Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure

Moore, J., McKnight, A.J., Simmonds, M. J. , Courtney, A. E., Hanvesakul, R., Brand, O. J., Briggs, D., Ball, S., Cockwell, P., Patterson, C.C., Maxwell, A. P., Gough, S. C. L. and Borrows, R. (2010) Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure. JAMA - Journal of the American Medical Association, 303 (13). pp. 1282-1287. ISSN 0098-7484

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Context Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis. Objective To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis. Design, Setting, and Patients Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median followup, 81 months) were analyzed for common variation in CAV1 using a singlenucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n=697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model. Main Outcome Measure Death-censored allograft failure, defined as a return to dialysis or retransplantation. Results The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio HR, 1.97; 95% confidence interval CI, 1.29-3.16; P=.002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P=.02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%). Conclusion Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

Keywords:caveolin 1, caveolin 1, adult, article, cohort analysis, controlled study, dialysis, DNA polymorphism, female, follow up, genetic association, genetic variability, genotype, graft failure, graft recipient, graft survival, histopathology, human, kidney allograft, kidney donor, kidney fibrosis, kidney transplantation, major clinical study, male, nucleotide sequence, priority journal, retransplantation, risk assessment, single nucleotide polymorphism, surgical mortality, United Kingdom, validation study, allotransplantation, donor, fibrosis, genetic polymorphism, genetic predisposition, genetics, kidney, middle aged, pathology, pathophysiology, treatment failure, Adult, Cohort Studies, England, Genetic Predisposition to Disease, Humans, Polymorphism, Genetic, Tissue Donors, Transplantation, Homologous, Treatment Failure
Subjects:C Biological Sciences > C420 Human Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:22609
Deposited On:18 Mar 2016 10:02

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