Genetics of Primary Biliary Cirrhosis

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.

Keywords: primary biliary cirrhosis; autoimmunity; complex disease; genome‐wide association study; iCHIP association study; genetic heterogeneity; missing heritability; rare variants

Figure 1.

PBC risk variants and differentiation of TH0 cells into TH1 cells. Although speculative, it is possible that variants associated with PBC affect the process by which the TH1 immune response is established. For example, in this figure, immature dendritic cells (DCs) are activated by interaction of pathogen‐associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs, potentially including C‐type lectin like domain family 16A (CLEC16A)). Differentiation into inflammatory DCs is promoted by proinflammatory cytokines such as TNF, which cause increased expression of TNF, IL‐6, IL‐12 and IFN‐γ. Signalling by PRRs is mediated by NF‐κB and IRF5 and negatively regulated by RPS6KA4, whereas signalling by TNFRSF1A is mediated by NF‐κB and negatively regulated by DENND1B. Naïve CD4+ TH0 cells are activated by interaction of the T‐cell receptor (TCR) with complementary antigen, presented in the peptide‐binding groove of class II HLA on antigen‐presenting cells (APCs), with costimulation by CD80 and CD86 on APC interacting with CD28 on T‐cells. Differentiation of the activated TH0 cell into TH1 cells is driven by IL‐12, which interacts with IL‐12R. Signals from IL‐12R are mediated by tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription 4 (STAT4), which are negatively regulated by suppressor of cytokine signalling 1 (SOCS1). In turn, TH1 cells produce IFN‐γ and TGF‐β, inducing proinflammatory APC, promoting IL‐12 and suppressing IL‐4, thereby sustaining the TH1 response.

Figure 2.

Network map showing sharing of genome‐wide significant risk loci for autoimmune conditions that are phenotypically associated with PBC. Note that several risk loci are shared by two or more autoimmune conditions, providing one potential explanation for co‐occurrence of these disorders. Possibly shared risk loci define one or more fundamental mechanisms of autoimmunity. There are also many risk loci that are associated with only one condition. Possibly these loci contribute to specific phenotypic characteristics of the disorders (e.g. organ specificity). CeD, coeliac disease; GrD, Grave disease; HT, hypothyroidism; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis. For gene names, see http://www.ncbi.nlm.nih.gov/gene. For this figure, a list of genome‐wide significant risk loci for each autoimmune disorder was obtained from the Catalog of Published Genome‐Wide Association Studies at http://www.genome.gov/gwastudies/index.cfm?pageid=26525384 on 1 November 2012.

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Mells, George F, and Hirschfield, Gideon M(Apr 2013) Genetics of Primary Biliary Cirrhosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024406]