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.
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Acknowledgments. The authors thank the other investigators, the staff, and the participants of the studies for valuable contributions. Funding. This research was supported by the GUARDIAN Study DK-085175 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and from the following grants: HL-047887 (IRAS), HL-047889 (IRAS), HL-047890 (IRAS), HL-47902 (IRAS), HL-060944 (IRAS-FS), HL-061019 (IRAS-FS), HL-060919 (IRAS-FS), DK-061628 (BetaGene), American Diabetes Association Distinguished Clinical Scientist Award (BetaGene), HL-088457 (MACAD), HL-0697974 (HTN-IR), HL-055798 (NIDDM-Athero), and DK-079888 (work related to insulin clearance in HTN-IR, MACAD, and NIDDM-Athero). Research support for the Translation cohorts was provided by U10-EY-011753 (LALES), R01-EY-022651 (MAGGS, Mexican American Glaucoma Genetic Study), P30-EY-001792 (LALES), an unrestricted departmental grant from Research to Prevent Blindness (LALES), DK-073541 (Starr County Health Studies), DK-085501 (Starr County Health Studies), DK-020595 (Starr County Health Studies), HL-102830 (Starr County Health Studies), and Consejo Nacional de Ciencia y Tecnología grants 138826, 128877, and CONACyT-SALUD 2009-01-115250 (SIGMA Type 2 Diabetes Consortium, UNAM/INCMNSZ Diabetes Study). MESA was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by grants UL1-TR-000040 and UL1-RR-025005 from the National Center for Research Resources. Funding for MESA Family was provided by grants R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, and UL1-RR-025005. Funding for MESA SHARe (SNP Health Association Resource) genotyping was provided by National Heart, Lung, and Blood Institute contract N02-HL-6-4278. The provision of genotyping data was supported in part by UL1-TR-000124 (Clinical and Translational Science Institute) and DK-063491 (Diabetes Research Center). Computing resources were provided in part by the Wake Forest School of Medicine Center for Public Health Genomics. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. N.D.P. and M.O.G. contributed to the writing of the manuscript. C.D.L. contributed to the meta-analysis of the data and writing of the manuscript. N.W. contributed to the initial analysis in GUARDIAN and meta-analysis of the data. X.Gu., K.D.T., A.H.X., J.C., A.W.M., and Y.-D.I.C. contributed to the initial analysis in GUARDIAN. T.E.F., J.M.N., D.S., R.N.B., J.L.N., and F.K. contributed to the phenotyping. T.A.B., L.F.H., D.W.B., S.S.R., L.J.R., and J.I.R. contributed to the study design, management, and coordination of the project. T.H. contributed to the genotyping in GUARDIAN. J.T.Z. and A.H.W. contributed to the meta-analysis of the data. X.Ga., J.G., and R.V. contributed to the LALES coordination and data analysis. C.L.H., N.J.C., H.M.H., and J.E.B. contributed to the Starr County Health Studies coordination and data analysis. A.L.W., N.P.B., C.A.A.-S., A.H.-C., C.G.-V., L.O., and C.A.H. contributed to the SIGMA T2D Consortium coordination and data analysis. M.Y.T., W.C.J., J.Y., L.R.-T., and J.P. contributed to the MESA and MESA Family Studies coordination and data analysis. B.S., R.D.J., and S.L. contributed to the WHI coordination and data analysis. R.M.W. contributed to the study design, management, and coordination of the project; meta-analysis of the data; and writing of the manuscript. L.E.W. contributed to the study design, management, and coordination of the project and writing of the manuscript. All authors gave final approval of the manuscript. J.I.R., R.M.W., and L.E.W. are the guarantors of this work and, as such, had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the analysis.
This research was supported by the GUARDIAN Study DK-085175 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and from the following grants: HL-047887 (IRAS), HL-047889 (IRAS), HL-047890 (IRAS), HL-47902 (IRAS), HL-060944 (IRAS-FS), HL-061019 (IRASFS), HL-060919 (IRAS-FS), DK-061628 (BetaGene), American Diabetes Association Distinguished Clinical Scientist Award (BetaGene), HL-088457 (MACAD), HL-0697974 (HTN-IR), HL-055798 (NIDDM-Athero), and DK-079888 (work related to insulin clearance in HTN-IR, MACAD, and NIDDM-Athero)
© 2015 by the American Diabetes Association.