Haplotypes of Transcription Factor 7–Like 2 (TCF7L2) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans

Haplotypes of Transcription Factor 7–Like 2 ( TCF7L2 ) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans Donna M. Lehman 1 , Kelly J. Hunt 2 , Robin J. Leach 3 , Jeanette Hamlington 1 , Rector Arya 1 , Hanna E. Abboud 4 , Ravindranath Duggirala 5 , John Blangero 5 , Harald H.H. Göring 5 and Michael P. Stern 1 1 Department of Medicine, Clinical Epidemiology Division, University of Texas Health Science Center, San Antonio, Texas 2 Department of Biostatistics, Bioinformatics & Epidemiology, Medical University of South Carolina, Charleston, South Carolina 3 Departments of Cellular and Structural Biology and Pediatrics, University of Texas Health Science Center, San Antonio, Texas 4 Department of Medicine, Nephrology Division, University of Texas Health Science Center, San Antonio, Texas 5 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas Address correspondence and reprint requests to Donna M. Lehman, Department of Medicine/Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, Texas 78229. E-mail: lehman{at}uthscsa.edu Abstract TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2 . We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels ( P = 0.001–0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis ( P = 4.2 × 10 −5 , relative risk [RR] 0.69; P = 6.7 × 10 −6 , respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 ( P = 0.02, RR 1.64). These data provide evidence that vari