Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

Centre of Epidemiology Biostatistic and Clinical Research School of Public Health Brussels Belgium

Department of Immunology and Histocompatibility Hôpital Saint Louis Paris France

Department of Microbiology and Immunology KU Leuven University of Leuven Leuven Belgium

Department of Nephrology Antwerp University Hospital Antwerpen Belgium

Department of Nephrology Centre Hospitalier Régional Universitaire de Tours Tours France

Department of Nephrology Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Department of Nephrology Centre Hospitalier Universitaire de Poitiers Poitiers France

Department of Nephrology Centre Hospitalier Universitaire de Saint Etienne Saint Etienne France

Department of Nephrology Centre Hospitalier Universitaire la Cavale blanche Brest France

Department of Nephrology Centre Régional Hospitalier Universitaire de Lille Lille France

Department of Nephrology Dialysis and Transplantation Hôpital Erasme Brussels Belgium

Department of Nephrology Dialysis Transplantation Centre Hospitalier Universitaire de Limoges and INSERM UMR 850 Limoges France

Department of Nephrology Transplant Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Nephrology University Hospitals Leuven Leuven Belgium

Department of Renal Transplantation Université Paris Descartes and Hôpital Necker Assistance Publique Hôpitaux de Paris Paris France

Institute of Interdisciplinary Research in Molecular and Human biology Université Libre de Bruxelles Brussels Belgium

Medical Genetics Department Hôpital Erasme Brussels Belgium

Unit of Animal Genomics Groupe Interdisciplinaire de Génoprotéomique Appliquée Research University of Liège Liège Belgium

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An exome-wide study of renal operational tolerance