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A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD

DC FieldValueLanguage
dc.contributor.author김원호-
dc.contributor.author김한상-
dc.contributor.author박수정-
dc.contributor.author박준희-
dc.contributor.author이민구-
dc.contributor.author정은석-
dc.contributor.author천재희-
dc.date.accessioned2018-07-20T08:11:29Z-
dc.date.available2018-07-20T08:11:29Z-
dc.date.issued2017-
dc.identifier.issn0017-5749-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/160941-
dc.description.abstractOBJECTIVE: Myelosuppression is a life-threatening complication of thiopurine therapy, and the incidence of thiopurine-induced myelosuppression is higher in East Asians than in Europeans. We investigated genetic factors associated with thiopurine-induced leukopenia in patients with IBD. DESIGN: A genome-wide association study (GWAS) was conducted in thiopurine-treated patients with IBD, followed by high-throughput sequencing of genes identified as significant in the GWAS or those involved in thiopurine metabolism (n=331). Significant loci associated with thiopurine-induced leukopenia were validated in two additional replication cohorts (n=437 and n=330). Functional consequences of FTO (fat mass and obesity-associated) variant were examined both in vitro and in vivo. RESULTS: The GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920, FTO intron; rs2834826, RUNX1 intergenic). High-throughput targeted sequencing indicated that an FTO coding variant (rs79206939, p.A134T) linked to rs16957920 is associated with thiopurine-induced leukopenia. This result was further validated in two replication cohorts (combined p=1.3×10-8, OR=4.3). The frequency of FTO p.A134T is 5.1% in Koreans but less than 0.1% in Western populations. The p.A134T variation reduced FTO activity by 65% in the nucleotide demethylase assay. In vivo experiments revealed that Fto-/- and Fto+/- mice were more susceptible to thiopurine-induced myelosuppression than wild-type mice. CONCLUSIONS: The results suggest that the hypomorphic FTO p.A134T variant is associated with thiopurine-induced leukopenia. These results shed light on the novel physiological role of FTO and provide a potential pharmacogenetic biomarker for thiopurine therapy.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherBritish Medical Assn.-
dc.relation.isPartOfGUT-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAdolescent-
dc.subject.MESHAdult-
dc.subject.MESHAged-
dc.subject.MESHAlpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics*-
dc.subject.MESHAnimals-
dc.subject.MESHAzathioprine/adverse effects*-
dc.subject.MESHAzathioprine/therapeutic use-
dc.subject.MESHCase-Control Studies-
dc.subject.MESHCohort Studies-
dc.subject.MESHFemale-
dc.subject.MESHGenetic Markers-
dc.subject.MESHGenome-Wide Association Study-
dc.subject.MESHHigh-Throughput Nucleotide Sequencing-
dc.subject.MESHHumans-
dc.subject.MESHImmunosuppressive Agents/adverse effects*-
dc.subject.MESHImmunosuppressive Agents/therapeutic use-
dc.subject.MESHInflammatory Bowel Diseases/drug therapy*-
dc.subject.MESHInflammatory Bowel Diseases/genetics-
dc.subject.MESHLeukopenia/chemically induced*-
dc.subject.MESHLeukopenia/genetics-
dc.subject.MESHMale-
dc.subject.MESHMercaptopurine/adverse effects*-
dc.subject.MESHMercaptopurine/therapeutic use-
dc.subject.MESHMice-
dc.subject.MESHMice, Knockout-
dc.subject.MESHMiddle Aged-
dc.subject.MESHPolymorphism, Single Nucleotide*-
dc.subject.MESHRepublic of Korea-
dc.subject.MESHSequence Analysis, DNA-
dc.subject.MESHYoung Adult-
dc.titleA coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Internal Medicine-
dc.contributor.googleauthorHan Sang Kim-
dc.contributor.googleauthorJae Hee Cheon-
dc.contributor.googleauthorEun Suk Jung-
dc.contributor.googleauthorJoonhee Park-
dc.contributor.googleauthorSowon Aum-
dc.contributor.googleauthorSoo Jung Park-
dc.contributor.googleauthorSungho Eun-
dc.contributor.googleauthorJinu Lee-
dc.contributor.googleauthorUlrich Rüther-
dc.contributor.googleauthorGiles S H Yeo-
dc.contributor.googleauthorMarcella Ma-
dc.contributor.googleauthorKyong Soo Park-
dc.contributor.googleauthorTakeo Naito-
dc.contributor.googleauthorYoichi Kakuta-
dc.contributor.googleauthorJi Hyun Lee-
dc.contributor.googleauthorWon Ho Kim-
dc.contributor.googleauthorMin Goo Lee-
dc.identifier.doi10.1136/gutjnl-2016-311921-
dc.contributor.localIdA00774-
dc.contributor.localIdA01098-
dc.contributor.localIdA01539-
dc.contributor.localIdA01678-
dc.contributor.localIdA02781-
dc.contributor.localIdA03685-
dc.contributor.localIdA04030-
dc.relation.journalcodeJ00953-
dc.identifier.eissn1468-3288-
dc.identifier.pmid27558924-
dc.identifier.urlhttp://gut.bmj.com/content/66/11/1926.long-
dc.subject.keywordAZATHIOPRINE-
dc.subject.keywordDRUG TOXICITY-
dc.subject.keywordGENETICS-
dc.subject.keywordINFLAMMATORY BOWEL DISEASE-
dc.contributor.alternativeNameKim, Won Ho-
dc.contributor.alternativeNameKim, Han Sang-
dc.contributor.alternativeNamePark, Soo Jung-
dc.contributor.alternativeNamePark, Joonhee-
dc.contributor.alternativeNameLee, Min Goo-
dc.contributor.alternativeNameJung, Eun Suk-
dc.contributor.alternativeNameCheon, Jae Hee-
dc.contributor.affiliatedAuthorKim, Won Ho-
dc.contributor.affiliatedAuthorKim, Han Sang-
dc.contributor.affiliatedAuthorPark, Soo Jung-
dc.contributor.affiliatedAuthorPark, Joonhee-
dc.contributor.affiliatedAuthorLee, Min Goo-
dc.contributor.affiliatedAuthorJung, Eun Suk-
dc.contributor.affiliatedAuthorCheon, Jae Hee-
dc.citation.volume66-
dc.citation.number11-
dc.citation.startPage1926-
dc.citation.endPage1935-
dc.identifier.bibliographicCitationGUT, Vol.66(11) : 1926-1935, 2017-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers

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