An exome-wide study of renal operational tolerance

Frontiers in Medicine

Medicine

Ben Caljon¹  Richard Danger²  Sophie Brouard³  Magali Giral³  Mary J. Emond⁴  Daniel Abramowicz⁵  Lidia Ghisdal⁶  Julio Pascual⁷  Isabelle Pirson⁸  Camille Perazzolo⁸  Sarah Duerinckx⁹  Valérie Jacquemin⁹  Marc Abramowicz^1,10  Annick Massart^1,11  Dorien Daneels^1,12  Catharina Olsen^1,12  Didier Croes^1,13  Guillaume Smits^1,14  Julie Soblet^1,15  Mehmet Sukru Sever^1,16  Marius Miglinas^1,17  Petra Hruba^1,18  Ondrej Viklicky^1,18 

[1] 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;CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, CR2TI, UMR 1064, ITUN, Nantes, France;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;Department of Biostatistics, University of Washington, Seattle, WA, United States;Department of Nephrology, Antwerp University Hospital and Laboratory of Experimental Medicine, University of Antwerp, Antwerp, Belgium;Department of Nephrology, Hospital Centre EpiCURA, Baudour, Belgium;Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research, Barcelona, Spain;Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain;Human Genetics Unit, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium;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;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;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;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;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;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;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;Istanbul Tip Fakültesi, Istanbul School of Medicine, Internal Medicine, Nephrology, Istanbul, Türkiye;Nephrology Center, Santaros Klinikos, Medical Faculty, Vilnius University, Vilnius, Lithuania;Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czechia;

关键词: exome sequencing;    renal transplantation;    operational tolerance;    NGAL;    LCN2;    Homer2;    IQCH;    primary cilium;   

DOI  :  10.3389/fmed.2022.976248

 received in 2022-06-23, accepted in 2022-10-31,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundRenal 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.MethodsWe 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.ResultsWe 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.ConclusionRare 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.

【 授权许可】

Unknown   
Copyright © 2023 Massart, Danger, Olsen, Emond, Viklicky, Jacquemin, Soblet, Duerinckx, Croes, Perazzolo, Hruba, Daneels, Caljon, Sever, Pascual, Miglinas, the Renal Tolerance Investigators, Pirson, Ghisdal, Smits, Giral, Abramowicz, Abramowicz and Brouard.