Genetics of Primary Biliary Cholangitis

The genetic basis underlying PBC has been progressively better understood, with remarkable contribution provided by GWAS. The MHC locus remains the most significant genomic region despite its dissection is is still difficult; in addition, specific HLA haplotypes are not assessed in clinical practice. Many non-HLA loci have been discovered, with a large overlap of signals with other non-liver-related autoimmune diseases, reinforcing the strong autoimmune identity of the disease. Themajor effort of the genetic community interested in PBC is now focused on the dissection of the downstream pathways for the identification of causal genes and druggable targets. The translation to clinical practice remains complex, due to the historical adoption of clinical endpoints related to cholestasis, which poorly correlate with immunologic pathways pinpointed by GWAS signals. The study of the chrX has recently gainedmore traction, because it is predicted to bring information on both the genetic architecture and the female predominance. Open questions remain about the lack of genetic signals related to cholangiocyte physio(patho)logy, the role of genetic variants in shaping treatment response, and the discovery of rare and ultrarare variants associated with PBC.