[en] [en] BACKGROUND: Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.
METHODS: We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft function without immunosuppression for at least 1 year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples.
RESULTS: We identified rare variants of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs. 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium, a key structure in immune responses.
CONCLUSION: Rare protein coding variants are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine.ClinicalTrials.gov, identifier: NCT05124444.
Disciplines :
Genetics & genetic processes
Author, co-author :
Massart, Annick; Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium ; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Department of Nephrology, Antwerp University Hospital and Laboratory of Experimental Medicine, University of Antwerp, Antwerp, Belgium
Danger, Richard; CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, CR2TI, UMR 1064, ITUN, Nantes, France
Olsen, Catharina; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), VUB-ULB, Brussels, Belgium ; Center for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel, UZ Brussel, Brussels, Belgium
Emond, Mary J; Department of Biostatistics, University of Washington, Seattle, WA, United States
Viklicky, Ondrej; Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czechia
JACQUEMIN, VALERIE ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium ; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium
Soblet, Julie; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium ; Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium
Duerinckx, Sarah; Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium ; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium
Croes, Didier; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), VUB-ULB, Brussels, Belgium ; Center for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel, UZ Brussel, Brussels, Belgium ; Center for Human Genetics, Clinique Universitaires Saint Luc, Brussels, Belgium
Perazzolo, Camille; Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium
Hruba, Petra; Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czechia
Daneels, Dorien; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), VUB-ULB, Brussels, Belgium ; Center for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel, UZ Brussel, Brussels, Belgium
Caljon, Ben; Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), VUB-ULB, Brussels, Belgium ; Center for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel, UZ Brussel, Brussels, Belgium
Sever, Mehmet Sukru; Istanbul Tip Fakültesi, Istanbul School of Medicine, Internal Medicine, Nephrology, Istanbul, Türkiye
Pascual, Julio; Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research, Barcelona, Spain ; Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
Miglinas, Marius; Nephrology Center, Santaros Klinikos, Medical Faculty, Vilnius University, Vilnius, Lithuania
Renal Tolerance Investigators
Pirson, Isabelle; Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium
Ghisdal, Lidia; Department of Nephrology, Hospital Centre EpiCURA, Baudour, Belgium
Smits, Guillaume; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium
Giral, Magali; CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, CR2TI, UMR 1064, ITUN, Nantes, France ; CHU Nantes, Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Nantes, France ; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
Abramowicz, Daniel; Department of Nephrology, Antwerp University Hospital and Laboratory of Experimental Medicine, University of Antwerp, Antwerp, Belgium
Abramowicz, Marc; Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium ; Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles - Vrije Universiteit Brussel (ULB-VUB), Brussels, Belgium ; Department of Genetic Medicine and Development, Faculty of Medicine, Université de Geneve, Geneva, Switzerland
Brouard, Sophie; CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, CR2TI, UMR 1064, ITUN, Nantes, France ; CHU Nantes, Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Nantes, France ; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
AM was supported by the Fonds Erasme; the Fonds de la Recherche Scientifique M\u00E9dicale (FRSM, PDR 23670170); the Fonds Carine VYGHEN; and the Fonds Horlait-Dapsens). MA was supported by the Belgian FNRS (T.0174.15); and Fonds Erasme. RD was supported by a Marie Sk\u0142odowska-Curie fellowship (IF-EF) from the European Union's Horizon 2020 research and innovation program under Grant Agreement No. 706296 and the ANR project KTD-innov (ANR-17-RHUS-0010) thanks to the French government financial support managed by the French National Research Agency (ANR) within investments into the future program. This work was performed in the context of the IHU-Cesti project (ANR-10-IBHU-005), the DHU Oncogreffe, the LabEx IGO program (no. ANR-11-LABX-0016), the ANR project PRELUD (ANR-18-CE17-0019) and the ANR project BIKET (ANR-17-CE17-0008). The IHU-Cesti project was also supported by Nantes M\u00E9tropole and R\u00E9gion Pays de la Loire. The laboratory received funding from the European Union's Horizon 2020 Research and Innovation Program under Grant Agreement No. 754995. OV was supported by the Ministry of Health of the Czech Republic (NV19-06-00031). TOMOGRAM was also supported logistically and financially by the ERA-EDTA \u2013 DESCARTES working group, the Department of Nephrology at Antwerp University Hospital, Belgium and the Institute for Clinical and Experimental Medicine (IKEM) in Prague, Czech Republic. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Open access funding provided by University of Geneva.
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