Effect of Donor GSTM3 Rs7483 Genetic Variant on Tacrolimus Elimination in the Early Period After Liver Transplantation

Overview

Journal PeerJ

Specialties Biology
Environmental Health
General Medicine

Date 2024 Oct 28

PMID 39465171

Authors

Tao Zhang

Xiaorong Chen

Yuan Liu

Lei Zhang

Affiliations

Soon will be listed here.

Abstract

Purpose: Glutathione S-transferase mu (GSTM) belongs to the group of phase II drug-metabolizing enzymes, and the GSTM1 genetic variant has been reported to have a potential association with the metabolism of immunosuppressive drug after renal transplantation. The effect of donor and recipient GSTMs genetic variants on tacrolimus (Tac) metabolism was the focus of our investigation in this study.

Methods: A total of 203 liver transplant patients were recruited for the study. In the training set ( = 110), twenty-one SNPs in five genes (GSTM1-5) were genotyped by the drug-metabolizing enzymes and transporter (DMET) microarray. CYP3A5 rs776746 and GSTM3 rs7483 were genotyped using a Mass ARRAY platform in the validating set ( = 93).

Results: Tac C/D ratios of donor GSTM3 rs7483 AA carriers were significantly lower than those with the G allele at weeks 1, 2, 3 and 4 after liver transplantation (LT). Multivariate analysis was conducted on the training set and validating set, donor and recipient CYP3A5 rs776746, donor GSTM3 rs7483 and total bilirubin were identified as independent predictors of Tac C/D ratios in the early period after LT. Combining CYP3A5 rs776746 and donor GSTM3 rs7483 genotypes, Tac C/D ratios were observed to be increasingly lower with increasing numbers of alleles associated with fast metabolism. Moreover, the risk of a supratherapeutic C (Tac > 15 ug/L) was significantly higher for poor metabolizers than the other groups at week 1 after LT.

Conclusions: There was a significant association between the donor GSTM3 rs7483 genetic variant and Tac metabolism in the early period after LT. Genotype classification might have a better predictive ability of the initial Tac doses.

References

Shaked O, Loza B, Olthoff K, Reddy K, Keating B, Testa G . Donor and recipient genetics: Implications for the development of posttransplant diabetes mellitus. Am J Transplant. 2024; 24(10):1794-1802. DOI: 10.1016/j.ajt.2024.05.014. View

Sallustio B, Noll B, Hu R, Barratt D, Tuke J, Coller J . Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients. Br J Clin Pharmacol. 2021; 87(10):3901-3909. DOI: 10.1111/bcp.14806. View

Di Martino M, Arbitrio M, Guzzi P, Leone E, Baudi F, Piro E . A peroxisome proliferator-activated receptor gamma (PPARG) polymorphism is associated with zoledronic acid-related osteonecrosis of the jaw in multiple myeloma patients: analysis by DMET microarray profiling. Br J Haematol. 2011; 154(4):529-33. PMC: 3638364. DOI: 10.1111/j.1365-2141.2011.08622.x. View

Uno Y, Uehara S, Tanaka S, Murayama N, Yamazaki H . Systematic characterization of glutathione S-transferases in common marmosets. Biochem Pharmacol. 2020; 174:113835. DOI: 10.1016/j.bcp.2020.113835. View

Tatemichi M, Iwasaki M, Sasazuki S, Tsugane S . Association between polymorphisms in glutathione S-transferase Mu3 and IgG titer levels in serum against Helicobacter pylori. J Hum Genet. 2009; 54(10):557-63. DOI: 10.1038/jhg.2009.77. View

Singh R, Manchanda P, Kesarwani P, Srivastava A, Mittal R . Influence of genetic polymorphisms in GSTM1, GSTM3, GSTT1 and GSTP1 on allograft outcome in renal transplant recipients. Clin Transplant. 2009; 23(4):490-8. DOI: 10.1111/j.1399-0012.2009.00985.x. View

Everton J, Patricio F, Faria M, Ferreira T, Romao E, Silva G . CYP3A5 and PPARA genetic variants are associated with low trough concentration to dose ratio of tacrolimus in kidney transplant recipients. Eur J Clin Pharmacol. 2021; 77(6):879-886. DOI: 10.1007/s00228-020-03076-8. View

Hayes J, Strange R . Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000; 61(3):154-66. DOI: 10.1159/000028396. View

Azhie A, Sheth P, Hammad A, Woo M, Bhat M . Metabolic Complications in Liver Transplantation Recipients: How We Can Optimize Long-Term Survival. Liver Transpl. 2021; 27(10):1468-1478. DOI: 10.1002/lt.26219. View

10.

Evans W, McLeod H . Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med. 2003; 348(6):538-49. DOI: 10.1056/NEJMra020526. View

11.

Du W, Wang X, Zhang D, Zuo X . Exploratory associations of tacrolimus exposure and clinical outcomes after lung transplantation: A retrospective, single center experience. Eur J Clin Pharmacol. 2024; 80(5):747-757. DOI: 10.1007/s00228-024-03640-6. View

12.

Zhang X, Men T, Liu H, Li X, Wang J, Lv J . Genetic risk factors for post-transplantation diabetes mellitus in Chinese Han renal allograft recipients treated with tacrolimus. Transpl Immunol. 2018; 49:39-42. DOI: 10.1016/j.trim.2018.04.001. View

13.

Tang J, Xu J, Zhang Y, Liu R, Liu M, Hu Y . Incorporation of Gene-Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients. J Clin Pharmacol. 2019; 59(6):890-899. DOI: 10.1002/jcph.1379. View

14.

Liu Y, Li C, Cui Z, Fu X, Zhang S, Fan L . The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: a meta-analysis. Gene. 2013; 531(2):476-88. DOI: 10.1016/j.gene.2013.09.024. View

15.

Fan J, Zhang X, Ren L, Chen D, Wu S, Guo F . Donor IL-18 rs5744247 polymorphism as a new biomarker of tacrolimus elimination in Chinese liver transplant patients during the early post-transplantation period: results from two cohort studies. Pharmacogenomics. 2015; 16(3):239-50. DOI: 10.2217/pgs.14.166. View

16.

Nuchjumroon A, Vadcharavivad S, Singhan W, Poosoonthornsri M, Chancharoenthana W, Udomkarnjananun S . Comparison of Tacrolimus Intra-Patient Variability during 6-12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers. J Clin Med. 2022; 11(21). PMC: 9658797. DOI: 10.3390/jcm11216320. View

17.

Santos K, Lodge C, Abramson M, Erbas B, Bennett C, Hui J . Early-Life Exposure to Oral Antibiotics and Lung Function Into Early Adulthood. Chest. 2019; 157(2):334-341. DOI: 10.1016/j.chest.2019.10.004. View

18.

Huang S, Song W, Jiang S, Li Y, Wang M, Yang N . Pharmacokinetic interactions between tacrolimus and Wuzhi capsule in liver transplant recipients: Genetic polymorphisms affect the drug interaction. Chem Biol Interact. 2024; 391:110906. DOI: 10.1016/j.cbi.2024.110906. View

19.

Tan X, Wang Y, Han Y, Chang W, Su T, Hou J . Genetic variation in the GSTM3 promoter confer risk and prognosis of renal cell carcinoma by reducing gene expression. Br J Cancer. 2013; 109(12):3105-15. PMC: 3859948. DOI: 10.1038/bjc.2013.669. View

20.

Garcia Rodriguez A, de la Casa M, Johnston S, Gosalvez J, Roy R . Association of polymorphisms in genes coding for antioxidant enzymes and human male infertility. Ann Hum Genet. 2018; 83(1):63-72. DOI: 10.1111/ahg.12286. View