A polymorphism at the BACH2 locus associates with skewed T cell differentiation in patients with primary sclerosing cholangitis

Background Genome-wide association studies (GWAS) associated primary sclerosing cholangitis (PSC) to several polymorphisms in immune-related genes. We here addressed the question whether specific polymorphisms may affect T cell differentiation, immune cell phenotype and clinical course of patients with PSC.

Methods In an ongoing study, patients with PSC (n=270) were genotyped for the disease-associated risk variants rs56258221 (BACH2), rs80060485 (FOXP1), rs4147359 (IL2RA) and rs7426056 (CD28). Comprehensive immunophenotyping and functional experiments on naive CD4+ T cells from peripheral blood were performed.

Results Carriers of the risk variant rs56258221 (BACH2) showed an increased frequency of naive CD4+ (34,6% vs. 24,6%, p=0,048) with concomitant decrease in memory CD4+ T cells (49,6% vs. 61,8%, p=0,024) in the peripheral blood, compared to non-carriers. Functional in vitro experiments with naive CD4+ T cells revealed an increased capacity of these cells to differentiate into T Helper 17 cells (TH17) (5,5% vs. 2,2%, p=0,042), whereas the conversion into induced regulatory T cells (iTREG) was decreased in carriers of rs56258221 (9,6% vs. 17,3%, p=0,022). In order to assess a potential clinical impact of the risk variant rs56258221, we compared the prevalence of liver transplantation between the genotypes and observed a higher rate in the cohort of rs56258221-carriers, compared to non-carriers (17,5% vs. 12,2%).

Conclusion The gene polymorphism rs56258221 (BACH2) associates with skewed T cell differentiation in patients with PSC and thereby might contribute to the immune-related pathogenesis in PSC. Potential implications for the course of disease warrant further investigation.

Publication History

Article published online:
26 January 2022