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 ,  the Renal Tolerance Investigators , Pirson Isabelle , Ghisdal Lidia , Smits Guillaume , Giral Magali , Abramowicz Daniel , Abramowicz Marc , Brouard Sophie , Aguilar Rodríguez Maria , Bachmann Friederike , Shahi Rajendra Bahadur , Bemelman Frederike , Bena Luboslav , Biancone Luigi , Braun Laura , Budde Klemens , Camargo-Salamanca Alejandro , Clemente Katia , Colak Hulya , Covic Adrian , Degreve Jacques , Gatault Philippe , Glowacki François , Hadaya Karine , Hazzan Marc , Janbon Bénédicte , Legendre Christophe , Maggiore Umberto , Miglinas Marius , Mühlfeld Anja , Naesens Maarten , Noël Christian , Oberbauer Rainer , Pillebout Evangeline , Piredda Gian Benedetto , Pisani Francesco , Puga Ana Ramírez , Reischig Tomas , González-Roncero Francisco , Sørensen Søren Schwartz , Micas Daniel Seron , Seyahi Nurhan , Siriopol Dimitrie , Spasovski Goce , Subra Jean-François , Teugels Erik , Tuǧlular Serhan , Van Dooren Sonia , Vilain Catheline , Villemain Florence , Warling Xavier , Watschinger Bruno , Weekers Laurent 

TITLE=An exome-wide study of renal operational tolerance

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.976248

DOI=10.3389/fmed.2022.976248

ISSN=2296-858X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>We identified rare variants of <italic>HOMER2</italic> (3/36, FDR 0.0387), <italic>IQCH</italic> (5/36, FDR 0.0362), and <italic>LCN2</italic> (3/36, FDR 0.102) in 10 tolerant patients <italic>vs</italic>. 0 controls. One patient carried a variant in both <italic>HOMER2</italic> and <italic>LCN2</italic>. 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.</p></sec><sec><title>Conclusion</title><p>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.</p><p><ext-link ext-link-type="uri" xlink:href="https://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, identifier: NCT05124444.</p></sec>