Objectives: CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the HMG-CoA reductase inhibitor simvastatin. The objective of this study was to investigate whether a new CYP3A4 functional single nucleotide polymorphism (SNP) in intron 6 (CYP3A4*22) modifies the effect of simvastatin on total cholesterol (TOTc) or LDL cholesterol (LDLc) reduction in a population-based cohort study. Methods: In a total of 80 incident simvastatin users, the association between the CYP3A4 intron 6 C>T SNP (rs35599367) and reduction in cholesterol levels was analyzed using linear regression analysis and adjusting for potential confounding factors. Results: The CYP3A4*22 allele was associated with a trend towards a stronger simvastatin lipid-lowering response, as reflected by the greater reduction in both TOTc and LDLc levels when compared with homozygous wild type. We observed that the CYP3A4*22 allele carriers had an increased reduction in TOTc and LDLc:-0.25 mmol/l (95% confidence interval [CI95%]=[-0.52; 0.01], P=0.058) and-0.29 mmol/l (CI95%=[-0.58; 0.01], P=0.054) when compared with homozygous CC. When we adjusted the model for potential confounding factors, the corresponding reduction in TOTc was-0.31 mmol/l (CI95%=[-0.59;-0.04], P=0.028) and for LDLc-0.34 mmol/l (CI95%=[-0.66;-0.02], P=0.034) greater for CYP3A4*22 allele carriers when compared with homozygotes wild type. Conclusion: The CYP3A4*22 intron 6 SNP T-variant allele was associated with reduced CYP3A4 activity, resulting in a better lipid lowering response to simvastatin, when data were adjusted for confounding factors. This observation is a step towards the clarification of the reasons of interindividual variability in statins response and may potentially lead to improved tailoring of simvastatin therapy.

Additional Metadata
Keywords 22, CYP3A4, hypercholesterolemia, pharmacogenetics, rs35599367, simvastatin, single nucleotide polymorphism
Persistent URL dx.doi.org/10.1097/FPC.0b013e32834c6edb, hdl.handle.net/1765/34564
Citation
Elens, L., Becker, M.L., Haufroid, V., Hofman, A., Visser, L.E., Uitterlinden, A.G., … van Schaik, R.H.N.. (2011). Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenetics and Genomics, 21(12), 861–866. doi:10.1097/FPC.0b013e32834c6edb