The effects of ABCB1 single nucleotide polymorphisms on tacrolimus pharmacokinetics and allograft outcomes after renal transplant

Background The ATP-binding cassette subfamily B member 1 transporter (ABCB1) encodes P-glycoprotein 1 that is responsible for efflux of tacrolimus. The ABCB1 gene is highly polymorphic. Previous data on the impact of single nucleotide polymorphisms (SNPs) in ABCB1 on pharmacokinetics of tacrolimus are conflicting. The retrospective research was designed to explore effects of the three SNPs in ABCB1 : rs1045642 (c.3435T>C), rs2032582 (c.2677T>G/A) and rs2032583 (c.2685 + 49T>C), on tacrolimus pharmacokinetics and allograft outcomes among renal allograft recipients. Methods Genotyping for the three SNPs in the ABCB1 gene was performed in 383 renal allograft recipients who underwent transplant at the University Hospital Essen between January 2011 and December 2015 and were maintained on tacrolimus-based immunosuppression. Patients were followed up for a mean time period of 5 years after transplant. Results Homozygous carriers of ABCB1 rs2032583 TT genotype expressed significantly higher concentration-to-dose (C/D) ratios of tacrolimus during the first 6 months posttransplant compared to carriers of ABCB1 rs2032583 C-allele. The ABCB1 rs1045642 TT/TC genotype carriers presented higher C/D ratios than CC genotype carriers whereas for ABCB1 rs2032582 the C/D ratios obtained within the first 6 months after transplant did not differ between the respective genotypes. The TT/TC genotype of ABCB1 rs1045642 (p = 0.01) and the TT genotype of ABCB1 rs2032583 (p = 0.02) were associated with reduced Cytomegalovirus (CMV)-free survival. The ABCB1 rs2032583 TT genotype carriers had lower BK viremia-free survival rates than the ABCB1 rs2032583 C-allele carriers (p = 0.008). BK viremia (p = 0.02) and subsequent BKV-associated nephropathy (p = 0.05) occurred earlier among ABCB1 rs2032582 TT/TA genotype carriers compared to the ABCB1 rs2032582 GG/GT/GA genotype carriers. Combination of ABCB1 rs2032583 TT genotype with ABCB1 rs2032582 TT/TA genotypes exerted a stronger effect on BK viremia-free survival and BKV-associated nephropathy-free survival than the two single polymorphisms. The proportion of allograft loss, decrease of renal allograft function and the calcineurin inhibitor mediated toxicity was significantly higher among ABCB1 rs1045642 CC genotype carriers than among ABCB1 rs1045642 TC/TT genotype carriers. Conclusion The genotypes ABCB1 rs1045642, rs2032582 and rs2032583 had an influence on common viral complications after renal transplant such as CMV and BK viremia and BKV-associated nephropathy that might be related to tacrolimus overexposure.