Peroxisome proliferator activated receptor delta genotype in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolaemic men.

OBJECTIVES: Peroxisome proliferator activated receptor delta (PPARD) is a transcription factor implicated in the regulation of genes involved in cholesterol metabolism. We recently discovered a common polymorphism in the 5'-untranslated region (5'-UTR) of the human PPARD, +294T/C, that is associated with an increased plasma low-density lipoprotein cholesterol (LDL-C) concentration in healthy subjects. Whether the +294C allele is associated with LDL-C elevation independently of the background lipoprotein phenotype and whether it confers increased risk of coronary heart disease (CHD) is unknown. Against this background, we investigated the relationships between the PPARD polymorphism and plasma lipoprotein concentrations and the risk for contracting CHD in the West of Scotland Coronary Prevention Study (WOSCOPS). DESIGN: A nested case-control study of participants in a randomized double-blind placebo-controlled trial of pravastatin in mildly-to-moderately hypercholesterolaemic men. SUBJECTS: A total of 580 cases of incident CHD and 1160 individuals who remained free of CHD (controls). MAIN OUTCOME MEASURES: Plasma lipoprotein concentrations and risk of CHD according to PPARD genotype. RESULTS: Individuals carrying the rare PPARD +294C allele had a significantly lower high-density lipoprotein cholesterol (HDL-C) concentration than subjects homozygous for the common T-allele. Homozygous carriers of the C-allele also showed a tendency towards higher risk of CHD compared with homozygous carriers of the T-allele. In addition, a gene-gene interaction involving the PPARD polymorphism and the PPAR alpha L162V polymorphism may influence the plasma LDL-C concentration. CONCLUSIONS: PPARD plays a role in cholesterol metabolism in man.