title: Genetic variation in the UGT1A locus is associated with simvastatin efficacy in a clinical practice setting.
abstract: Aim: Simvastatin is a lactone prodrug that exists in equilibrium with its active hydroxyacid through a process mediated by UGT1A enzymes. The UGT1A locus has been associated with simvastatin response and disposition in humans. Therefore, we fine-mapped the UGT1A locus to identify genetic variations contributing to simvastatin disposition and response variability. Methods: Using de-identified electronic medical records linked to a DNA biobank, we extracted information about dose and low-density lipo-protein cholesterol (LDL-C) concentrations for patients who received more than two different doses of simvastatin. Pharmacodynamic measures of simvastatin potency and efficacy were calculated from dose-response curves (E0= baseline LDL-C, ED50= dose yielding 50% maximum response, and Emax= maximum decrease in LDL-C) in 1100 patients. We selected 153 polymorphisms in UGT1A1 and UGT1A3 for genotyping and conducted genotype-phenotype associations using a prespecified additive model. Results: Two variants in UGT1A1 (rs2003569 and rs12052787) were associated with Emax(p = 0.0059 and 0.031, respectively; for rs2003569 the mean Emaxwas 59.3 ± 23.0, 62.0 ± 22.4, and 69.7 ± 24.8 mg/dl, for patients with 0, 1 or 2 copies of the minor A allele, respectively). When stratified by race, the difference in response was greater in African-Americans than in European Americans. Rs2003569 was also negatively associated with total serum bilirubin levels (p = 7.85 × 10-5). Four rare SNPs were nominally associated with E0and ED50. Conclusion: We identified a UGT1A1 promoter variant (rs2003569) associated with simvastatin efficacy. Original submitted 26 March 2014; Revision submitted 26 August 2014.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Otito F
authors.initials: OF
authors.lastname: Iwuchukwu
authors.forename: QiPing
authors.initials: Q
authors.lastname: Feng
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Wei
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.forename: Russell A
authors.initials: RA
authors.lastname: Wilke
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
keywords: LDL-cholesterol; UGT1A1; pharmacodynamics; pharmacokinetics; promoter variants; simvastatin