Common Genetic Variants in Peroxisome Proliferator-Activated Receptor-γ (PPARG) and Type 2 Diabetes Risk Among Women's Health Initiative Postmenopausal Women

Context: Peroxisome proliferator-activated receptor-gamma (PPARG) plays a pivotal role in adipogenesis and glucose homeostasis. Objective: We investigated whether PPARG gene variants were associated with type 2 diabetes (T2D) risk in the multiethnic Women's Health Initiative (WHI). Research Design and Methods: We assessed PPARG single-nucleotide polymorphisms (SNPs) in a case-control study nested in the prospective WHI observational study (WHI-OS) (1543 T2D cases and 2170 matched controls). After identifying 24 tagSNPs, we used multivariable logistic regression models and haplotype-based analyses to estimate these tagSNP-T2D associations. Single-SNP analyses were also conducted in another study of 5642 African American and Hispanic American women in the WHI SNP Health Association Resource (WHI-SHARe). Results: We found a borderline significant association between the Pro12Ala (rs1801282) variant and T2D risk in WHI-OS [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.31-0.83, P = .01, combined group, additive model; P = .04, Hispanic American] and WHI-SHARe (OR 0.25,95% CI 0.08-0.77, P = .02, Hispanic American) participants. In promoterregion, rs6809631, rs9817428, rs10510411, rs12629293, and rs12636454 were also associated with T2D risk(range ORs 0.68-0.78,95% CIs 0.52-0.91 to 0.60-1.00, P = .05) in WHI-OS, in which rs9817428 was replicated in then WHI-SHARe Hispanic American group (P = .04). Conclusions: The association between PPARG Pro12Ala SNP and increased T2D susceptibility was confirmed, with Pro12 as risk allele. Additional significant loci included 5PPARG promoter variants. (J Clin Endocrinol Metab 98: E600-E604, 2013)