An exome-wide study of renal operational tolerance
Status PubMed-not-MEDLINE Language English Country Switzerland Media electronic-ecollection
Document type Journal Article
PubMed
37265662
PubMed Central
PMC10230038
DOI
10.3389/fmed.2022.976248
Knihovny.cz E-resources
- Keywords
- Homer2, IQCH, LCN2, NGAL, exome sequencing, operational tolerance, primary cilium, renal transplantation,
- Publication type
- Journal Article MeSH
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.
Brussels Interuniversity Genomics High Throughput Core VUB ULB Brussels Belgium
Center for Human Genetics Clinique Universitaires Saint Luc Brussels Belgium
Department of Biostatistics University of Washington Seattle WA United States
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
Interuniversity Institute of Bioinformatics in Brussels Brussels Belgium
Istanbul Tip Fakültesi Istanbul School of Medicine Internal Medicine Nephrology Istanbul Türkiye
LabEx IGO Immunotherapy Graft Oncology Nantes France
Nephrology Center Santaros Klinikos Medical Faculty Vilnius University Vilnius Lithuania
Transplant Laboratory Institute for Clinical and Experimental Medicine Prague Czechia
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ClinicalTrials.gov
NCT05124444
