Genome-Wide Association Study of Acute Renal Graft Rejection.
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.
Department of Nephrology, Dialysis, and Transplantation, Hôpital Erasme (Université Libre de Bruxelles), Brussels, Belgium.
L
L
Ghisdal
Department of Nephrology, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
C
C
Baron
Department of Nephrology, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
Y
Y
Lebranchu
Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
O
O
Viklický
Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
A
A
Konarikova
Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium.|Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.
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M
Naesens
Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium.|Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.
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D
Kuypers
Department of Nephrology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.
M
M
Dinic
Department of Nephrology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.
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E
Alamartine
Department of Nephrology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
G
G
Touchard
Department of Nephrology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
T
T
Antoine
Department of Nephrology, Dialysis, Transplantation, Centre Hospitalier Universitaire de Limoges and INSERM UMR 850 (Université de Limoges), Limoges, France.
M
M
Essig
Department of Nephrology, Dialysis, Transplantation, Centre Hospitalier Universitaire de Limoges and INSERM UMR 850 (Université de Limoges), Limoges, France.
J P
JP
Rerolle
Department of Nephrology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
P
P
Merville
Department of Immunology and Histocompatibility, Hôpital Saint-Louis, Paris, France.
J L
JL
Taupin
Department of Nephrology, Centre Hospitalier Universitaire la Cavale blanche, Brest, France.
Y
Y
Le Meur
Department of Nephrology, Centre Hospitalier Universitaire la Cavale blanche, Brest, France.
A
A
Grall-Jezequel
Department of Nephrology, Centre Régional Hospitalier Universitaire de Lille, Lille, France.
F
F
Glowacki
Department of Nephrology, Centre Régional Hospitalier Universitaire de Lille, Lille, France.
C
C
Noël
Department of Renal Transplantation, Université Paris Descartes and Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.
C
C
Legendre
Department of Renal Transplantation, Université Paris Descartes and Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.
D
D
Anglicheau
Department of Nephrology, Dialysis, and Transplantation, Hôpital Erasme (Université Libre de Bruxelles), Brussels, Belgium.
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0000-0001-5377-9335
N
Broeders
Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Research (GIGA-R), University of Liège, Liège, Belgium.
W
W
Coppieters
Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Research (GIGA-R), University of Liège, Liège, Belgium.
E
E
Docampo
Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Research (GIGA-R), University of Liège, Liège, Belgium.
M
M
Georges
Institute of Interdisciplinary Research in Molecular and Human biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
Z
Z
Ajarchouh
Department of Nephrology, Dialysis, and Transplantation, Hôpital Erasme (Université Libre de Bruxelles), Brussels, Belgium.|Institute of Interdisciplinary Research in Molecular and Human biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
A
A
Massart
Centre of Epidemiology, Biostatistic and Clinical Research, School of Public Health (Université Libre de Bruxelles), Brussels, Belgium.
J
J
Racapé
Department of Nephrology, Dialysis, and Transplantation, Hôpital Erasme (Université Libre de Bruxelles), Brussels, Belgium.|Department of Nephrology, Antwerp University Hospital, Antwerpen, Belgium.
D
D
Abramowicz
Institute of Interdisciplinary Research in Molecular and Human biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.|Medical Genetics Department, Hôpital Erasme (Université Libre de Bruxelles), Brussels, Belgium.
M
M
Abramowicz
D000208:Acute Disease; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C576056:DEUP1 protein, human; D005819:Genetic Markers; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; C516888:PTPRO protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
basic (laboratory) research/science; biomarker; genetics; genomics; immunogenetics; immunosuppression/immune modulation; kidney transplantation/nephrology; microarray/gene array; rejection: T cell mediated (TCMR)