Genetics in PBC: What Do the “Risk Genes” Teach Us?

Primary biliary cirrhosis is characterised by a progressive and destructive lymphocytic cholangitis, targeting small intra-hepatic bile ducts. In association with the histologic liver injury, patients characteristically express highly specific auto-antibodies that recognise a conserved epitope of the pyruvate dehydrogenase complex found on the inner membrane of the mitochondria. Family studies demonstrate a clear increased incidence and prevalence of associated autoimmune diseases; and historically, a clear HLA association with disease has been evident. With the use of a high-throughput whole-genome array technology, significant insights into the non-HLA loci associated with risk for disease development have been made. These studies, which have primarily incorporated genome-wide association screens and targeted analysis of immune genes, have highlighted the integral roles for immune cell development and function in disease risk. This has revealed the IL-12/JAK-STAT signalling pathway as a key etiologic factor. In conjunction with a better understanding of environmental triggers, such work lays the foundation for better disease insights mechanistically and, hopefully, therapeutically. Obstacles to uncovering all the associated genetic risk and the correlation between genotype and phenotype remain to be circumvented, as do better appreciation of the processes that underpin not only disease initiation but also presentation and outcome.