Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear
transcription factors that regulate
fatty acid biosynthesis. Our objectives were to determine the effects of
PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with
fluvastatin. We genotyped 372
Lipoprotein and
Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in
PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or
5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma
triglyceride levels and their responses to treatment with
fluvastatin were associated with PPARD haplotypes (P = 0.01).
Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma
apolipoprotein (
apo)B (P = 0.021) and
apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in
triglyceride (P = 0.01) and
apoC-III (P = 0.047) levels in response to
fluvastatin. Plasma
triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to
fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between
PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of
lipids, severity of
coronary atherosclerosis and its response to
therapy.