Effect of gene polymorphisms on the levels of calcineurin inhibitors in Indian renal transplant recipients

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The outcome of renal transplantation is improved by cyclosporine and tacrolimus. However, its success is limited by drug-induced nephrotoxicity. Therefore, monitoring their levels is important. These levels are influenced mainly by CYP3A4, CYP3A5 and MDR- 1 genes. These levels also affect target molecules of CNIs, mainly IL-2. Inter-individual differences in these levels have been attributed to SNPs in these genes and hence study of these SNPs assumes significance. So far no study has been carried out on Indian renal transplant recipients covering the SNPs of the genes involved in metabolism, efflux and drug target of CNIs, hence the data is lacking for Indian population. The aim is to study A-392G SNP of CYP3A4, A6986G SNP of CYP3A5, C3435T SNP of MDR-1 and T-330G SNP of IL-2 genes and correlate with CNI blood levels. Hundred healthy subjects and 100 consecutive renal transplant recipients; 56 on CsA and 44 on tacrolimus were genotyped by PCR followed by restriction enzyme assay for mentioned SNPs. No significant difference was observed between level/dose (L/D) ratio of CNIs and CYP3A4 and IL-2 SNPs. However, median L/D ratio for tacrolimus was significantly higher in subjects with CYP3A5*3/*3 (n = 24) (P = 0.011) and MDR- 1 3435TT (n = 18) (P = 0.0122). The findings from this study show that homozygous mutant patients for CYP3A5 and MDR-1 gene SNPs could be managed with lower tacrolimus dose to avoid nephrotoxicity.