Evidence of Interaction Between Peroxisome Proliferator-Activated Receptor-{gamma}2 (PPARG2) and Hepatocyte Nuclear Factor-4{alpha} (HNF4A) Contributing to Variation in Insulin Sensitivity in Mexican Americans

Abstract

Objective: We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are be associated with type 2 diabetes (T2D)-related quantitative traits (QT) in Mexican-American families of a proband with previous gestational diabetes mellitus (GDM). Research Design and Methods: The BetaGene project genotyped PPARG2 Pro12Ala and 9 HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. Results: Neither PPARG2 Pro12Ala nor any of the 9 HNF4A SNPs were independently associated with T2D-related QTs. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (S(I)) (Bonferroni p=0.0006) and 2-hr insulin (Bonferroni p=0.039). Subjects with at least one PPARG2 Ala allele and homozygous for HNF4A rs2144908 A allele had 40% higher S(I) compared to individuals with at least one G allele. S(I) did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for S(I) was replicated by the IRAS Family Study (p=0.018) in their San Antonio sample (n=484) where subjects with at least one PPARG2 Ala allele and homozygous for HNF4A rs2144908 A allele had a 29% higher S(I) compared to individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n=496; p=0.401). Conclusions: Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican-Americans at risk for T2D