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

Malin, Riikkaa; Laaksonen, Reijob; Knuuti, Juhanic; Janatuinen, Tuulac; Vesalainen, Ristoc; Nuutila, Pirjoc; Lehtimäki, Terhoa

Pharmacogenetics and Genomics: October 2001 - Volume 11 - Issue 7 - p 625-633
Original Article

Paraoxonase (PON) is an enzyme carried by high-density lipoprotein cholesterol (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 also lipid and apolipoprotein concentrations. Our purpose was to examine the effect of the PON genotype on HDL-C and apolipoprotein AI (apo AI) responses to pravastatin treatment. Fifty-one mildly hypercholesterolemic male subjects (mean age 35 ± 4 years) were enrolled by this prospective, randomized, double-blind study. Lipid concentrations were measured at baseline and after 6 months of pravastatin (n = 25) or placebo (n = 26) therapy. Low active (MM, ML or QQ) and high active (LL or RQ, RR) PON genotype groups were related to lipid and apolipoprotein concentration changes. Pravastatin increased the apo AI concentration 12% (P = 0.017, RANOVA) and tended to increase the HDL-C concentration (P = 0.095, RANOVA) in R allele carriers but not in QQ homozygotes. Significant predictors of the change in apo AI concentration during pravastatin treatment were R/Q192 genotype (P = 0.002), apo AI concentration at baseline (P = 0.002) and M/L55 genotype (P = 0.042). Correspondingly, R/Q192 (P = 0.009) and M/L55 (P = 0.050) genotypes were the statistically significant determinants of HDL-C concentration change. The PON genotype thus modifies the effect of pravastatin on serum HDL-C and apo AI concentrations. This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concentration.

aLaboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital and University of Tampere, Medical School, Tampere, bDepartment of Internal Medicine, Tampere University Hospital, Tampere and Department of Clinical Pharmacology, University of Helsinki, Helsinki and cTurku PET Centre, University of Turku, Turku, Finland

Received 17 January 2001; accepted 16 March 2001

Correspondence to Riikka Malin, Tampere University Hospital, Laboratory of Atherosclerosis Genetics, FinnMedi 2, Third Floor, PO Box 2000, 33521 Tampere, Finland Tel: +358 324 74051; fax: +358 324 74168; e-mail:

© 2001 Lippincott Williams & Wilkins, Inc.