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An exome-wide study of renal operational tolerance
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 l...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230038/ https://www.ncbi.nlm.nih.gov/pubmed/37265662 http://dx.doi.org/10.3389/fmed.2022.976248 |
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author | Massart, Annick Danger, Richard Olsen, Catharina Emond, Mary J. Viklicky, Ondrej Jacquemin, Valérie Soblet, Julie Duerinckx, Sarah Croes, Didier Perazzolo, Camille Hruba, Petra Daneels, Dorien Caljon, Ben Sever, Mehmet Sukru Pascual, Julio Miglinas, Marius Pirson, Isabelle Ghisdal, Lidia Smits, Guillaume Giral, Magali Abramowicz, Daniel Abramowicz, Marc Brouard, Sophie |
author_facet | Massart, Annick Danger, Richard Olsen, Catharina Emond, Mary J. Viklicky, Ondrej Jacquemin, Valérie Soblet, Julie Duerinckx, Sarah Croes, Didier Perazzolo, Camille Hruba, Petra Daneels, Dorien Caljon, Ben Sever, Mehmet Sukru Pascual, Julio Miglinas, Marius Pirson, Isabelle Ghisdal, Lidia Smits, Guillaume Giral, Magali Abramowicz, Daniel Abramowicz, Marc Brouard, Sophie |
author_sort | Massart, Annick |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10230038 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-102300382023-06-01 An exome-wide study of renal operational tolerance Massart, Annick Danger, Richard Olsen, Catharina Emond, Mary J. Viklicky, Ondrej Jacquemin, Valérie Soblet, Julie Duerinckx, Sarah Croes, Didier Perazzolo, Camille Hruba, Petra Daneels, Dorien Caljon, Ben Sever, Mehmet Sukru Pascual, Julio Miglinas, Marius Pirson, Isabelle Ghisdal, Lidia Smits, Guillaume Giral, Magali Abramowicz, Daniel Abramowicz, Marc Brouard, Sophie Front Med (Lausanne) Medicine 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. Frontiers Media S.A. 2023-05-17 /pmc/articles/PMC10230038/ /pubmed/37265662 http://dx.doi.org/10.3389/fmed.2022.976248 Text en 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. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Massart, Annick Danger, Richard Olsen, Catharina Emond, Mary J. Viklicky, Ondrej Jacquemin, Valérie Soblet, Julie Duerinckx, Sarah Croes, Didier Perazzolo, Camille Hruba, Petra Daneels, Dorien Caljon, Ben Sever, Mehmet Sukru Pascual, Julio Miglinas, Marius Pirson, Isabelle Ghisdal, Lidia Smits, Guillaume Giral, Magali Abramowicz, Daniel Abramowicz, Marc Brouard, Sophie An exome-wide study of renal operational tolerance |
title | An exome-wide study of renal operational tolerance |
title_full | An exome-wide study of renal operational tolerance |
title_fullStr | An exome-wide study of renal operational tolerance |
title_full_unstemmed | An exome-wide study of renal operational tolerance |
title_short | An exome-wide study of renal operational tolerance |
title_sort | exome-wide study of renal operational tolerance |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230038/ https://www.ncbi.nlm.nih.gov/pubmed/37265662 http://dx.doi.org/10.3389/fmed.2022.976248 |
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