Mutation screening of the PPAR alpha gene in type 2 diabetes associated with coronary heart disease

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a liga nd-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR alpha plays a key role in lipid and glucose metabolism, inflammatory response and energy homeostasis. The aim of our study was to s creen the PPAR alpha gene for mutations, and to test the genetic contributi on of PPAR alpha in diabetes and its vascular complications. The first two non coding exons and the coding region of the PPAR alpha gene were screened by single strand conformation polymorphism (SSCP) and sequencing in 74 unr elated Type 2 diabetic patients with history of coronary heart disease (CHD ) (18 Caucasian and 56 Indian subjects). A total of 7 nucleotide variants w ere detected: two single amino acid substitutions, a silent mutation, four intron base changes. Association studies were undertaken in two populations of Type 2 diabetic patients from Pondichery and from France,to test the di stribution of allelic frequencies for L162V (exon 5) and A268V (exon 7) pol ymorphisms. No association was found between these PPAR alpha variants and diabetes or CHD. However, in the Caucasian diabetic male population with CH D, the Val162 allele carriers showed higher concentrations of total cholest erol and Apo B when compared to non-carriers (p = 0.01 and p = 0.005, respe ctively). A trend toward elevated concentrations of total cholesterol and A po B was also observed in the Caucasian diabetic male patients without CHD carrying Val162 allele. In conclusion, it is likely that PPAR alpha gene do es not have a major role in diabetes and CHD in our populations, although w e can not exclude a minor contribution of the PPAR alpha gene to the risk o f CHD associated with Type 2 diabetes through a modulation of atherogenic p lasma lipids.