title: Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs.
abstract: Cytochrome P450 3A4 (CYP3A4) metabolizes ∼50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6-6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2-0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.
authors.affiliation: Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, Ohio State University, Columbus, OH 43210, USA. wang.808@osu.edu
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.forename: S A
authors.initials: SA
authors.lastname: Wrighton
authors.forename: G E
authors.initials: GE
authors.lastname: Cooke
authors.forename: W
authors.initials: W
authors.lastname: Sadee
mesh_terms: D022981:Allelic Imbalance; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D050171:Dyslipidemias / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006239:Haplotypes; D056945:Hep G2 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007438:Introns; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology*; D016015:Logistic Models; D016017:Odds Ratio; D009820:Ohio; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012332:RNA, Heterogeneous Nuclear / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
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