Genetics of Primary Biliary Cirrhosis

Abstract

Abstract Primary biliary cirrhosis (PBC) is an autoimmune liver disease affecting 0.1% of women over the age of 40 years. PBC is characterised by autoreactive T‐cells and B‐cells specific for mitochondrial self‐antigens, typically the E2‐domain of pyruvate dehydrogenase complex (PDC‐E2), which mediate progressive destruction of the small, intrahepatic bile ducts, eventually leading to cirrhosis. It is believed that environmental factors trigger loss of immune tolerance to PDC‐E2 in those individuals with a genetic predisposition towards PBC. Knowledge of the genetic basis of PBC has improved following four genome‐wide association studies and two immunochip association studies of PBC, undertaken in large case‐control cohorts from North America, Europe and Japan. These studies have clarified the well‐established human leucocyte antigen (HLA) association and identified 27 non‐HLA risk loci, which harbour highly plausible candidate genes, mainly involved in regulation of the immune system. Key Concepts: Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease characterised by progressive, autoimmune destruction of the small, interlobular bile ducts, leading in many cases to end‐stage liver disease with attendant need for liver transplantation. PBC is a complex disorder, meaning that it results from an interaction of genetic and environmental factors. Genome‐wide association studies (GWAS) and iCHIP studies of PBC have substantially improved knowledge of the genetic architecture of PBC. To date, four GWAS and two iCHIP studies of PBC have been undertaken in populations of European or Japanese ancestry. The HLA complex makes an important contribution to the genetic basis of PBC. Risk haplotypes associated with PBC include those carrying DRB1*08 and DRB1*04 alleles. Protective haplotypes include those carrying DRB1*11 and DRB1*15 alleles. A total of 27 non‐HLA risk loci for PBC have been identified in GWAS or iCHIP studies. Many loci harbour highly plausible candidate genes, mainly involved in innate or acquired immune processes. Many risk loci for PBC are also the risk loci for other autoimmune conditions, such as multiple sclerosis, coeliac disease or inflammatory bowel disease. The genetic architecture of PBC in the Japanese population appears to be distinct from the genetic architecture of PBC in populations of European ancestry. This suggests that susceptibility to PBC is characterised by genetic heterogeneity. Known independent risk variants for PBC account for less than 20% of PBC heritability. This is an example of ‘missing heritability’. The iCHIP studies of PBC suggest that PBC risk loci may be polymorphic. The iCHIP studies of PBC suggest that rare and low‐frequency variants make a substantial contribution to the genetic variance of the diseases; identification of rare variants will require large‐scale sequencing efforts.