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 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; UGT1A1; pharmacodynamics; pharmacokinetics; promoter variants; simvastatin.

Figure 1. Simvastatin acyl glucuronide formation and interconversion to simvastatin open hydroxy-acid

Proposed metabolism of statins depicting the acid to lactone interconversion by various pathways. Statin lactones are hydrolyzed to the open acid chemically and enzymatically. The statin acids are then rapidly converted to corresponding lactones by glucuronidation (via their unstable acyl glucuronides) and to a lesser extent by a coenzyme-A-dependent pathway. The same considerations apply to the oxidative metabolites of both lactone and hyroxyacid forms of statins. Green text represents active uptake by OATP1B1 (or SLCO1B1) transport proteins. Blue text represents phase I metabolism by CYP3A4 enzymes. Red text represents UGTs responsible for glucuronidation. Adapted from Prueksaritanont et al. [3] with Permission from American Society for Pharmacology and Experimental Therapeutics [ASPET]). Please see color figure at www.futuremedicine.com/doi/pdf/10.2217/pgs.14.128

Figure 2. Population distribution of the phenotypic trait E_max by rs2003569 genotype

Mean differences by genotype for the phenotypic trait E_max (maximal LDL-C lowering) for the top SNP rs2003569 in (A) the entire cohort, (B) African–Americans and (C) European Americans. *p-value less than 0.05 for difference in means (GG and AA) and ^†p-value less than 0.05 for difference in means (AG and AA). LDL-C: Low-density lipoprotein cholesterol.

Figure 3. Location of the UGT1A1 variant rs2003569

Linearized depiction of the UGT1A1 gene and its location on Chromosome 2 showing the transcribed intronic and exonic regions (exons 2–5 are common for all UGT1A1 gene products) and the approximate location of the rs2003569 variant in relation to the transcription start site and the TA repeat polymorphism, rs8175347. MAF: Minor allele frequency.