Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis
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Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis. / Poch, Tobias; Bahn, Jonas; Casar, Christian; Krause, Jenny; Evangelakos, Ioannis; Gilladi, Hilla; Kunzmann, Lilly K; Laschtowitz, Alena; Iuso, Nicola; Schäfer, Anne-Marie; Liebig, Laura A; Steinmann, Silja; Sebode, Marcial; Folseraas, Trine; Engesæter, Lise K; Karlsen, Tom H; Franke, Andre; Metabolic Sciences, Max Delbrück Centre for Molecular Medicine in the Helmholtz Association, Cardiovascular; Schlein, Christian; Galun, Eithan; Huber, Samuel; Lohse, Ansgar W; Gagliani, Nicola; Schwinge, Dorothee; Schramm, Christoph.
in: CELL REP MED, Jahrgang 5, Nr. 7, 16.07.2024, S. 101620.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis
AU - Poch, Tobias
AU - Bahn, Jonas
AU - Casar, Christian
AU - Krause, Jenny
AU - Evangelakos, Ioannis
AU - Gilladi, Hilla
AU - Kunzmann, Lilly K
AU - Laschtowitz, Alena
AU - Iuso, Nicola
AU - Schäfer, Anne-Marie
AU - Liebig, Laura A
AU - Steinmann, Silja
AU - Sebode, Marcial
AU - Folseraas, Trine
AU - Engesæter, Lise K
AU - Karlsen, Tom H
AU - Franke, Andre
AU - Metabolic Sciences, Max Delbrück Centre for Molecular Medicine in the Helmholtz Association, Cardiovascular
AU - Schlein, Christian
AU - Galun, Eithan
AU - Huber, Samuel
AU - Lohse, Ansgar W
AU - Gagliani, Nicola
AU - Schwinge, Dorothee
AU - Schramm, Christoph
N1 - Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2024/7/16
Y1 - 2024/7/16
N2 - 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+ TN) 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+ TN 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.
AB - 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+ TN) 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+ TN 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.
U2 - 10.1016/j.xcrm.2024.101620
DO - 10.1016/j.xcrm.2024.101620
M3 - SCORING: Journal article
C2 - 38901430
VL - 5
SP - 101620
JO - CELL REP MED
JF - CELL REP MED
SN - 2666-3791
IS - 7
ER -