Variation in the PPAR alpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects

Aims/hypothesis. Peroxisome proliferator activated receptor alpha (PPAR alp ha) regulates genes involved in lipid metabolism, haemostasis and inflammat ion, in response to fatty acids and fibrates, making it a candidate gene fo r risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasm a non-esterified fatty acids art: increased in subjects with Type II (non-i nsulin-dependent) diabetes mellitus, suggesting that PPAR alpha could link Type II diabetes and dyslipidaemia, and affect response to fibrates. This h as been investigated in association studies in healthy and diabetic subject s and in vitro studies. Methods. The human PPAR alpha gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determi ned for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 va riant was examined in co-transfection assays. Results. We identified two polymorphisms, one in intron 3 and a missense mu tation, leucine 162 to valine, in the DNA binding domain. In Type II diabet ic patients, V162 allele carriers had higher total cholesterol, HDL cholest erol and apoAI whereas intron 3 rare allele carriers had higher apoAI conce ntrations. By contrast, no effect was observed in healthy rare allele carri ers. In vitro, the V162 variant showed greater transactivation of a reporte r gene construct. Conclusion/interpretation. Naturally occurring variation alters PPAR alpha function, influencing plasma lipid concentrations in Type II diabetic patie nts but not healthy people. This demonstrates that PPAR alpha is a link bet ween diabetes and dyslipidaemia, and so could influence the risk of coronar y artery disease, the greatest cause of morbidity and mortality in Type II diabetes.