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

 Jihoon G Yoon  ;  Seung Hwan Song  ;  Sungkyoung Choi  ;  Jaeseong Oh  ;  In-Jin Jang  ;  Young Jin Kim  ;  Sanghoon Moon  ;  Bong-Jo Kim  ;  Yuri Cho  ;  Hyo Kee Kim  ;  Sangil Min  ;  Jongwon Ha  ;  Ho Sik Shin  ;  Chul Woo Yang  ;  Hye Eun Yoon  ;  Jaeseok Yang  ;  Min Goo Lee  ;  Jae Berm Park  ;  Myoung Soo Kim 
 TRANSPLANTATION, Vol.105(10) : 2213-2225, 2021-10 
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Background: 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.
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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
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Song, Seung Hwan(송승환)
Yoon, Jihoon G.(윤지훈) ORCID logo https://orcid.org/0000-0002-4401-7803
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
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