title: Individual and Combined Associations of Genetic Variants in CYP3A4, CYP3A5, and SLCO1B1 With Simvastatin and Simvastatin Acid Plasma Concentrations.
abstract: Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.
authors.affiliation: *Department of Pharmacology, Center for Pharmacogenomics, The Ohio State University Wexner Medical Center, Columbus, OH; †Children's Hospital Oakland Research Institute, Oakland, CA; ‡Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and §Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA; and ‖Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Jasmine A
authors.initials: JA
authors.lastname: Luzum
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Theusch
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Ann
authors.initials: A
authors.lastname: Wang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Kitzmiller
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000097:blood*
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; C063287:simvastatin acid; D019821:Simvastatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human