Frontiers in Medicine (May 2023)

An exome-wide study of renal operational tolerance

  • Annick Massart,
  • Annick Massart,
  • Annick Massart,
  • Richard Danger,
  • Catharina Olsen,
  • Catharina Olsen,
  • Catharina Olsen,
  • Mary J. Emond,
  • Ondrej Viklicky,
  • Valérie Jacquemin,
  • Valérie Jacquemin,
  • Julie Soblet,
  • Julie Soblet,
  • Julie Soblet,
  • Sarah Duerinckx,
  • Sarah Duerinckx,
  • Didier Croes,
  • Didier Croes,
  • Didier Croes,
  • Didier Croes,
  • Camille Perazzolo,
  • Petra Hruba,
  • Dorien Daneels,
  • Dorien Daneels,
  • Dorien Daneels,
  • Ben Caljon,
  • Ben Caljon,
  • Mehmet Sukru Sever,
  • Julio Pascual,
  • Julio Pascual,
  • Marius Miglinas,
  • the Renal Tolerance Investigators,
  • Isabelle Pirson,
  • Lidia Ghisdal,
  • Guillaume Smits,
  • Guillaume Smits,
  • Magali Giral,
  • Magali Giral,
  • Magali Giral,
  • Daniel Abramowicz,
  • Marc Abramowicz,
  • Marc Abramowicz,
  • Marc Abramowicz,
  • Sophie Brouard,
  • Sophie Brouard,
  • Sophie Brouard,
  • Maria Aguilar Rodríguez,
  • Friederike Bachmann,
  • Rajendra Bahadur Shahi,
  • Frederike Bemelman,
  • Luboslav Bena,
  • Luigi Biancone,
  • Laura Braun,
  • Klemens Budde,
  • Alejandro Camargo-Salamanca,
  • Katia Clemente,
  • Hulya Colak,
  • Adrian Covic,
  • Jacques Degreve,
  • Philippe Gatault,
  • François Glowacki,
  • Karine Hadaya,
  • Marc Hazzan,
  • Bénédicte Janbon,
  • Christophe Legendre,
  • Umberto Maggiore,
  • Marius Miglinas,
  • Anja Mühlfeld,
  • Maarten Naesens,
  • Christian Noël,
  • Rainer Oberbauer,
  • Evangeline Pillebout,
  • Gian Benedetto Piredda,
  • Francesco Pisani,
  • Ana Ramírez Puga,
  • Tomas Reischig,
  • Francisco González-Roncero,
  • Søren Schwartz Sørensen,
  • Daniel Seron Micas,
  • Nurhan Seyahi,
  • Dimitrie Siriopol,
  • Goce Spasovski,
  • Jean-François Subra,
  • Erik Teugels,
  • Serhan Tuǧlular,
  • Sonia Van Dooren,
  • Catheline Vilain,
  • Florence Villemain,
  • Xavier Warling,
  • Bruno Watschinger,
  • Laurent Weekers

DOI
https://doi.org/10.3389/fmed.2022.976248
Journal volume & issue
Vol. 9

Abstract

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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.

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