与定量葡萄糖稳态性状相关的基因变异在墨西哥裔美国人中转化为2型糖尿病：GUARDIAN（西班牙裔糖尿病遗传学）联盟。
Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.
作者信息
Palmer Nicholette D, Goodarzi Mark O, Langefeld Carl D, Wang Nan, Guo Xiuqing, Taylor Kent D, Fingerlin Tasha E, Norris Jill M, Buchanan Thomas A, Xiang Anny H, Haritunians Talin, Ziegler Julie T, Williams Adrienne H, Stefanovski Darko, Cui Jinrui, Mackay Adrienne W, Henkin Leora F, Bergman Richard N, Gao Xiaoyi, Gauderman James, Varma Rohit, Hanis Craig L, Cox Nancy J, Highland Heather M, Below Jennifer E, Williams Amy L, Burtt Noel P, Aguilar-Salinas Carlos A, Huerta-Chagoya Alicia, Gonzalez-Villalpando Clicerio, Orozco Lorena, Haiman Christopher A, Tsai Michael Y, Johnson W Craig, Yao Jie, Rasmussen-Torvik Laura, Pankow James, Snively Beverly, Jackson Rebecca D, Liu Simin, Nadler Jerry L, Kandeel Fouad, Chen Yii-Der I, Bowden Donald W, Rich Stephen S, Raffel Leslie J, Rotter Jerome I, Watanabe Richard M, Wagenknecht Lynne E
机构信息
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
出版信息
Diabetes. 2015 May;64(5):1853-66. doi: 10.2337/db14-0732. Epub 2014 Dec 18.
Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.
胰岛素敏感性、胰岛素分泌、胰岛素清除率和葡萄糖效能均表现出很强的遗传成分，尽管很少有研究探讨它们的遗传结构或对2型糖尿病（T2D）风险的影响。我们推测，影响这些数量性状变异的基因座会影响T2D。我们完成了一项多队列全基因组关联研究，以在4176名墨西哥裔美国人中寻找影响T2D相关数量性状的基因座。数量性状通过频繁采样静脉葡萄糖耐量试验（四个队列）或正常血糖钳夹试验（三个队列）进行测量，并使用随机效应模型来检验基因座与数量性状之间的关联，同时对年龄、性别和混合比例进行校正（发现阶段）。分析显示，11q14.3（MTNR1B）与急性胰岛素反应存在显著关联（P < 5.00×10⁻⁸）。在6463例T2D病例和9232例墨西哥裔对照受试者中，对数量性状中P < 0.0001的基因座进行了向T2D风险的转化研究（转化阶段）。对发现阶段和转化阶段队列进行的非参数荟萃分析确定，6p24（SLC35B3/TFAP2A）与葡萄糖效能/T2D、11p15（KCNQ1）与处置指数/T2D、6p22（CDKAL1）和11q14（MTNR1B）与急性胰岛素反应/T2D存在显著关联。这些结果表明，T2D与胰岛素分泌及敏感性既有共同的遗传因素，也有不同的遗传因素，这可能描绘了驱动T2D风险的这些数量性状的基因组成分。
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