Evidence for gene-nutrient interaction at the PPAR gamma locus

The importance of the nuclear receptor peroxisome proliferator-activated re ceptor-gamma (PPAR gamma) in regulating insulin resistance and blood pressu re has been demonstrated in families with loss of function mutations. Gain of function mutations has been associated with severe obesity. However, pre vious population studies of the common variant Pro12Ala have produced confl icting results. As it is likely that the natural ligands for this receptor may include fatty acids, we hypothesized that the effect of this common var iant may be altered by the character of the diet, particularly the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio). We studied 592 n ondiabetic participants in an ongoing population-based cohort study who wer e genotyped for the Pro12Ala polymorphism in the PPAR gamma2 isoform. As th e Ala homozygotes were uncommon (2.0%), all analyses were conducted compari ng Pro homozygotes (79.1%) to Ala allele carriers. There was no difference in fasting insulin concentration or BMI between Ala allele carriers and Pro homozygotes. The fasting insulin concentration was negatively associated w ith the P:S ratio (P = 0.0119) after adjustment for age and sex, and a stro ng interaction was evident between the P:S ratio and the Pro12Ala polymorph ism for both BMI (P = 0.0038) and fasting insulin (P = 0.0097). The data su ggest that when the dietary P:S ratio is low, the BMI in Ala carriers is gr eater than that in Pro homozygotes, but when the dietary ratio is high, the opposite is seen. This gene-nutrient interaction emphasizes the difficulty of examining the effect of common polymorphisms in the absence of data on nongenetic exposures, and may explain the heterogeneity of findings in prev ious studies.