Intergenic risk variant rs56258221 skews the fate of naive CD4 + T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.

Autor:	Poch T; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Bahn J; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Casar C; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Bioinformatics Core, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Krause J; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany., Evangelakos I; Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Gilladi H; The Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel., Kunzmann LK; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Laschtowitz A; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany., Iuso N; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Schäfer AM; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Liebig LA; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Cardiovascular and Metabolic Sciences, Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany., Steinmann S; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany., Sebode M; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany., Folseraas T; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany; Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway., Engesæter LK; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany; Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway., Karlsen TH; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany; Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway., Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany., Hubner N; Cardiovascular and Metabolic Sciences, Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany; Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany., Schlein C; Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Galun E; The Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel., Huber S; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany; Hamburg Centre for Translational Immunology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Lohse AW; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany; Hamburg Centre for Translational Immunology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Gagliani N; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Hamburg Centre for Translational Immunology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Department for General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17177 Solna, Sweden., Schwinge D; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany., Schramm C; I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany; Hamburg Centre for Translational Immunology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: c.schramm@uke.de.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Jul 16; Vol. 5 (7), pp. 101620. Date of Electronic Publication: 2024 Jun 19.
DOI:	10.1016/j.xcrm.2024.101620
Abstrakt:	Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4 + T (CD4 + T N ) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4 + T N is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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