title: Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Matthijs L
authors.initials: ML
authors.lastname: Becker
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Loes E
authors.initials: LE
authors.lastname: Visser
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Bruno Ch
authors.initials: BCh
authors.lastname: Stricker
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D000368:Aged; D000483:Alleles; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007438:Introns; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human