Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study
Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study
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DOI：
10.2337/db07-1169
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发表时间：
2008-04-01
期刊：
影响因子：
7.7
通讯作者：
Bowden, Donald W.
中科院分区：
文献类型：
--
作者：
Palmer, Nicholette D.;Goodarzi, Mark O.;Bowden, Donald W.
目的：评估胰岛素抵抗动脉粥样硬化家族研究(IRAS-FS)中西班牙裔美国人和非洲裔美国人全基因组关联研究中发现的2型糖尿病易感变异与血糖稳态的定量测量之间的关联，并确定它们在活体中的生物学作用。研究设计和方法-来自IRAS-FS的17个2型糖尿病相关单核苷酸多态(SNPs)在1,268名西班牙裔和581名非洲裔美国人参与者中进行了基因分型。结果：在拉美裔美国人中，细胞周期蛋白依赖性蛋白5调节亚基相关蛋白I亚基I(CDKAL1)的风险变异与空气质量降低(P<；0.0046)相关。此外，在拉美裔美国人中，假设基因(11号染色体；LOC387761)的变异与空气显著相关(P=0.0046)，风险等位基因显示保护作用，即增加空气。在西班牙裔和非裔美国人群体中，溶质携带者家族30，成员8(SLC30A8)基因座的风险变异名义上与倾向指数降低相关(P<；0.078)。在拉美裔美国人中，胰岛素样生长因子2mR NA结合蛋白2(IGF2BP2)基因的风险变异与倾向指数降低有关(P=0.011)。结论--这些数据表明，与糖尿病相关的基因数量明显有限，更具体地说，在欧洲人群中发现的基因中的SNPs，与拉美裔美国人和非裔美国人的血糖稳态特征相关的证据不多。我们观察到有证据表明CDKAL1、SLC30A8、IGF2BP2和LOC387761的糖尿病风险是通过胰岛素分泌缺陷特异性地调节的。其他易感基因的作用机制尚待阐明。
OBJECTIVE-Evaluate type 2 diabetes susceptibility variants identified from genome-wide association studies in Hispanic Americans and African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) for association with quantitative measures of glucose homeostasis and determine their biological role in vivo.RESEARCH DESIGN AND METHODS-Seventeen type 2 diabetes-associated single nucleotide polymorphisms (SNPs) were genotyped in 1,268 Hispanic- and 581 African-American participants from the IRAS-FS. SNPs were tested for association with quantitative measures of glucose homeostasis, including insulin sensitivity index (S,), acute insulin response (AIR), and disposition index.RESULTS-Previously identified risk variants in cyclin-dependent kinase 5 regulatory subunit associated protein I-like I (CDKAL1) were associated with reduced AIR (P < 0.0046) in Hispanic Americans. Additionally in Hispanic Americans, the variant in a hypothetical gene (chromosome 11; LOC387761) was significantly associated with AIR (P = 0.0046) with the risk allele showing protective effects, i.e., increased AIR. In both Hispanic- and African-American populations, risk variants at the solute carrier family 30, member 8 (SLC30A8) locus were nominally associated with decreased disposition index (P < 0.078). Risk variants in the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) locus were associated with a decreased disposition index (P = 0.011) exclusively in Hispanic Americans.CONCLUSIONS-These data indicate a distinct, limited number of diabetes-related genes, more specifically the SNPs in the genes identified in European-derived populations, with modest evidence for association with glucose homeostasis traits in Hispanic Americans and African Americans. We observe evidence that diabetes risk for CDKAL1, SLC30A8, IGF2BP2, and LOC387761 is specifically mediated through defects in insulin secretion. The mechanisms of other predisposing genes remain to be elucidated.