The Pro12Ala substitution in the peroxisome proliferator activated receptor gamma 2 is associated with an insulin-sensitive phenotype in families with familial combined hyperlipidemia and in nondiabetic elderly subjects with dyslipidemia

Dyslipidemias and insulin resistance often present simultaneously, as in familial combined hyperlipidemia (FCHL), and therefore may have a common genetic background. In our previous study the Pro12Ala substitution of peroxisome proliferator receptor γ 2 (PPARγ2) associated with insulin sensitivity, low body mass index (BMI) and high-density lipoprotein (HDL) cholesterol levels. In this study, we investigated the role of this substitution in dyslipidemias. Therefore, 228 nondiabetic members of FCHL families and 866 nondiabetic elderly subjects with (n=217) and without dyslipidemia (n=649) were genotyped. The allele frequencies of the Pro12Ala substitution did not differ between elderly subjects with or without dyslipidemia or 27 probands with FCHL. However, this substitution was associated with low fasting insulin levels both in FCHL family members (P=0.036 adjusted for gender and age) and elderly subjects with dyslipidemia (P=0.050) but not in elderly subjects without dyslipidemia (P=0.080). In addition, the Ala12 allele of PPARγ2 was associated with low BMI (P=0.034) and low total triglycerides (P=0.027), and increased HDL-cholesterol (P<0.001) in elderly subjects with dyslipidemia (n=299) but not among any other study groups. We conclude that the Ala12 isoform of PPARγ2 ameliorates the insulin resistance and unfavorable lipid and lipoprotein profiles in FCHL and hyperlipidemic elderly subjects.