Date Published: February 01, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Maria P. Hernandez‐Fuentes, Christopher Franklin, Irene Rebollo‐Mesa, Jennifer Mollon, Florence Delaney, Esperanza Perucha, Caragh Stapleton, Richard Borrows, Catherine Byrne, Gianpiero Cavalleri, Brendan Clarke, Menna Clatworthy, John Feehally, Susan Fuggle, Sarah A. Gagliano, Sian Griffin, Abdul Hammad, Robert Higgins, Alan Jardine, Mary Keogan, Timothy Leach, Iain MacPhee, Patrick B. Mark, James Marsh, Peter Maxwell, William McKane, Adam McLean, Charles Newstead, Titus Augustine, Paul Phelan, Steve Powis, Peter Rowe, Neil Sheerin, Ellen Solomon, Henry Stephens, Raj Thuraisingham, Richard Trembath, Peter Topham, Robert Vaughan, Steven H. Sacks, Peter Conlon, Gerhard Opelz, Nicole Soranzo, Michael E. Weale, Graham M. Lord.
Improvements in immunosuppression have modified short‐term survival of deceased‐donor allografts, but not their rate of long‐term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short‐ and long‐term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large‐scale genome‐wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant‐pairs with replication in 5866 complete pairs. We studied deceased‐donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long‐ or short‐term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
Kidney transplantation is a highly successful treatment for end‐stage renal failure, with significant benefits for recipients both in survival and quality of life. Early outcomes have steadily improved over the last 10 years,1 with risk‐adjusted and death‐censored, 1‐year renal graft survival rates of 94% and 97% for deceased and living donor transplants, respectively.2 However, both late allograft loss and increased mortality among transplant recipients remain key challenges for the transplant community. There are a wide number of factors that are known to influence long‐term transplant outcome, including donor factors such as age and comorbidity, recipient factors such as comorbidity and response to immunosuppression, as well as allograft ischemic time, the degree of HLA mismatch, and the development of donor‐specific antibodies.3, 4, 5 However, a comprehensive understanding of the pathophysiology of graft failure has remained elusive, with the observed variation in patient outcomes still inadequately explained by our current understanding of risk factors. An improved understanding of the determinants of transplantation outcome would allow the development of truly personalized approaches to the management of transplant recipients.
In this article, we report the results of the first large‐scale GWAS in renal transplantation. Despite our considerable sample size, we did not replicate any proposed findings from previous candidate gene studies nor did we discover any convincing new variants in our own analyses. There are a number of plausible reasons that may explain this.
M.P.H. conducted a literature search, did data and sample collection, manuscript preparation and review, and grant provision and supervision. C.F. and I.R.M. conducted a literature search, did data analysis and interpretation, manuscript preparation and review, and grant provision and supervision. J.M. conducted a literature search. F.D. did data and sample collection. E.P. conducted a literature search, did data and sample collection, did data analysis and interpretation, and manuscript preparation and review. C.S. did data analysis and interpretation. R.B., C.B., B.C., M.C., J.F., S.F., S.G., A.H., R.H., A.J., M.K., T.L., I.Mc., P.B.M., J.M., P.M., W.McK., A.McL., C.H., T.A., P.P., S.P., P.R., H.S., R.T., P.T., did data and sample collection and data analysis and interpretation. N.S. and E.S. did grant provision and supervision. R.T. did study design and grant provision and supervision. R.V. and S.S. did study design, data and sample collection, and data analysis and interpretation. G.C. and P.C. conducted a literature search, did the study design, data and sample collection, manuscript preparation and review, and grant provision and supervision. G.O. did data sample and collection. N.S. did manuscript preparation and review and grant provision and supervision. M.W. did study design, data analysis and interpretation, manuscript preparation and review, and grant provision and supervision. G.L. did study design, manuscript preparation and review, and grant provision and supervision.
The authors of this article have conflicts of interest to disclose as described by the American Journal of Transplantation. M.E.W. is an employee of Genomics plc, a company providing genomic analysis services to the pharmaceutical and health care sectors. M.H.F. and I.R.B. are employees of UCB Celltech, a pharmaceutical company. Their involvement in the conduct of this research was solely in their capacity as academics at King’s College London.