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

Journal of Clinical Endocrinology and Metabolism

CONTEXT
Peroxisome proliferator-activated receptor- (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 promoter region, 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 5 PPARG promoter variants.