Geoepidemiology and (epi-)genetics in primary biliary cholangitis

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Abstract

Primary biliary cholangitis (PBC) is a rare female preponderant chronic autoimmune cholestatic liver disease, characterized by intrahepatic ductopenia and progressive fibrosis. During last decades incidence and prevalence showed an increasing rate which vary widely worldwide demonstrating an important interaction between environmental and genetic factors. Heritability suggested by familial occurrence and monozygotic twins concordance have been confirmed in more studies. Epigenetics mechanisms such as histone modification and DNA methylation can partially explain predisposition and inheritance of this disease. Nevertheless, an association with specific class II human leukocyte antigen (HLA) variants have been reported, showing an increase risk in susceptibility. More recently, data regarding a strong protective association between PBC and HLA alleles confirmed this association. After recent genome-wide association studies (GWAS), a more intricate interaction between PBC and the HLA region has been shown. Furthermore, GWAS also identified several immune-related-genes implicated. More genome-wide association studies on this disease are needed to reach a complete and systematic knowledge of this disease. In this review we discuss more recent issued data on geoepidemiology of PBC and the role of (epi-)genetic mechanisms in its pathogenesis.

Introduction

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by intrahepatic bile duct destruction and progressive biliary fibrosis. If misdiagnosed and untreated, PBC may lead to hepatic failure, cirrhosis and hepatocellular carcinoma [1].

The disease is female predominant and in European populations, the incidence is between 1-2 per 100,000 population per year and mostly affects middle-aged women with an 8:1 female to male ratio [1]. To date, only few population-based studies on the epidemiology of PBC have been reported and large systematic data still lack. However, recent studies based on large administrative data show that incidence and prevalence vary worldwide with an apparent increase in their rate during the years.

Since 1974, when the first retrospective study on epidemiology of PBC was performed by Hamlyn and Sherlock [2], attention has been focused on environmental and genetic factors.

During last years, several studies tried to explain female predominance and the incomplete concordance of the disease among twins focusing on genetic and epigenetics factors.

We here critically review what is known on geoepidemiology and evidences supporting the role of genetic and epigenetic factors in PBC.

Section snippets

Epidemiology of primary biliary cholangitis

Recent epidemiology data and large population-based study have a primary role in achieving a full comprehension of etiology and environmental factors implicated in the disease in predisposed individuals. More studies show an increase in prevalence, probably due to improved diagnostic accuracy, new laboratory screening and large databases.

Genetics in primary biliary cholangitis

For years, several studies highlighted an increased risk of PBC in family members, showing a strong association in familial occurrence and monozygotic twins concordance [18] but weak associations with genetic polymorphism [19]. Furthermore, the deep interaction between genetics and molecular pathways of pathogenesis of PBC identified a molecular connectome which shares pathogenetic characteristics with other cholangiopathies [20].

Genetics gain a primary role if we consider the frequent

Practice points

  • •

    Primary biliary cholangitis is confirmed to have a female preponderance but a lower female to male ratio than expected

  • •

    Genetic and epigenetic factors play an important role to determine female preponderance

  • •

    Genome-wide associations studies represent a new era in comprehension of primary biliary cholangitis and other diseases

Research agenda

  • •

    Large population-based studies are needed to confirm this epidemiologic data and geographical distribution of PBC

  • •

    More genome-wide association studies on large scale are needed to find new gene interactions in pathogenesis

  • •

    Research about molecular pathways involved in PBC can lead to new therapies and possibility of treatment

Conflicts of interest

No conflict of interest has been declared by the authors.

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