Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies
Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies
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DOI：
10.1007/s00592-008-0080-5
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发表时间：
2009-09-01
影响因子：
3.8
通讯作者：
Perusse, Louis
中科院分区：
文献类型：
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作者：
Ruchat, Stephanie-May;Elks, Cathy E.;Perusse, Louis
全基因组关联研究 (GWAS) 已鉴定出几种与 2 型糖尿病 (T2DM) 风险相关的单核苷酸多态性 (SNP)。本研究的目的是调查这些 SNP 对 T2DM 中间表型的影响，以阐明它们对疾病病因发挥作用的生理机制。我们分析了魁北克家庭研究中最多 712 名男性和女性的 9 个 T2DM 基因（CDKAL1、CDKN2B、HHEX/IDE、IGF2BP2、KCNJ11、SLC30A8、TCF2、TCF7L2 和 WFS1）中的 23 个 SNP。参与者接受了 75 克口服葡萄糖耐量试验 (OGTT)，并测量了葡萄糖、胰岛素和 C 肽水平。胰岛素敏感性和胰岛素分泌指数源自禁食和 OGTT 测量。我们证实了 CDKAL1、CDKN2B、HHEX/IDE、KCNJ11 和 TCF7L2 中的变异与胰岛素分泌的显着关联，并且还发现其中一些变异与胰岛素敏感性和葡萄糖耐量的关联。 IGF2BP2 和 SLC30A8 SNP 与胰岛素分泌无关，但与胰岛素敏感性和葡萄糖耐量相关（0.002 千分之一货币符号 P 千分之一货币符号 0.02）。为了检查这些变异的联合效应及其对 T2DM 内表型方差的贡献，使用逐步回归模型并计算模型 R (2)。由变异组合解释的表型变异范围为 2.0% 至 8.5%。 CDKAL1、CDKN2B、HHEX/IDE、IGF2BP2、KCNJ11、SLC30A8 和 TCF7L2 中与糖尿病相关的变异与导致 T2DM 的生理改变相关，例如葡萄糖不耐受、胰岛素分泌受损或胰岛素抵抗，支持它们在疾病病因学中的作用。这些变异被发现占 T2DM 相关性状变异的 2.0-8.5%。
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 a parts per thousand currency sign P a parts per thousand currency sign 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.