Risk of coronary artery disease (CAD) is determined by a combination of genetic and environmental factors which influence plasma lipid homeostasis, haemostasis and inflammation. Peroxisome proliferator activated receptor alpha (PPARa) is a ligand-inducible transcription factor [1] which regulates the expression of genes involved in fatty acid oxidation, extracellular lipid metabolism, haemostasis [2] and inflammation [3]. Ligands for PPARa include long chain fatty acids, eicosanoids, peroxisome proliferators, non-steroidal anti-inflammatory drugs and the fibrate class of hypolipidaemic drugs [4±6]. PPARa is highly expressed in tissues with a high rate of fatty Diabetologia (2000) Methods. The human PPARa gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II 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 II 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 PPARa function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARa 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 II diabetes. [Diabetologia (2000) 43: 673±680]

Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.

Abstract-Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (NOS 3) influence NO production (as assessed by the plasma levels of nitrogen oxides, NO x ) in middle-aged men. We also determined whether plasma NO x or NOS 3 genotype predicted the risk of ischemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8