Human loci involved in drug biotransformation: worldwide genetic variation, population structure, and pharmacogenetic implications.

摘要: Understanding the role of inheritance in individual variation drug response is focus pharmacogenetics (PGx). A key part this understanding quantifying genetic ancestry phenotypic outcome. To provide insight into relationship between ethnicity and response, study first infers global distribution PGx defines its structure. Second, evaluates if geographic population structure stems from all loci general, or caused by specific genes. Lastly, we identify variants contributing greatest proportion such Our describes across 52 populations Human Genome Diversity Cell-Line Panel, most inclusive set human freely available for studies on variation. By analysing at 1,001 single nucleotide polymorphisms (SNPs) involved biotransformation exogenous substances, describe between-populations variation, as well geographical groupings diversity. In addition, with discriminant analysis principal component (DAPC), infer how many which groups are supported SNPs actually contribute to groups. results show that intergenic, synonymous non-synonymous similar levels globe. Conversely, coding Cytochrome P450s (mainly metabolizing substances) significantly higher diversity than other gene categories. Overall, correlates distances populations, apportionment observed rest genome. words, pattern has been mainly shaped demographic history our species, case The defined supports presence six clusters reflecting location samples. particular, DAPC analyses 27 substantially three functions. Among these SNPs, some, intronic rs1403527 NR1I2 rs699 AGT, known be associated responses. Their substantial different may have important implications practical applications.