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

摘要: The study of genetic influences on drug response and efficacy (‘pharmacogenetics’) has existed for over 50 years. Yet, we still lack a complete picture how variation, both common rare, affects each individual's responses to medications. Exome sequencing is promising alternative method pharmacogenetic discovery as it provides information rare variation in large numbers individuals. Using exome data from 2203 AA 4300 Caucasian individuals through the NHLBI Sequencing Project, conducted survey coding within 12 Cytochrome P450 (CYP) genes that are collectively responsible catalyzing nearly 75% all known Phase I oxidation reactions. In addition identifying many polymorphisms with effects, discovered 730 novel nonsynonymous alleles across CYP interest. These include diverse functional effects such premature stop codons, aberrant splicesites mutations at conserved active site residues. Our analysis considering novel, predicted well known, actionable reveals deleterious contributes markedly overall burden populations considered, contribution this three times greater compared Caucasians. While most these impactful individually 7.6–11.7% interrogated carry least one newly described potentially major drug-metabolizing CYP.