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This version published online on October 30, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-1225
A more recent version of this article appeared on January 1, 2008
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Submitted on June 1, 2007
Accepted on October 24, 2007

Association of TCF7L2 Gene Polymorphisms with Reduced Acute Insulin Response in Hispanic Americans

Nicholette D. Palmer Ph.D., Allison B. Lehtinen Ph.D., Carl D. Langefeld Ph.D., Joel K. Campbell M.S., Steven M. Haffner M.D., Jill M. Norris Ph.D., Richard Bergman Ph.D., Mark O. Goodarzi Ph.D., Jerome I. Rotter M.D., and Donald W. Bowden Ph.D.*

Department of Biochemistry, Department of Internal Medicine, Department of Public Health Sciences, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA

* To whom correspondence should be addressed. E-mail: dbowden{at}wfubmc.edu.

Context: Genetic variation at the transcription factor 7-like 2 (TCF7L2) locus has been linked to type 2 diabetes in predominantly European-derived populations. The biological basis of these associations remains to be determined.

Objective: The objective of this study was to evaluate previously associated variants for association with measures of glucose homeostasis in Hispanic Americans and African Americans and determine the biological mechanism(s) through which these variants exert their effect.

Design: Insulin Resistance Atherosclerosis Family Study (IRAS-FS).

Setting: The IRAS-FS is a community based study of Hispanic Americans (San Antonio, TX, and San Luis Valley, CO) and African Americans (Los Angeles, CA).

Participants: A total of 1040 Hispanic Americans and 500 African American individuals from the IRAS-FS formed the basis of this study.

Main Outcomes Measures(s): The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled intravenous glucose tolerance test (FSIGT) and include: insulin sensitivity (SI), acute insulin response (AIR) and disposition index (DI).

Results: In Hispanic Americans, significant evidence of association was observed between SNPs rs7903146 and rs112255372 with reduced insulin secretion as measured by AIR and adjusted for the degree of insulin sensitivity (P = 0.032 and 0.036, respectively). Other quantitative measures, e.g. insulin sensitivity or disposition index, were not associated with the SNPs examined. In African Americans there was no evidence of association observed.

Conclusions: These results suggest that TCF7L2 variants could play a role in the pathogenesis of type 2 diabetes in the Hispanic-American population through a mechanism involving insulin secretion.






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