Genome-Wide Association Study of Acute Renal Graft Rejection.
L. Ghisdal
(1)
,
C. Baron
(2)
,
Y. Lebranchu
(2)
,
O. Viklický
(3)
,
A. Konarikova
(3)
,
M Naesens
(4)
,
D. Kuypers
(5)
,
M Dinic
(6)
,
E. Alamartine
(6)
,
G. Touchard
(7)
,
T. Antoine
(8)
,
M Essig
,
J. Rerolle
,
P. Merville
,
J.L. Taupin
(9)
,
Yves Le Meur
(10, 11)
,
A. Grall-Jezequel
(12, 11)
,
F. Glowacki
(13, 14)
,
C. Noël
(15)
,
C. Legendre
(16)
,
D Anglicheau
(17)
,
N. Broeders
(1)
,
W. Coppieters
(18)
,
E. Docampo
(18)
,
Mathias Georges
(19)
,
Z. Ajarchouh
(20)
,
A. Massart
(1)
,
J Racapé
(21)
,
D Abramowicz
(22)
,
M Abramowicz
(20, 23)
1
Department of Nephrology - Dialysis and Renal Transplantation
2 Service de néphrologie et immunologie clinique [CHRU Tours]
3 Department of Nephrology
4 Department of microbiology and Immunology
5 Department of Nephrology and Renal Transplantation
6 Department of Nephrology
7 Département de Néphrologie
8 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
9 AP-HP - Hopital Saint-Louis [AP-HP]
10 LBAI - Lymphocytes B, Autoimmunité et Immunothérapies
11 CHRU - Service de néphrologie, dialyse et transplantation rénale
12 LabEX IGO Immunothérapie Grand Ouest
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
15 INRS ( Vandoeuvre lès Nancy) - Institut national de recherche et de sécurité (Vandoeuvre lès Nancy)
16 Service de néphrologie adultes [CHU Necker]
17 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
18 GIGA-Research - Groupe Interdisciplinaire de Génoprotéomique Appliquée
19 SPCTS - Science des Procédés Céramiques et de Traitements de Surface
20 IRIBHM - Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire = Insitute of Interdisciplinary Research [Bruxelles, Belgique]
21 Centre of Epidemiology Biostatistic and Clinical Research
22 Department of Nephrology Antwerp
23 Medical Genetics Department, Brussels
2 Service de néphrologie et immunologie clinique [CHRU Tours]
3 Department of Nephrology
4 Department of microbiology and Immunology
5 Department of Nephrology and Renal Transplantation
6 Department of Nephrology
7 Département de Néphrologie
8 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
9 AP-HP - Hopital Saint-Louis [AP-HP]
10 LBAI - Lymphocytes B, Autoimmunité et Immunothérapies
11 CHRU - Service de néphrologie, dialyse et transplantation rénale
12 LabEX IGO Immunothérapie Grand Ouest
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
15 INRS ( Vandoeuvre lès Nancy) - Institut national de recherche et de sécurité (Vandoeuvre lès Nancy)
16 Service de néphrologie adultes [CHU Necker]
17 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
18 GIGA-Research - Groupe Interdisciplinaire de Génoprotéomique Appliquée
19 SPCTS - Science des Procédés Céramiques et de Traitements de Surface
20 IRIBHM - Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire = Insitute of Interdisciplinary Research [Bruxelles, Belgique]
21 Centre of Epidemiology Biostatistic and Clinical Research
22 Department of Nephrology Antwerp
23 Medical Genetics Department, Brussels
Résumé
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.