The <i>Pro12Ala PPARγ2</i> gene missense mutation is associated with obesity and insulin resistance in Swedish middle‐aged men

A missense mutation in exon B of the adipocyte-specific isoform peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) has recently been described, leading to the substitution of proline to alanine at codon 12, which causes a reduction in the transcriptional activity of PPARgamma2. The Pro12Ala PPARgamma2 polymorphism has been variably associated with obesity, insulin sensitivity, and dyslipidemia.In the present study, we addressed the hypothesis that the Pro12Ala variant is associated with obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones including salivary cortisol in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of exon B of the PPARgamma2 gene followed by digestion with the restriction enzyme BstUI.Tests for differences between the PPARgamma2 genotypes revealed that the PPARgamma2 Ala homozygotes (n = 6) had higher body mass index (P = 0.022), abdominal sagittal diameter (P = 0.038), and nearly 3 times higher fasting insulin levels (P < 0.001) as well as higher HOMA insulin-resistance index (P = 0.011) compared to the PPARgamma2 Pro homozygotes (n = 186). This association was independent of body mass and fat distribution. In addition, subjects with the Ala/Ala genotype had lower total cholesterol (P = 0.012) as well as a trend toward lower high- and low-density lipoprotein cholesterol (P = 0.071 and P = 0.095) compared to the other PPARgamma2 genotypes.In summary, these findings both confirm and expand the current notion that the PPARgamma2 gene might play a role in the etiology of obesity and that genetic variability in PPARgamma2 is associated with variations in body fat mass and insulin sensitivity.