Interactions Between Variants in the β3-Adrenergic Receptor and Peroxisome Proliferator–Activated Receptor-γ2 Genes and Obesity

Abstract

OBJECTIVE—Previous studies have reported modest associations between measures of obesity and the Trp64Arg variant of the β₃-adrenergic receptor (ADRβ3) and the Pro12Ala variant of the peroxisome proliferator–activated receptor (PPAR)-γ2. We hypothesized that these single gene variants may mark mutations that act through convergent pathways to produce synergistic effects on obesity. RESEARCH DESIGN AND METHODS—The sample included 453 subjects from 10 large Mexican-American families participating in the population-based San Antonio Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framework. Analyses were conditioned on the pedigree structures to account for the correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustment for age, sex, and diabetes status. RESULTS—The allele frequencies for the ADRβ3 Trp64Arg and PPARγ2 Pro12Ala variants were 18 and 12%, respectively. The ADRβ3 variant was not significantly associated with any of the obesity-related traits, but subjects with the PPARγ2 variant (n = 98) had significantly higher levels of fasting insulin (P = 0.03), leptin (P = 0.009), and waist circumference (P = 0.03) than those without. Subjects with both gene variants (n = 32) had significantly higher BMI, insulin, and leptin levels than those with only the PPARγ2 variant (n = 66) (P for interaction: 0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively). CONCLUSIONS—Our results suggest that epistatic models with genes that have modest individual effects may be useful in understanding the genetic underpinnings of typical obesity in humans.