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

Abstract

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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN2666-3791
DOIs
StatusVeröffentlicht - 16.07.2024

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Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

PubMed 38901430