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Global spectrum of population-specific common missense variation in cytochrome P450 pharmacogenes.
Chong, Cheng-Shoong; Limviphuvadh, Vachiranee; Maurer-Stroh, Sebastian.
Afiliação
  • Chong CS; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • Limviphuvadh V; Innovations in Food and Chemical Safety Programme (IFCS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • Maurer-Stroh S; National University of Singapore Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore, Singapore.
Hum Mutat ; 42(9): 1107-1123, 2021 09.
Article em En | MEDLINE | ID: mdl-34153149
Next-generation sequencing technology has afforded the discovery of many novel variants that are of significance to inheritable pharmacogenomics (PGx) traits but a large proportion of them have unknown consequences. These include missense variants resulting in single amino acid substitutions in cytochrome P450 (CYP) proteins that can impair enzyme function, leading to altered drug efficacy and toxicity. While most unknown variants are rare, an overlooked minority are variants that are collectively rare but enriched in specific populations. Here, we analyzed sequence variation data in 141,456 individuals from across eight study populations in gnomAD for 38 CYP genes to identify such variants in addition to common variants. By further comparison with data from two PGx-specific databases (PharmVar and PharmGKB) and ClinVar, we identified 234 missense variants in 35 CYP genes, of which 107 were unknown to these databases. Most unknown variants (n = 83) were population-specific common variants and several (n = 7) were found in important CYP pharmacogenes (CYP2D6, CYP4F2, and CYP2C19). Overall, 29% (n = 31) of 107 unknown variants were predicted to affect CYP enzyme function although further biochemical characterization is necessary. These variants may elucidate part of the unexplained interpopulation differences observed in drug response.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Citocromo P-450 CYP2D6 / Sistema Enzimático do Citocromo P-450 Limite: Humans Idioma: En Revista: Hum Mutat Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Citocromo P-450 CYP2D6 / Sistema Enzimático do Citocromo P-450 Limite: Humans Idioma: En Revista: Hum Mutat Ano de publicação: 2021 Tipo de documento: Article