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 lipo­protein 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 E_max = 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 E_max (p = 0.0059 and 0.031, respectively; for rs2003569 the mean E_max was 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 E₀ and ED₅₀. Conclusion: We identified a UGT1A1 promoter variant (rs2003569) associated with simvastatin efficacy.

Original submitted 26 March 2014; Revision submitted 26 August 2014

Keywords::

• LDL-cholesterol
• pharmacodynamics
• pharmacokinetics
• promoter variants
• simvastatin
• UGT1A1

Financial & competing interests disclosure

This work was supported in part by funding by the NIH through the Vanderbilt CTSA UL1TR000445 and NIH grants U19HL069757, U19 HL065962, GM109145 and T32 GM007569. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported in part by funding by the NIH through the Vanderbilt CTSA UL1TR000445 and NIH grants U19HL069757, U19 HL065962, GM109145 and T32 GM007569. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.