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Unraveling the Genomic Architecture of the CYP3A Locus and ADME Genes for Personalized Tacrolimus Dosing

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dc.contributor.author김명수-
dc.contributor.author송승환-
dc.contributor.author윤지훈-
dc.contributor.author이민구-
dc.date.accessioned2021-10-21T00:17:45Z-
dc.date.available2021-10-21T00:17:45Z-
dc.date.issued2021-10-
dc.identifier.issn0041-1337-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/185463-
dc.description.abstractBackground: Tacrolimus (TAC) is an immunosuppressant widely prescribed following an allogenic organ transplant. Due to wide interindividual pharmacokinetic (PK) variability, optimizing TAC dosing based on genetic factors is required to minimize nephrotoxicity and acute rejections. Methods: We enrolled 1133 participants receiving TAC from 4 cohorts, consisting of 3 with kidney transplant recipients and 1 with healthy males from clinical trials. The effects of clinical factors were estimated to appropriately control confounding variables. A genome-wide association study, haplotype analysis, and a gene-based association test were conducted using the Korea Biobank Array or targeted sequencing for 114 pharmacogenes. Results: Genome-wide association study verified that CYP3A5*3 is the only common variant associated with TAC PK variability in Koreans. We detected several CYP3A5 and CYP3A4 rare variants that could potentially affect TAC metabolism. The haplotype structure of CYP3A5 stratified by CYP3A5*3 was a significant factor for CYP3A5 rare variant interpretation. CYP3A4 rare variant carriers among CYP3A5 intermediate metabolizers displayed higher TAC trough levels. Gene-based association tests in the 61 absorption, distribution, metabolism, and excretion genes revealed that CYP1A1 are associated with additional TAC PK variability: CYP1A1 rare variant carriers among CYP3A5 poor metabolizers showed lower TAC trough levels than the noncarrier controls. Conclusions: Our study demonstrates that rare variant profiling of CYP3A5 and CYP3A4, combined with the haplotype structures of CYP3A locus, provide additive value for personalized TAC dosing. We also identified a novel association between CYP1A1 rare variants and TAC PK variability in the CYP3A5 nonexpressers that needs to be further investigated.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherLippincott Williams & Wilkins-
dc.relation.isPartOfTRANSPLANTATION-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleUnraveling the Genomic Architecture of the CYP3A Locus and ADME Genes for Personalized Tacrolimus Dosing-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Surgery (외과학교실)-
dc.contributor.googleauthorJihoon G Yoon-
dc.contributor.googleauthorSeung Hwan Song-
dc.contributor.googleauthorSungkyoung Choi-
dc.contributor.googleauthorJaeseong Oh-
dc.contributor.googleauthorIn-Jin Jang-
dc.contributor.googleauthorYoung Jin Kim-
dc.contributor.googleauthorSanghoon Moon-
dc.contributor.googleauthorBong-Jo Kim-
dc.contributor.googleauthorYuri Cho-
dc.contributor.googleauthorHyo Kee Kim-
dc.contributor.googleauthorSangil Min-
dc.contributor.googleauthorJongwon Ha-
dc.contributor.googleauthorHo Sik Shin-
dc.contributor.googleauthorChul Woo Yang-
dc.contributor.googleauthorHye Eun Yoon-
dc.contributor.googleauthorJaeseok Yang-
dc.contributor.googleauthorMin Goo Lee-
dc.contributor.googleauthorJae Berm Park-
dc.contributor.googleauthorMyoung Soo Kim-
dc.identifier.doi10.1097/TP.0000000000003660-
dc.contributor.localIdA00424-
dc.contributor.localIdA04963-
dc.contributor.localIdA04987-
dc.contributor.localIdA02781-
dc.relation.journalcodeJ02754-
dc.identifier.eissn1534-6080-
dc.identifier.pmid33654003-
dc.identifier.urlhttps://journals.lww.com/transplantjournal/Fulltext/2021/10000/Unraveling_the_Genomic_Architecture_of_the_CYP3A.18.aspx-
dc.contributor.alternativeNameKim, Myoung Soo-
dc.contributor.affiliatedAuthor김명수-
dc.contributor.affiliatedAuthor송승환-
dc.contributor.affiliatedAuthor윤지훈-
dc.contributor.affiliatedAuthor이민구-
dc.citation.volume105-
dc.citation.number10-
dc.citation.startPage2213-
dc.citation.endPage2225-
dc.identifier.bibliographicCitationTRANSPLANTATION, Vol.105(10) : 2213-2225, 2021-10-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers

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