%0 Journal Article
%T Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.
%A Poch T
%A Bahn J
%A Casar C
%A Krause J
%A Evangelakos I
%A Gilladi H
%A Kunzmann LK
%A Laschtowitz A
%A Iuso N
%A Schäfer AM
%A Liebig LA
%A Steinmann S
%A Sebode M
%A Folseraas T
%A Engesæter LK
%A Karlsen TH
%A Franke A
%A Hubner N
%A Schlein C
%A Galun E
%A Huber S
%A Lohse AW
%A Gagliani N
%A Schwinge D
%A Schramm C
%J Cell Rep Med
%V 5
%N 7
%D 2024 Jul 16
%M 38901430
%F 16.988
%R 10.1016/j.xcrm.2024.101620
%X 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.