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Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.

TitleQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
Publication TypeJournal Article
Year of Publication2014
AuthorsGordon AS, Tabor HK, Johnson AD, Snively BM, Assimes TL, Auer PL, Ioannidis JPA, Peters U, Robinson JG, Sucheston LE, Wang D, Sotoodehnia N, Rotter JI, Psaty BM, Jackson RD, Herrington DM, O'Donnell CJ, Reiner AP, Rich SS, Rieder MJ, Bamshad MJ
Secondary AuthorsNickerson DA
Corporate AuthorsNHLBI GO Exome Sequencing Project
JournalHum Mol Genet
Volume23
Issue8
Pagination1957-63
Date Published2014 Apr 15
ISSN1460-2083
KeywordsCytochrome P-450 Enzyme System, Databases, Genetic, European Continental Ancestry Group, Exome, Humans, Pharmaceutical Preparations, Pharmacogenetics, Polymorphism, Genetic
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.

DOI10.1093/hmg/ddt588
Alternate JournalHum Mol Genet
PubMed ID24282029
PubMed Central IDPMC3959810
Grant ListRC2 HL-102926 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
P20 MD006899 / MD / NIMHD NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States