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. 2021 Sep;110(3):777-785.
doi: 10.1002/cpt.2260. Epub 2021 Apr 30.

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use

Frank R Wendt  1   2 , Dora Koller  1   2 , Gita A Pathak  1   2 , Daniel Jacoby  3 , Edward J Miller  3 , Renato Polimanti  1   2
Affiliations

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use

Frank R Wendt et al. Clin Pharmacol Ther. 2021 Sep.

Abstract

Studying drug-metabolizing enzymes, encoded by pharmacogenes, may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, pharmacogenes could not be studied at biobank scale. In 7,649 unrelated African-ancestry (AFR) and 326,214 unrelated European-ancestry (EUR) participants from the UK Biobank, we associated pharmacogene haplotypes from 50 genes with 265 (EUR) and 17 (AFR) medication use phenotypes using generalized linear models. In EUR, N-acetyltransferase 2 (NAT2) metabolizer phenotype and activity score were associated with simvastatin use. The dose of NAT2*1 was associated with simvastatin use when compared with NAT2*5 (the most common haplotype). This association was robust to effects of low-density lipoprotein cholesterol (LDL-C) concentration (NAT2*1 odds ratio (OR) = 1.07, 95% CI: 1.05-1.09, P = 1.14 × 10-8 ) and polygenic risk for LDL-C concentration (NAT2*1 OR = 1.09, 95% CI: 1.04-1.14, P = 2.26 × 10-4 ). Interactive effects between NAT2*1 and simvastatin use on LDL-C concentration (OR = 0.957, 95% CI: 0.916-0.998, P = 0.045) were replicated in the electronic Medical Records and Genomics Pharmacogenetic Sequencing Pilot (eMERGE-PGx) cohort (OR = 0.987, 95% CI: 0.976-0.998, P = 0.029). We used biobank-scale data to uncover and replicate an association between NAT2 locus variation and better response to statin therapy. Testing NAT2 alleles may be useful for making clinical decisions regarding the potential benefit (e.g., absolute risk reduction) in LDL-C concentration prior to statin treatment.

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Conflict of interest statement

Conflict of Interest: EJM reports grants from Bracco and Eidos, consulting for General Electric, Alnylam, and Pfizer. DJ has served as consultant and steering committee member for MyoKardia, Inc. All other authors declare no competing interests for this work.

Figures

Figure 1.
Figure 1.
Overview of study design and analyses performed.
Figure 2.
Figure 2.. Star allele frequencies.
Frequency of 262 star alleles observed in African (AFR) and European (EUR) ancestry participants of the UK Biobank (Table S4). Each bar represents variation at a single pharmacogene listed on the x-axis; the segments in each bar indicates the relative frequency of a given star allele at that pharmacogene; the color of a segment indicates the proportion of activity score (“unk”=unknown activity score) assigned by Stargazer.
Figure 3.
Figure 3.. NAT2 allele dose effects.
Heatmap of generalized linear models results of simvastatin use considering the dose of each indicated NAT2 allele relative to the indicated GLM Referent NAT2 Allele. Each model was covaried with sex, age, age2, sex×age, sex×age2, and ten ancestry PCs. In the main text, we use the most frequent allele, NAT2*5, as reference for the analyses presented. The numbers reported within each cell represent the 95% confidence interval of the effects estimated. Cell color indicates effect point estimates; different colored text used for clarity.
Figure 4.
Figure 4.. Effect of NAT2 on simvastatin use.
(A) Main effect of NAT2*1 dose on simvastatin use; (B) Diplotype-specific effects of NAT2*1-carriers on simvastatin use relative to the referent NAT2*5|*5. “Original” results were covaried with sex, age, age2, sex×age, sex×age2, and ten ancestry PCs. The effect of NAT2 on simvastatin use was further covaried with low-density lipoprotein cholesterol (LDL-C) levels (“LDL-C Cov.”) and polygenic risk scores for LDL-C levels (“LDL-C PRS”). Data points in (B) are colored according to the diplotype activity score.
Figure 5.
Figure 5.. Interaction between NAT2 and simvastatin use.
Violin plots showing significantly greater (p<0.05) reduction of low-density lipoprotein cholesterol concentration (LDL-C; mmol/L) in simvastatin users who carry heterozygous NAT2*1|1 diplotypes relative to *1|*5 and *5|*5 diplotypes. Each facet is labeled with the NAT2 diplotype for UKB participants included in the analysis. The difference (“Diff”) in LDL-C concentration between simvastatin users and non-users is provided in each facet. All differences were statistically significant (p<0.05). Red data point and range represent mean and one standard deviation.
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