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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.

Original publication

DOI

10.1681/ASN.2012030260

Type

Journal article

Journal

J Am Soc Nephrol

Publication Date

11/2012

Volume

23

Pages

1891 - 1899

Keywords

Adult, Calcineurin Inhibitors, Cohort Studies, Cyclophilins, Cytochrome P-450 CYP3A, Female, Genetic Association Studies, Graft Survival, Humans, Kaplan-Meier Estimate, Kidney Transplantation, Linkage Disequilibrium, Male, Middle Aged, P-Glycoprotein, P-Glycoproteins, Polymorphism, Single Nucleotide, Receptors, Steroid, Risk Factors, Tissue Donors, United Kingdom