Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol

Paraoxonase (PON) is an enzyme carried by high-density lipoprotein choleste rol (HDL-C). Two gene polymorphisms leading to amino acid substitutions of methionine for leucine at position 55 (M/L55) and arginine for glutamine at position 192 (R/Q192) modulate the activity of the enzyme and possibly als o lipid and apolipoprotein concentrations. Our purpose was to examine the e ffect of the PON genotype on HDL-C and apolipoprotein Al (apo At) responses to pravastatin treatment. Fifty-one mildly hypercholesterolemic male subje cts (mean age 35 +/- 4 years) were enrolled by this prospective, randomized , double-blind study. Lipid concentrations were measured at baseline and af ter 6 months of pravastatin (n = 25) or placebo (n = 26) therapy. Low activ e (MM, ML or QQ) and high active (LL or RQ, RR) PON genotype groups were re lated to lipid and apolipoprotein concentration changes. Pravastatin increa sed the apo Al concentration 12% (P = 0.017, RANOVA) and tended to increase the HDL-C concentration (P = 0.095, RANOVA) in R allele carriers but not i n QQ homozygotes. Significant predictors of the change in apo At concentrat ion during pravastatin treatment were R/Q192 genotype (P = 0.002), apo Al c oncentration at baseline (P = 0.002) and M/L55 genotype (P = 0.042). Corres pondingly, R/Q192 (P = 0.009) and M/L55 (P = 0.050) genotypes were the stat istically significant determinants of HDL-C concentration change. The PON g enotype thus modifies the effect of pravastatin on serum HDL-C and apo At c oncentrations. This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concent ration. Pharmacogenetics 11:625-633 (C) 2001 Lippincott Williams & Wilkins.