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Aim: Genetic variation has been shown to influence statin response in terms of lowering LDL cholesterol. The recently discovered CYP3A4*22 allele (defined as rs35599367) has been shown to affect statin-induced LDL cholesterol lowering. Our objective was to investigate whether this polymorphism modifies the risk reduction for myocardial infarction (MI) by statins., Patients & Methods: We analyzed the interaction between the *22 minor allele and statin use in the independent Utrecht Cardiovascular Pharmacogenetics study and Rotterdam Study, using logistic and Cox regression models., Results: In total, 771 MI cases and 6131 controls were included in the analyses. There was no effect of the CYP3A4*22 allelic status in the studies separately, nor when the estimates from both studies were combined (interaction odds ratio: 1.27; 95% CI: 0.73-2.21; p = 0.40 for carriers of the minor T-allele)., Conclusion: We found no association of the CYP3A4*22 minor allele (rs35599367) with the effectiveness of statins in reducing MI risk.

Aim: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin., Materials & Methods: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression., Results: The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism., Conclusion: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4.