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Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations

Genomic‐guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of single‐nucleotide polymorphisms and struct...

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Autores principales: Luo, Shishi, Jiang, Ruomu, Grzymski, Joseph J., Lee, William, Lu, James T., Washington, Nicole L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453755/
https://www.ncbi.nlm.nih.gov/pubmed/33930192
http://dx.doi.org/10.1002/cpt.2279
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author Luo, Shishi
Jiang, Ruomu
Grzymski, Joseph J.
Lee, William
Lu, James T.
Washington, Nicole L.
author_facet Luo, Shishi
Jiang, Ruomu
Grzymski, Joseph J.
Lee, William
Lu, James T.
Washington, Nicole L.
author_sort Luo, Shishi
collection PubMed
description Genomic‐guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of single‐nucleotide polymorphisms and structural variation. Here, we introduce the Helix PGx database, an open‐source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short‐read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project. The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low‐frequency star alleles, as well as a disproportionate fraction (36%) of all novel predicted loss‐of‐function variants identified. Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10 times higher frequency in one or more subgroups with non‐European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high‐risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard‐of‐care screening of these 4 pharmacogenes could impact nearly half of the general population.
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spelling pubmed-84537552021-09-27 Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations Luo, Shishi Jiang, Ruomu Grzymski, Joseph J. Lee, William Lu, James T. Washington, Nicole L. Clin Pharmacol Ther Research Genomic‐guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of single‐nucleotide polymorphisms and structural variation. Here, we introduce the Helix PGx database, an open‐source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short‐read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project. The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low‐frequency star alleles, as well as a disproportionate fraction (36%) of all novel predicted loss‐of‐function variants identified. Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10 times higher frequency in one or more subgroups with non‐European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high‐risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard‐of‐care screening of these 4 pharmacogenes could impact nearly half of the general population. John Wiley and Sons Inc. 2021-06-07 2021-09 /pmc/articles/PMC8453755/ /pubmed/33930192 http://dx.doi.org/10.1002/cpt.2279 Text en © 2021 Helix OpCo, LLC. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Luo, Shishi
Jiang, Ruomu
Grzymski, Joseph J.
Lee, William
Lu, James T.
Washington, Nicole L.
Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations
title Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations
title_full Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations
title_fullStr Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations
title_full_unstemmed Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations
title_short Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations
title_sort comprehensive allele genotyping in critical pharmacogenes reduces residual clinical risk in diverse populations
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453755/
https://www.ncbi.nlm.nih.gov/pubmed/33930192
http://dx.doi.org/10.1002/cpt.2279
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