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 and 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.

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Keywords CYP3A4, HMG-CoA reductase inhibitors, pharmacogenetics, PPARA, rs4253728 G>A, rs4823613 A>G, statins
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Journal Pharmacogenomics
de Keyser, C.E, Becker, M.L, Uitterlinden, A.G, Hofman, A, Lous, J.J, Elens, L, … Stricker, B.H.Ch. (2013). Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenomics, 14(11), 1295–1304. doi:10.2217/pgs.13.112