Global spectrum of population‐specific common missense variation in cytochrome P450 pharmacogenes

Abstract

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.

Genomic landscape of drug binding and pharmacogenetic variation across diverse populations using SNPdrug3D

“…5). Functional CYP variants are known to be unequally distributed amongst the world populations 9,54 and here we found that this variant is more common in the East Asian or Chinese populations but its effects on drug metabolism remain unreported. If the variant effect is substrate-speci c, potential drug-drug interactions involving CYP2D6 substrates may arise if the drug has a stronger a nity for the enzyme than concomitantly administered CYP2D6 substrates.…”

“…Annotation and prediction of population-speci c effects on drug binding is invaluable for drug development efforts which can study and address such effects early in the development pipeline avoiding costly surprises at later stages [36][37][38] . This especially includes effects in the important CYP family of drug metabolizing enzymes 39 .…”