The Genetic and Molecular Pathogenesis of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic liver disease that affects over 1 in 5000 people in the UK. It usually affects middle-aged or older women. There is no effective treatment and many patients eventually develop cirrhosis and liver failure, for which the only treatment is liver transplantation. The cause of PBC is unknown. However, there is evidence that genetic factors are important. For example, PBC may affect more than one member of the same family. This is called familial PBC. The genes involved in causing PBC have not been clearly identified. We intend to study DNA from families in which several relatives have the disease. We will also study a laboratory mouse which develops a liver disease closely resembling PBC. By doing genetic studies of PBC families and the PBC mouse, we hope to identify genes involved in causing the disease. We will then study DNA from a large number of patients with non-familial (sporadic) PBC, to see whether the same genes are involved in causing sporadic disease. This is important because, if we identify the genes involved in causing PBC, investigators will have a better chance of finding a treatment which works.

Primary biliary cirrhosis (PBC) is an autoimmune, chronic liver disease characterized by progressive destruction of the small intra-hepatic bile ducts, eventually leading to cirrhosis. The aetiology of PBC is unknown; it is thought to be multifactorial. Epidemiological and twin studies support the role of genetic factors. However, only weak association with HLA-DR8 has been consistently demonstrated. Family based linkage studies have never been reported.
An animal model for PBC has recently been characterised. The NOD.c3c4 strain is a congenic mouse which develops an autoimmune biliary disease (ABD) closely resembling human PBC. In the NOD 2445 strain, the loci necessary for fully penetrant ABD have been refined to Abd1 on chromosome 4
and Abd2 on chromosome 3.
We have established a unique collection of families in which multiple kindred have PBC. Whole genome linkage analysis of one PBC family has identified two regions associated with disease, PBC1 and PBC2. PBC1 is syntenic to a region adjacent to Abd1 on mouse chromosome 4 (Pbc1). PBC2 harbours a gene implicated in familial cholestasis, ATP8B1. Sequencing of ATP8B1 has shown that affected kindred are homozygous for a mis-sense variant of uncertain pathogenicity. These findings indicate that further family studies will be valuable to dissect the genetic basis of PBC.
We plan to identify genes which confer susceptibility to PBC by studying multiplex PBC families. This will involve: (1) whole genome linkage analysis using high-density SNP arrays; (2) identification of candidate genes in regions linked to disease, and (3) sequencing of candidate genes to identify potentially pathogenic variants. Where variants are identified, their role in sporadic PBC will be investigated in case-control association studies, using tag SNPs from the same gene. Cases will be obtained from an existing PBC DNA collection, and controls from the Wellcome Trust Case Control Consortium.
Furthermore, we will undertake congenic mouse studies to investigate Pbc1. The NOD 1556 strain contains a B10-derived chromosome 4 region which includes Pbc1. Starting with the 1556 and 2445 strains, congenic mice will be generated to determine whether Pbc1 modifies the ABD phenotype. Sequence variation between NOD and B-10 Pbc1 will be sought to identify the alleles in Pbc1 which are associated with modified disease. This data will be used to guide case-control association studies of sporadic, human PBC.
By identifying susceptibility alleles, this study will elucidate the pathogenesis of PBC and provide new targets for therapeutic intervention.