NYMC Faculty Publications
Quantifying Rare, Deleterious Variation in 12 Human Cytochrome P450 Drug-Metabolism Genes in a Large-Scale Exome Dataset
Author Type(s)
Faculty
DOI
10.1093/hmg/ddt588
Journal Title
Human Molecular Genetics
First Page
1957
Last Page
1963
Document Type
Article
Publication Date
4-15-2014
Department
Pathology, Microbiology and Immunology
Keywords
Cytochrome P-450 Enzyme System, Databases, Genetic, Exome, Humans, Pharmaceutical Preparations, Pharmacogenetics, Polymorphism, Genetic, White People
Disciplines
Medicine and Health Sciences
Abstract
The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
Recommended Citation
Gordon, A., Nickerson, D., & Dozor, A. (2014). Quantifying Rare, Deleterious Variation in 12 Human Cytochrome P450 Drug-Metabolism Genes in a Large-Scale Exome Dataset. Human Molecular Genetics, 23 (8), 1957-1963. https://doi.org/10.1093/hmg/ddt588
Comments
Please see link to outside source for full list of authors.