{Reference Type}: Journal Article
{Title}: Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.
{Author}: Poch T;Bahn J;Casar C;Krause J;Evangelakos I;Gilladi H;Kunzmann LK;Laschtowitz A;Iuso N;Schäfer AM;Liebig LA;Steinmann S;Sebode M;Folseraas T;Engesæter LK;Karlsen TH;Franke A;Hubner N;Schlein C;Galun E;Huber S;Lohse AW;Gagliani N;Schwinge D;Schramm C;
{Journal}: Cell Rep Med
{Volume}: 5
{Issue}: 7
{Year}: 2024 Jul 16
{Factor}: 16.988
{DOI}: 10.1016/j.xcrm.2024.101620
{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.