Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans

Context: Genetic variation at the transcription factor 7-like 2 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: This study was the 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-American 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 iv glucose tolerance test and include insulin sensitivity, acute insulin response, and disposition index. Results: In Hispanic-Americans, significant evidence of association was observed between single nucleotide polymorphisms rs7903146 and rs112255372 with reduced insulin secretion as measured by acute insulin response 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 single nucleotide polymorphisms examined. In African-Americans there was no evidence of association observed. Conclusions: These results suggest that transcription factor 7-like 2 variants could play a role in the pathogenesis of type 2 diabetes in the Hispanic-American population through a mechanism involving insulin secretion.