants CDKAL1 rs7756992, KCNJ11 rs5219, and IGF2BP2 rs4402960 in different populations. In a case-control study of 250 unrelated Moroccan diabetic patients and 250 healthy controls, we used TaqMan allelic discrimination assays to genotype the three SNPs and meta-analysis to investigate the association between the polymorphisms and diabetes in Arab populations. The results showed a significant diabetes association only with the variant rs4402960 of the IGF2BP2 gene under additive 2 (GG vs. TT; p = 0.009) and recessive (TT vs. GG+GT; p = 0.003) models. Meta-analysis indicated significant association between the IGF2BP2 rs4402960 and CDKAL1 rs7756992 polymorphisms and increased risk of diabetes in Arab populations. According to our results, the case-control study and meta-analysis revealed a significant association between the IGF2BP2 rs4402960 variant and type 2 diabetes in Moroccan and Arab populations.
    Full-text · Article · Jun 2014 · Biochemical Genetics
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