Unraveling the Genomic Architecture of the CYP3A Locus and ADME Genes for Personalized Tacrolimus Dosing.
| Autor: | Yoon JG; Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Seoul, Republic of Korea., Song SH; Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.; Department of Surgery, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea., Choi S; Department of Applied Mathematics, Hanyang University (ERICA), Ansan, Republic of Korea., Oh J; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea., Jang IJ; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea., Kim YJ; Division of Genome Research, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, Republic of Korea., Moon S; Division of Genome Research, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, Republic of Korea., Kim BJ; Division of Genome Research, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, Republic of Korea., Cho Y; Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim HK; Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea., Min S; Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea., Ha J; Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea., Shin HS; Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea., Yang CW; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea., Yoon HE; Divison of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea., Yang J; Department of Surgery, Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea., Lee MG; Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Seoul, Republic of Korea., Park JB; Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Kim MS; Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea. |
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| Jazyk: | angličtina |
| Zdroj: | Transplantation [Transplantation] 2021 Oct 01; Vol. 105 (10), pp. 2213-2225. |
| DOI: | 10.1097/TP.0000000000003660 |
| Abstrakt: | 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. Competing Interests: The authors declare no conflicts of interest. (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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