Interaction effect between common polymorphisms in PPARγ₂ (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity

Abstract.

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) γ₂ gene is associated with a reduced risk of type 2 diabetes. A beneficial effect on insulin sensitivity is reported in some but not all populations. It is possible that this genetic variant produces a characteristic phenotype only against a certain genetic background. We therefore tested the hypothesis that carriers of the Ala allele of PPARγ₂ exhibit a different phenotype against the background of the Gly972Arg polymorphism in the insulin receptor substrate (IRS) 1. We determined insulin sensitivity in the four combinations defined by the absence or presence of the polymorphic allele (healthy, glucose tolerant subjects), by the oral glucose tolerance test (OGTT; using a validated index, n=318) and hyperinsulinemic clamp (n=201). Insulin sensitivity was not or was only marginally different between Pro/Pro and X/Ala in the overall population. Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARγ₂) + X/Arg (IRS-1) than in Pro/Pro (PPARγ₂) + X/Arg (IRS-1). On the other hand, insulin sensitivity was similar in the X/Ala (PPARγ₂) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARγ₂) + Gly/Gly (IRS-1). The results were practically identical using insulin sensitivity from the clamp. In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARγ) which was not present in the whole population or against the Gly972 (IRS-1) background. This suggests that the Ala allele of PPARγ₂ becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism. Allowing for gene-gene interaction effects may reveal novel information regarding metabolic effects of genetic variants.