rs57494551 increases CXCR5 expression and IgM

backgroundPrimary biliary cholangitis (PBC) is a chronic, progressive, cholestatic liver disease caused by autoimmune reactions. A previous international meta-analysis of a genome-wide association study (GWAS) reported a robust association of the human chr.11q23.3 locus including C-X-C motif chemokine receptor 5 (CXCR5) with susceptibility to PBC. However, the molecular mechanism by which CXCR5 confers disease susceptibility in PBC remains unclear.

methodsCutting-edge post-GWAS analyses were conducted using in silico and in vitro functional approaches, including multi-omics analysis, machine-learning-based transcription factor prediction, and prime editor as a genome-editing technology. Expression data for CXCR5 and correlated genes were obtained by RNA-seq and immunohistochemistry analyses.

resultsAmong the variants around CXCR5, rs57494551 was identified as a disease-causal variant for PBC. rs57494551 regulates endogenous CXCR5 expression in B-cells through binding to the transcription repressor TEA domain transcription factor 3 (TEAD3). CXCR5 expression was correlated with disease activity, as identified by hierarchical clustering of mRNA expression patterns, and portal inflammation markers, such as serum IgM, Aspartate Transferase (AST), and Mac-2 binding protein glycosylation isomer (M2BPGi). The number of IgM

conclusionsImmune dysregulation and portal inflammation are affected by increased expression of CXCR5 on IgM HIGHLIGHTS: Among hundreds of genetic variants in CXCR5, rs57494551 was identified as a disease-causal variant using cutting-edge post-GWAS in silico and in vitro analyses, including multi-omics analysis, machine learning-based prediction, and the genome-editing technology "Prime Editor." The disease risk allele of rs57494551 increases endogenous CXCR5 expression in B-cells by releasing the binding of the transcriptional repressor TEAD3. RNA-seq and immunohistochemistry analyses revealed that CXCR5 expression is correlated with disease activity and portal inflammation markers. Furthermore, the number of IgM+ CXCR5+ B-cells was increased in the portal area of PBC with high disease activity. As well as PBC, the signifi cant associations between CXCR5 and susceptibility to various autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, systemic sclerosis, celiac disease, and Sjögren's syndrome, could be explained by the effect of rs57494551.