Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome 英文参考文献.docVIP

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Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome 英文参考文献.doc

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Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome 英文参考文献

HarvestingCandidateGenesResponsibleforSerious AdverseDrugReactionsfromaChemical-Protein Interactome LunYang1,2*,JianChen1,LinHe1,2,3* 1Bio-XCenter,KeyLaboratoryfortheGeneticsofDevelopmentalandNeuropsychiatricDisorders(MinistryofEducation),ShanghaiJiaoTongUniversity,Shanghai,China, 2InstituteofBiomedicalSciences,FudanUniversity,Shanghai,China,3InstituteforNutritionalSciences,ShanghaiInstitutesofBiologicalSciences,ChineseAcademyof Sciences,Shanghai,China Abstract Identifying genetic factors responsible for serious adverse drug reaction (SADR) is of critical importance to personalized medicine. However, genome-wide association studies are hampered due to the lack of case-control samples, and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesizethatdrugscausingthesametypeofSADRmightshareacommonmechanismbytargetingunexpectedlythe same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI), a matrix of binding strengths among 162 drug moleculesknowntocauseatleastonetypeofSADRand845proteins.DrugssharingthesameSADRoutcomewerealso foundtopossesssimilaritiesintheirCPIprofilestowardsthis845proteinset.Thismethodologyidentifiedthecandidate gene ofsulfonamide-induced toxic epidermal necrolysis (TEN):all ninesulfonamidesthat cause TENwerefound tobind stronglytoMHCI(Cw*4),whereasnoneofthe17controldrugsthatdonotcauseTENwerefoundtobindtoit.Throughan insightintotheCPI,wefoundtheY116SsubstitutionofMHCI(B*5703)enhancestheunexpectedbindingofabacavirtoits antigenpresentationgroove,whichexplainswhyB*5701,notB*5703,istheriskalleleofabacavir-inducedhypersensitivity. Inconclusion,SADRtargetsandthepatient-specificoff-targetscouldbeidentifiedthroughasystematicinvestigationofthe CPI,generatingimportanthypothesesforprospectiveexperimentalvalidationofthecandidategenes. Citation:YangL,ChenJ,HeL(2009)Harvesting