Variation in the PPAR-a Gene Is Associated With Altered Function In Vitro and Plasma Lipid Concentrations in Type 2 Diabetic Subjects

Aims/hypothesis
Peroxisome proliferator activated receptor-a (PPAR-a) regulates genes involved in lipid metabolism, haemostasis and inflammation, in response to fatty acids and fibrates, making it a candidate gene for risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasma non-esterified fatty acids are increased in subjects with Type 2 (non-insulin-dependent) diabetes mellitus, suggesting that PPAR-a could link Type 2 diabetes and dyslipidaemia, and affect response to fibrates. This has been investigated in association studies in healthy and diabetic subjects and in vitro studies.

Methods
The human PPAR-a gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type 2 diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays.

Results
We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type 2 diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct.

Conclusion/interpretation
Naturally occurring variation alters PPAR-a function, influencing plasma lipid concentrations in Type 2 diabetic patients but not healthy people. This demonstrates that PPAR-a is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type 2 diabetes. 



 

Last Modified: 3/4/2013