title: Lack of association of the p450 oxidoreductase *28 single nucleotide polymorphism with the lipid-lowering effect of statins in hypercholesterolemic patients.
abstract: OBJECTIVE
  Inter-individual variability exists in the statin (HMG-CoA reductase inhibitor) lipid-lowering response, which is partially attributed to genetic factors. The polymorphic enzyme P450 oxidoreductase (POR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to cytochrome P450 (CYP) 3A enzymes, which metabolize atorvastatin and simvastatin. The POR*28 allele is associated with increased activity of CYP3A enzymes. We analyzed the association of the POR*28 allele with response to atorvastatin and simvastatin.
  
  
  METHODS
  A total of 207 atorvastatin-treated adults were included in the study. An independent population of 210 simvastatin-treated adults served as a replication cohort. Total cholesterol (TChol) and low-density lipoprotein cholesterol (LDL-C) were measured at baseline and after 6 months of treatment. The POR*28 allele was analyzed with a TaqMan(®) assay.
  
  
  RESULTS
  The POR*28 allele was associated with a non-significant trend towards lower percentage mean reduction of TChol (-35.5 % in *1/*1, -33.7 % in *1/*28, and -29.5 % in *28/*28 individuals) and LDL-C (-42.6 % in *1/*1, -41.7 % in *1/*28, and -37.8 % in *28/*28 individuals) in response to atorvastatin. This trend was not observed in the replication cohort of simvastatin-treated patients. No sex-gene interaction was observed regarding the effect of the POR*28 allele on the statin lipid-lowering response in either statin-treated patient cohort.
  
  
  CONCLUSIONS
  The POR*28 allele was not associated with the lipid-lowering effect of atorvastatin and the results were replicated in an independent simvastatin-treated population. The hypothesized effect of the POR*28 allele on the lipid-lowering response to CYP3A-metabolized statins can potentially be masked by relevant confounding or uncontrolled factors; therefore, further studies in different populations are required.
authors.affiliation: Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100, Alexandroupolis, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Ragia
authors.forename: Vana
authors.initials: V
authors.lastname: Kolovou
authors.forename: Anna
authors.initials: A
authors.lastname: Tavridou
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Alexandros D
authors.initials: AD
authors.lastname: Tselepis
authors.forename: Moses
authors.initials: M
authors.lastname: Elisaf
authors.forename: Ron H N
authors.initials: RH
authors.lastname: Van Schaik
authors.forename: Genovefa
authors.initials: G
authors.lastname: Kolovou
authors.forename: Vangelis G
authors.initials: VG
authors.lastname: Manolopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000627:therapeutic use*; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009251:NADPH-Ferrihemoprotein Reductase