Interactions between variants in the beta(3)-adrenergic receptor and peroxisome proliferator-activated receptor-gamma 2 genes and obesity

OBJECTIVE - Previous studies have reported modest associations between meas ures of obesity and the Trp64Arg variant or the beta (3)-adrenergic recepto r (ADR beta3) and the Pro12Ala variant of the peroxisome proliferator-activ ated receptor (PPAR)-gamma2. We hypothesized that these single gene variant s may mark mutations that act through convergent pathways to product synerg istic effects on obesity. RESEARCH DESIGN AND METHODS - The sample included 453 subjects from 10 larg e Mexican-American families participating in the population-based San Anton io Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framew ork. Analyses were conditioned on the pedigree structures to account for th e correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustments for age, sex, and diabetes s tatus. RESULTS - The allele frequencies for the ADR beta3 Trp64Arg and PPAR gamma2 Pro12Ala variants were 18 and 12% respectively The ADR beta3 variant was n ot significantly associated with any of the obesity-related traits, but sub jects with the PPAR gamma2 variant in = 98) had significantly, higher level s of fasting insulin (P = 0.03). leptin (P = 0.009), and waist circumferenc e (P = 0.03) than those without. Subjects with both gene variants (n = 32) had significantly higher BMI, insulin. and leptin levels than those with on ly the PPAR gamma2 variant (n = 66) (P for interaction 0.04, 0.02, and 0.01 for BMI fasting insulin, and leptin. respectively). CONCLUSIONS - Out results suggest that epistatic models with genes that hav e modest individual effects may be useful in understanding the genetic unde rpinnings of typical obesity in humans.