Donor ABCB1 variant associates with increased risk for kidney allograft failure

Moore, Jason, McKnight, Amy Jayne, Döhler, Bernd , Simmonds, Matthew J., Courtney, Aisling E., Brand, Oliver J., Briggs, David, Ball, Simon, Cockwell, Paul, Patterson, Christopher C., Maxwell, Alexander P., Gough, Stephen C. L., Opelz, Gerhard and Borrows, Richard (2012) Donor ABCB1 variant associates with increased risk for kidney allograft failure. Journal of the American Society of Nephrology, 23 (11). pp. 1891-1899. ISSN 1046-6673

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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 in fluence 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. Copyright © 2012 by the American Society of Nephrology.

Keywords:cyclophilin, cytochrome P450 3A4, cytochrome P450 3A5, multidrug resistance protein 1, pregnane X receptor, ABCB1 gene, adult, article, controlled study, CYP3A4 gene, CYP3A5 gene, female, gene, gene linkage disequilibrium, genetic association, genetic risk, genetic variability, genotype, graft failure, graft recipient, graft survival, human, kidney allograft, kidney allograft failure, kidney donor, kidney transplantation, major clinical study, male, mortality, NR1I2 gene, outcome assessment, PPIA gene, priority journal, protein expression, risk assessment, single nucleotide polymorphism, United Kingdom, Adult, Calcineurin, Cohort Studies, Cyclophilins, Cytochrome P-450 CYP3A, Genetic Association Studies, Great Britain, Humans, Kaplan-Meier Estimate, Linkage Disequilibrium, Middle Aged, P-Glycoprotein, Polymorphism, Single Nucleotide, Receptors, Steroid, Risk Factors, Tissue Donors
Subjects:C Biological Sciences > C420 Human Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:22602
Deposited On:01 Apr 2016 07:43

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