The Genomics/Genetics of Primary Biliary Cholangitis: The Case for a Functional SNP rs10893900 in ETS1/FLI1 and Review of the Literature.

ETS1 and FLI1 exhibit distinct roles in immunoregulation and autoimmune pathogenesis. Previous transethnic genome-wide meta-analyses incorporating our Han Chinese population established significant associations between ETS1 single-nucleotide polymorphisms (SNPs) and susceptibility to primary biliary cholangitis (PBC). In our earlier genome-wide association study (GWAS), ten SNPs within the ETS1 and FLI1 loci demonstrated modest yet suggestive associations with PBC susceptibility in the Han Chinese population. To validate these putative risk loci, we conducted an independent replication study of rs10893900 and rs2246290 using a separate Han Chinese PBC cohort. A meta-analysis combining data from two stages identified rs10893900 as a genome-wide significant variant (P = 4.55 × 10-8, OR = 1.19, 95% CI = 1.12-1.27). Subsequent functional characterization identified rs10893900 as a susceptibility-associated functional variant. Based on the literature review, we summarized ETS1 variants' susceptibility to human autoimmune diseases, including SLE, RA, and PBC, and evaluated these variants in silico analysis. Importantly, our research implicates the importance of ETS1 involving JAK-STAT signaling pathway, expanding the understanding of pathological mechanisms of PBC.