Synergistic Effect of Cytochrome P450 Family 3 Subfamily A Member 5 (CYP3A5) Genetic Variants in Tacrolimus Dose Determination in Indian Renal Transplant Patients

Tacrolimus (TAC) has a narrow therapeutic index and shows interindividual variabilities in its blood concentration. Although guidelines recommend a genetic variant (rs776746) to determine the optimized TAC dose, discrepancies in accuracy have been noted. Therefore, studying other variants of CYP3A5 may improve the accuracy of the TAC dose. Clinical exome sequencing (CES) was performed in 219 renal transplant patients. The SNPs of CYP3A5 covered by CES were recorded. The TAC blood trough concentration/dose (C-0/D) was calculated on day 7 and months 1, 3, 6, and 12 of post-transplantation, and association with CYP3A5 genotypes was studied. Further, biopsy-proven rejection and pathological events were analyzed for their association with CYP3A5 genotypes. Out of 35 variants of CYP3A5 covered in CES, rs776746, rs15524, rs4646449, and rs464645 were significantly associated with the TAC C-0/D on day 7 and months 1, 3, and 6. Further analysis showed that the slow-metabolizing genotypes of all four SNPs synergistically associated with the TAC C-0/D on day 7 and months 1, 3, 6, and 12. The "CC" genotype of rs776746 showed a significant association (RR = 1.613; p = 0.035) with allograft rejection. In addition, cox regression analysis showed that the presence of the "CA" genotype of rs4646453 increased (HR = 7.258; 95% CI = 1.354-38.904) the risk of development of pathological events, respectively. Four variants of CYP3A5 were synergistically associated with the TAC dose determination. In addition, rs776746 and rs4646453 may be associated with allograft rejection and pathological events, respectively.