Ala12Ala Genotype of the Peroxisome Proliferator-Activated Receptor γ2 Protects against Atherosclerosis

A mutation in the peroxisome proliferator-activated receptor γ2 (PPARγ2) gene with a cytosine to guanine substitution results in an exchange of proline (Pro) with alanine (Ala) in exon B (codon 12) of this gene. This polymorphism has been associated with high insulin sensitivity and low body weight, but no data have been published to date about its effect on early atherosclerosis. We investigated the relationship of the Pro12Ala polymorphism to early atherosclerosis, measured by the intima-media thickness (IMT). A total of 622 subjects were included, aged 40–70 yr, who were participants of the RIAD (Risk factors in Impaired glucose tolerance for Atherosclerosis and Diabetes) study and were at risk of developing type 2 diabetes. Altogether, 449 of the subjects had the common genotype (Pro12Pro), 162 had the Pro12Ala genotype, and 11 the Ala12Ala genotype. IMT was significantly decreased in subjects with the Ala12Ala genotype compared with subjects with the other two genotypes. Body mass index, free fatty acid levels, and leukocyte count were lower in subjects with the Ala12Ala genotype compared with subjects with the Pro12Pro or Pro12Ala genotypes. In multivariate analysis, the Ala12Ala genotype was a significant independent determinant of IMT. Furthermore, we demonstrated specific expression of the PPARγ2 gene in human atherosclerotic lesions as well as in cultured primary macrophages and foam cells. In conclusion, our data suggest that the Ala12Ala genotype of the PPARγ2 gene may protect from early atherosclerosis in subjects at risk for diabetes.