Human UDP-glycosyltransferases(UGTs)are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs.Different genetic polymorphisms in UGT genes are implicated in interin...Human UDP-glycosyltransferases(UGTs)are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs.Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk.However,the genetic complexity beyond these variants has not been comprehensively assessed.We here leveraged wholeexome and whole-genome sequencing data from 141,456 unrelated individuals across 7 major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family.Overall,9666 exonic variants were observed,of which 98.9%were rare.To interpret the functional impact of UGT missense variants,we developed a gene family-specific variant effect predictor.This algorithm identified a total of 1208 deleterious variants,most of which were found in African and South Asian populations.Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites.Combined,our analyses provide a systematic overview of UGT variability,which can yield insights into interindividual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.展开更多
基金support from the Swedish Research Council(grant numbers 2021-02801 and 2023-03015)Cancerfonden(grant23-0763 PT)+2 种基金by the SciLifeLab and Wallenberg National Program for Data-Driven Life Science(grant WASPDDLS22:006)the Robert Bosch Foundation,Stuttgart,Germany and from the National Autonomous University of Mexico(UNAM)DGECI program Initiation to Research 2023supported in part by the South African Medical Research Council(SAMRC)。
文摘Human UDP-glycosyltransferases(UGTs)are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs.Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk.However,the genetic complexity beyond these variants has not been comprehensively assessed.We here leveraged wholeexome and whole-genome sequencing data from 141,456 unrelated individuals across 7 major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family.Overall,9666 exonic variants were observed,of which 98.9%were rare.To interpret the functional impact of UGT missense variants,we developed a gene family-specific variant effect predictor.This algorithm identified a total of 1208 deleterious variants,most of which were found in African and South Asian populations.Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites.Combined,our analyses provide a systematic overview of UGT variability,which can yield insights into interindividual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.
