Influence of Cyp3A4, Cyp3A5 and ABCB1 Polymorphisms on Tacrolimus Concentrations and Rejection Risk in Indian Kidney Transplant Recipients

Abstract

Background: Tacrolimus metabolism is known to be determined by gene polymorphisms. Cyp3A5 genotype has most widely been seen to be associated with tacrolimus metabolism. Studies on other genes have produced mixed results. Objective: We studied the association of three polymorphisms CYP3A4*1B (-392 G>A), CYP3A5 (6986 A>G), and ABCB1 (3435 T>C) on tacrolimus levels and their association with either rejection or nephrotoxicity (infection or tacrolimus toxicity) in renal transplant recipients from India. Materials and Methods: In this prospective cohort study, patients who underwent kidney transplantation between July 2018 and July 2023 were studied. Inclusion criteria: Patients who underwent Kidney Transplantation and were (i) on tacrolimus-based immunosuppression and (ii) not on medications known to interact with calcineurin inhibitors, such as ketoconazole, phenytoin, and diltiazem, were studied. Tacrolimus levels, tacrolimus concentration/dose (C/D) and tacrolimus C/D per kg body weight, at monthly time points posttransplant for 6 months and biopsy-proven rejection, infection, tacrolimus toxicity, and acute tubular necrosis data were collected. Results: Three hundred and twenty-seven patients were included in the study. Two hundred and fifty-seven were male and 70 were female. A total of 1402 tacrolimus samples were collected, with an average of 3.2 ± 2.1 samples per patient. Tacrolimus levels were significantly lower in the Cyp3A5 AG and AA GG genotypes versus GG (5.27 ± 2.95 and 6.22 ± 2.79 vs. 8.05 ± 4.83, P < 0.001) as were C/D (3.45 ± 2.29 and 3.37 ± 1.91 vs. 6.47 ± 4.44, P < 0.001) and C/D/W (52.45 ± 33.98 and 52.19 ± 32.61 vs. 98.09 ± 73.80, P < 0.001). Cyp3A5 AA and AG had higher rejection rates than GG (20% vs. 13 vs. 8%, P = 0.03). The relative risk of rejection with A versus G polymorphism was 1.9 (confidence interval: 1.03–3.58), P = 0.03. Cyp3A4 and ABCB1 polymorphism studies did not show any association with the parameters studied. Conclusion: Our study showed that Cyp3A5 gene polymorphisms were significantly associated with tacrolimus metabolism, rejection episodes, and rejection risk. Cyp3A4 and ABCB1 were not significantly associated with the parameters studied.