Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20–2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21–2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08–3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.Calcineurin inhibitors (CNIs) remain principal components of most immunosuppression regimens in kidney transplantation. CNI dose adjustments based on CNI blood levels is the traditional approach to drug administration; however, this is an imperfect approach because CNIs have a narrow therapeutic index and high pharmacokinetic variability.¹ The unpredictable response to CNI drug dosing has been attributed to interindividual differences in expression of drug-metabolizing enzymes and transporters. Important components of this CNI disposition “axis” are the nuclear pregnane X receptor (PXR, encoded by the nuclear receptor subfamily 1, group I, member 2 [NR1I2] gene), which is proposed to be a “master regulator” of hepatic drug handling; cytochrome P450 (CYP) enzymes 3A4 and 3A5; the drug transporter P-glycoprotein (P-gp, encoded by the ATP-binding cassette, sub-family B, member 1 [ABCB1] gene, also known as the multidrug resistance 1 [MDR-1] gene); and cyclophilin A (Cyp, encoded by the peptidylprolyl isomerase A [PPIA] gene), the target of cyclosporine.^2–6Although data are inconsistent, there is evidence that single-nucleotide polymorphisms (SNPs) within these genes are associated with variation in cyclosporine and tacrolimus pharmacokinetics.^7–9 Preliminary and unreplicated reports also suggest that recipient genotype for ABCB1 is associated with delayed graft function¹⁰ and acute rejection,^11,12 and recipient CYP3A5 genotype is associated with mortality.¹³ However, with the exception of this report by Kreutz and colleagues,¹³ no studies have addressed the relationship between recipient genotype and the important “hard” clinical endpoints of renal transplantation (i.e., allograft failure or mortality), with limitations stemming from small sample sizes and short follow-up.¹⁴In contrast to studies of recipient genotype, far less information is available on the relationship between SNPs within genes of the kidney transplant donor and subsequent outcome. Although reduced expression of CYP3A5 and P-gp within the transplanted kidney have been associated with CNI toxicity,^15,16 only two small published studies to date have addressed the relationship between donor SNPs and clinical outcomes in cyclosporine-treated patients. These provide some evidence for an association between genetic variation in donor ABCB1 and acute cyclosporine nephrotoxicity¹⁷ and allograft failure.¹⁸ Both studies focused on the C3435T polymorphism within the ABCB1 gene, an exonic SNP whereby the TT genotype is associated with reduced P-gp expression.¹⁹The purpose of this study was to assess the relationship of both donor and recipient genotype with kidney allograft survival and recipient mortality. The study was not restricted to the limited number of SNPs previously studied but rather involved a comprehensive survey of common sequence variation in the target genes involved in CNI disposition. This was accomplished by interrogating the International HapMap resource²⁰ and selecting 52 tagging SNPs to capture the majority of common variation within five candidate genes. Preliminary positive findings from an initial discovery cohort were examined in two further independent populations, incorporating a total of 4471 renal transplant recipients followed for up to 20 years.