TY - JOUR
T1 - Genetic variants associated with quantitative glucose homeostasis traits translate to type 2 diabetes in Mexican Americans
T2 - The GUARDIAN (Genetics underlying diabetes in Hispanics) consortium
AU - Palmer, Nicholette D.
AU - Goodarzi, Mark O.
AU - Langefeld, Carl D.
AU - Wang, Nan
AU - Guo, Xiuqing
AU - Taylor, Kent D.
AU - Fingerlin, Tasha E.
AU - Norris, Jill M.
AU - Buchanan, Thomas A.
AU - Xiang, Anny H.
AU - Haritunians, Talin
AU - Ziegler, Julie T.
AU - Williams, Adrienne H.
AU - Stefanovski, Darko
AU - Cui, Jinrui
AU - Mackay, Adrienne W.
AU - Henkin, Leora F.
AU - Bergman, Richard N.
AU - Gao, Xiaoyi
AU - Gauderman, James
AU - Varma, Rohit
AU - Hanis, Craig L.
AU - Cox, Nancy J.
AU - Highland, Heather M.
AU - Below, Jennifer E.
AU - Williams, Amy L.
AU - Burtt, Noel P.
AU - Aguilar-Salinas, Carlos A.
AU - Huerta-Chagoya, Alicia
AU - Gonzalez-Villalpando, Clicerio
AU - Orozco, Lorena
AU - Haiman, Christopher A.
AU - Tsai, Michael Y.
AU - Johnson, W. Craig
AU - Yao, Jie
AU - Rasmussen-Torvik, Laura
AU - Pankow, James
AU - Snively, Beverly
AU - Jackson, Rebecca D.
AU - Liu, Simin
AU - Nadler, Jerry L.
AU - Kandeel, Fouad
AU - Chen, Yii Der I
AU - Bowden, Donald W.
AU - Rich, Stephen S.
AU - Raffel, Leslie J.
AU - Rotter, Jerome I.
AU - Watanabe, Richard M.
AU - Wagenknecht, Lynne E.
N1 - Publisher Copyright:
© 2015 by the American Diabetes Association.
PY - 2015/5
Y1 - 2015/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84969321555
UR - https://www.scopus.com/pages/publications/84969321555#tab=citedBy
U2 - 10.2337/db14-0732
DO - 10.2337/db14-0732
M3 - Article
C2 - 25524916
AN - SCOPUS:84969321555
SN - 0012-1797
VL - 64
SP - 1853
EP - 1866
JO - Diabetes
JF - Diabetes
IS - 5
ER -
