Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study

Pharmacogenet Genomics. 2011 Dec;21(12):861-6. doi: 10.1097/FPC.0b013e32834c6edb.


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 [CI(95%)]=[-0.52; 0.01], P=0.058) and -0.29 mmol/l (CI(95%)=[-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 (CI(95%)=[-0.59;-0.04], P=0.028) and for LDLc -0.34 mmol/l (CI(95%)=[-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Cholesterol / genetics
  • Cholesterol / metabolism*
  • Cohort Studies
  • Cytochrome P-450 CYP3A / genetics*
  • Female
  • Genotype
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Introns
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Simvastatin / therapeutic use*


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Cholesterol
  • Simvastatin
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human