Genetic variants associated with quantitative glucose homeostasis traits translate to type 2 diabetes in Mexican Americans: The GUARDIAN (Genetics underlying diabetes in Hispanics) consortium

Nicholette D. Palmer, Mark O. Goodarzi, Carl D. Langefeld, Nan Wang, Xiuqing Guo, Kent D. Taylor, Tasha E. Fingerlin, Jill M. Norris, Thomas A. Buchanan, Anny H. Xiang, Talin Haritunians, Julie T. Ziegler, Adrienne H. Williams, Darko Stefanovski, Jinrui Cui, Adrienne W. Mackay, Leora F. Henkin, Richard N. Bergman, Xiaoyi Gao, James GaudermanRohit Varma, Craig L. Hanis, Nancy J. Cox, Heather M. Highland, Jennifer E. Below, Amy L. Williams, Noel P. Burtt, Carlos A. Aguilar-Salinas, Alicia Huerta-Chagoya, Clicerio Gonzalez-Villalpando, Lorena Orozco, Christopher A. Haiman, Michael Y. Tsai, W. Craig Johnson, Jie Yao, Laura Rasmussen-Torvik, James Pankow, Beverly Snively, Rebecca D. Jackson, Simin Liu, Jerry L. Nadler, Fouad Kandeel, Yii Der I Chen, Donald W. Bowden, Stephen S. Rich, Leslie J. Raffel, Jerome I. Rotter, Richard M. Watanabe, Lynne E. Wagenknecht

Research output: Contribution to journalArticle

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Abstract

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 3 1028) 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.

Original languageEnglish (US)
Pages (from-to)1853-1866
Number of pages14
JournalDiabetes
Volume64
Issue number5
DOIs
StatePublished - May 2015

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    Palmer, N. D., Goodarzi, M. O., Langefeld, C. D., Wang, N., Guo, X., Taylor, K. D., Fingerlin, T. E., Norris, J. M., Buchanan, T. A., Xiang, A. H., Haritunians, T., Ziegler, J. T., Williams, A. H., Stefanovski, D., Cui, J., Mackay, A. W., Henkin, L. F., Bergman, R. N., Gao, X., ... Wagenknecht, L. E. (2015). Genetic variants associated with quantitative glucose homeostasis traits translate to type 2 diabetes in Mexican Americans: The GUARDIAN (Genetics underlying diabetes in Hispanics) consortium. Diabetes, 64(5), 1853-1866. https://doi.org/10.2337/db14-0732