A prospective study to assess the role of paraoxonase 1 genotype and phenotype on the lipid-lowering and antioxidant activity of statins

Human paraoxonase 1 (PON1) enzyme protects against atherosclerosis by preventing low-density lipoprotein from oxidative modification. Upregulation of PON1 enzymatic activity is suggested to contribute to atheroprotective potential of statins. Glutamine (Q) to arginine (R) at site 192 and leucine (L) to methionine (M) substitution at site 55 polymorphisms influence the PON1 activity. The study assessed the role of PON1 polymorphisms on lipid-lowering and PON1-modulating activity of statins in a Western Indian cohort of patients with dyslipidemia. Lipid profile and PON1 activity were determined at baseline and 3 months after initiation of statin treatment. PON1 genotypes (QQ, QR, RR; LL, LM, and MM) were determined by PCR-RFLP. Paraoxon was used as a substrate for assessing PON1 activity by spectrophotometry. A total of 140 statin-naïve patients were enrolled; of them, 116 were available for final analysis. Fifty-seven (50%) had QQ, 39 (35%) had QR, and 17 (15%) had RR genotypes. Seventy-six (67%) patients had LL, 35 (31%) had LM, and 2 (2%) had MM genotypes. We observed no impact of PON1 polymorphisms on lipid parameters posttreatment. A significant increase was observed in the serum PON1 activity from a median (range) of 47.92 U/L (9.03–181.25) to 72.22 U/L (7.64–244.44) (P < 0.05) following statin treatment, which was independent from high-density lipoprotein (HDL) concentration. This increase was significantly greater in QQ compared to QR and RR genotypes (P = 0.01). To conclude, the important antioxidant properties of statins are exerted via the rise in serum PON1 activity, independent of HDL cholesterol concentrations. The increase was greater in individuals with QQ genotype. Future large-scale studies will validate the premise that QQ homozygotes see added benefits from statin treatment compared to R carriers. In the meantime, PON1 enzymatic activity remains an important marker to be measured while assessing pleotropic effects of statins in CAD.