Genetic Variants in Peroxisome Proliferator-Activated Receptor-γ and Retinoid X Receptor-α Gene and Type 2 Diabetes Risk: A Case-Control Study of a Chinese Han Population

Background: The serum levels of adiponectin are paradoxically decreased in obesity and may play important roles in the development of type 2 diabetes mellitus (T2DM). Potentially functional polymorphisms in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha) genes may alter T2DM risks by increasing the human adiponectin promoter activity in cells. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in PPAR-gamma and RXR-alpha were associated with risk of T2DM. To test this hypothesis, three potentially functional SNPs of PPAR-gamma and four of RXR-alpha with a minor allele frequency of >= 0.05 in the Chinese Han population were identified from the National Center for Biotechnology Information dbSNPs database to evaluate their association with T2DM. Methods: Polymerase chain reaction-restriction fragment length polymorphism was performed to test the genotypes in T2DM patients (n = 540) and normal controls (n = 604). Results: The variant genotypes rs2920502CC, rs3856806CT, rs3856806CT/TT, and rs4240711AG/GG were associated with T2DM. Furthermore, the prevalences of haplotype GTC and CTG in PPAR-gamma and GTAC in RXR-a were less frequent in cases (17.1%, 2.6%, and 2.4%, respectively) than in controls (22.3%, 3.8%, and 6.6%, respectively), whereas GTGT in RXR-alpha was more frequent in cases (6.9%) than in controls (4.4%) (P < 0.05 for both two-sided chi(2) test and thousand times permutation tests). Patients with genotype CT/TT of rs3856806 and genotype AG/GG of rs4240711 had higher levels of serum adiponectin than those with the genotype CC and genotype AA (P = 0.026 and 0.021, respectively). Model X2 X5 X6 X7 (rs3856806, rs3132291, rs4240711, and rs4842194) was the best model with the highest test balanced accuracy (0.5764) (cross-validation consistency 10/10) in the multifactor dimensionality reduction method. Conclusions: The PPAR-g and RXR-a gene variants associated with the development of T2DM in this study must be investigated in a larger population to reveal any potential effects on metabolism.