Biobank scale pharmacogenomics informs the genetic underpinnings of simvastatin use

Abstract

Background and PurposeStudying drug metabolizing enzymes, encoded by pharmacogenes (PGx), may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, PGx loci could not be studied at biobank scale. Here we analyze PGx haplotype variation to detect associations with medication use in the UK Biobank. MethodsIn 7,649 unrelated African-ancestry (AFR) and 326,214 unrelated European-ancestry (EUR) participants from the UK Biobank, aged 37-73 at time of recruitment, we associated clinically-relevant PGx haplotypes with 265 (EUR) and 17 (AFR) medication use phenotypes using generalized linear models covaried with sex, age, age2, sexxage, sexxage2, and ten principal components of ancestry. Haplotypes across 50 genes were assigned with Stargazer. Our analyses focused on the association of PGx haplotype dose (quantitative predictor), diplotype (categorical predictor), and rare haplotype burden on medication use. ResultsIn EUR, NAT2 metabolizer phenotype (OR=1.05, 95% CI: 1.03-1.08, p=7.03x10-6) and activity score (OR=1.09, 95% CI: 1.05-1.14, p=2.46x10-6) were associated with simvastatin use. The dose of N-acetyltransferase 2 (NAT2)*1 was associated with simvastatin use relative to NAT2*5 (NAT2*1 OR=1.04, 95% CI=1.03-1.07, p=1.37x10-5) and was robust to effects of low-density lipoprotein cholesterol (LDL-C) concentration (NAT2*1 given LDL-C concentration: OR=1.07, 95% CI=1.05-1.09, p=1.14x10-8) and polygenic risk for LDL-C concentration (NAT2*1 given LDL-C PRS: OR=1.09, 95% CI=1.04-1.14, p=2.26x10-4). Interactive effects between NAT2*1, simvastatin use, and LDL-C concentration (OR: 0.957, 95% CI=0.916-0.998, p=0.045) were replicated in eMERGE PGx cohort (OR: 0.987, 95% CI: 0.976-0.998, p=0.029). Conclusions and relevanceWe used biobank-scale data to uncover and replicate a novel association between NAT2 locus variation (and suggestive evidence with several other genes) and better response to simvastatin (and other statins) therapy. The presence of NAT2*1 versus NAT2*5 may therefore be useful for making clinically informative decisions regarding the potential benefit (e.g., absolute risk reduction) in LDL-C concentration prior to statin treatment. Subject termsgenetics, genetic association studies, cardiovascular disease