An exome-wide study of renal operational tolerance

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...

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Published inFrontiers in medicine Vol. 9; p. 976248
Main Authors 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
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers media 17.05.2023
Frontiers Media S.A
Subjects
exome sequencing
Homer2
LCN2
Life Sciences
Medicine
NGAL
operational tolerance
renal transplantation
NGAL
exome sequencing
primary cilium
Homer2
renal transplantation
LCN2
operational tolerance
IQCH
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Summary: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. 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. We identified rare variants of (3/36, FDR 0.0387), (5/36, FDR 0.0362), and (3/36, FDR 0.102) in 10 tolerant patients . 0 controls. One patient carried a variant in both and . 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. 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.
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PMCID: PMC10230038
The names of the authors directly contributing to the consortium and the building of the dataset are listed in Appendix
Edited by: Xiaopeng Hu, Beijing Chaoyang Hospital, Capital Medical University, China
These authors have contributed equally to this work and share first authorship
Reviewed by: Swastika Sur, University of California, San Francisco, United States; Xin Geng, Eastern Hepatobiliary Surgery Hospital, China
This article was submitted to Nephrology, a section of the journal Frontiers in Medicine
These authors have contributed equally to this work and share last authorship
ISSN:2296-858X
2296-858X
DOI:10.3389/fmed.2022.976248