Dataset Information

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use.

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.

SUBMITTER: Wendt FR

PROVIDER: S-EPMC8376807 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use.

Wendt Frank R FR Koller Dora D Pathak Gita A GA Jacoby Daniel D Miller Edward J EJ Polimanti Renato R

Clinical pharmacology and therapeutics 20210430 3

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-ace ...[more]

PMID: 33837531

Similar Datasets

Project description:The initial decades of the 21st century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single metabolites and single genetic polymorphisms to the study of hundreds or thousands of metabolites and millions of genomic variants in a single cell or subject. It is now possible to merge and integrate large data sets generated by the use of different "-omics" techniques to increase our understanding of the molecular basis for variation in disease risk and/or drug response phenotypes. This "Brief Review" will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy. Studies that used pharmacometabolomics to inform and guide pharmacogenomics were reviewed. Clinical studies that were used as the basis for pharmacometabolomics-informed pharmacogenomic studies, published in five independent manuscripts, are described briefly. Within these five manuscripts, both pharmacokinetic and pharmacodynamic metabolomics approaches were used. Candidate gene and genome-wide approaches that were used in concert with these metabolomic data identified novel metabolite-gene relationships that were associated with drug response phenotypes in these pharmacometabolomics-informed pharmacogenomics studies. This "Brief Review" outlines the emerging discipline of pharmacometabolomics-informed pharmacogenomics in which metabolic profiles are associated with both clinical phenotypes and genetic variants to identify novel genetic variants associated with drug response phenotypes based on metabolic profiles.

Dataset Information

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use.

Publications

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets