Synergistic Effect of Cytochrome P450 Family 3 Subfamily A Member 5 (<i>CYP3A5)</i> 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 <i>CYP3A5</i> may improve the accuracy of the TAC dose. Clinical exome sequencing (CES) was performed in 219 renal transplant patients. The SNPs of <i>CYP3A5</i> covered by CES were recorded. The TAC blood trough concentration/dose (<i>C</i> ₀/<i>D</i>) was calculated on day 7 and months 1, 3, 6, and 12 of post-transplantation, and association with <i>CYP3A5</i> genotypes was studied. Further, biopsy-proven rejection and pathological events were analyzed for their association with <i>CYP3A5</i> genotypes. Out of 35 variants of <i>CYP3A5</i> covered in CES, rs776746, rs15524, rs4646449, and rs464645 were significantly associated with the TAC <i>C</i> ₀/<i>D</i> 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 <i>C</i> ₀/<i>D</i> on day 7 and months 1, 3, 6, and 12. The "CC" genotype of rs776746 showed a significant association (RR = 1.613; <i>p</i> = 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 <i>CYP3A5</i> were synergistically associated with the TAC dose determination. In addition, rs776746 and rs4646453 may be associated with allograft rejection and pathological events, respectively.