The C161-->T polymorphism in peroxisome proliferator-activated receptor gamma, but not P12A, is associated with insulin resistance in Hispanic and non-Hispanic white women: evidence for another functional variant in peroxisome proliferator-activated receptor gamma.

The P12A variant in the peroxisome proliferator-activated receptor gamma (PPARgamma) gene has been intensely studied for association with obesity-related or type-2 diabetes-related traits; however, the results have been somewhat inconsistent in different populations. We genotyped a large cohort of Hispanic and non-Hispanic white individuals from the San Luis Valley Diabetes Study for P12A and another common variant, C161-->T, in the PPARgamma gene to determine if these sites were associated with fasting glucose, insulin, free fatty acid levels, insulin sensitivity, or body fat. There were no statistically significant frequency differences at these two sites between Hispanic and non-Hispanic individuals. No significant association with the metabolic phenotypes was observed for either of the polymorphisms in men; however, in women, significant associations were shown between the C161-->T variant and fasting insulin (P=.008) and the homeostasis model assessment of insulin resistance (HOMA IR; P=.007). After adjusting for age, smoking, fat mass, and skin reflectance, linear regression showed that C161-->T explained 1.5% of the variation in both fasting insulin (P=.031) and HOMA IR (P=.028) whereas P12A contributed only 0.04% (fasting insulin, P=.268) and 0.02% (HOMA IR, P=.418) to the total trait variation. In the San Luis Valley Diabetes Study female patients, C161-->T appears to be a better predictor of fasting insulin levels and insulin resistance than P12A although the effect of this variant is small. These results support the hypothesis that C161-->T is in linkage disequilibrium with unidentified functional variation in PPARgamma or in a linked gene. This could explain some of the inconsistencies in the P12A association studies as the allele frequency and level of linkage disequilibrium of another functional polymorphism in the region could vary in different populations.