Semin Liver Dis 2017; 37(02): 159-174
DOI: 10.1055/s-0037-1603324
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epigenetics in the Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Angela C. Cheung
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Nicholas F. LaRusso
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Gregory J. Gores
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Konstantinos N. Lazaridis
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
› Author Affiliations
Further Information

Publication History

Publication Date:
31 May 2017 (online)

Abstract

Epigenomics, the study of modifications to genetic material that do not alter the underlying DNA sequence, is generating increasing interest as a means to help clarify disease pathogenesis and outcomes. Although genome-wide association studies have identified several potential candidate genes that may be implicated in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it is estimated that these genes explain less than 20% of the heritability of these diseases. Thus, to date, the origins of “missing heritability” for PBC and PSC remain elusive. The epigenome may provide a potentially elegant solution to this phenomenon, as it can be modified by both internal and external exposures (coined the “exposome”). This may explain differences in disease presentation, treatment response, and rates of progression between individuals. Epigenetic changes may also provide a framework for discovering potential biomarkers for diagnosis and screening of PBC and PSC. Importantly, because the epigenome is modifiable, it may also highlight novel pathways for therapeutic discovery and interventions of these diseases.

Key Points

• The epigenome is comprised of heritable changes occurring upon the genome that lead to phenotypic changes without altering the underlying DNA sequence.


• The epigenome may provide an explanation for the disconnect between the low risk associated with the large number of susceptibility loci identified by GWAS and the much higher magnitude of calculated attributable heritability.


• The epigenome, being modifiable, may be altered by numerous external and internal factors (the totality of which is included in the term “exposome”), thus presenting a vast new area of inquiry into the cause of disease in susceptible individuals.


• In PBC, both animal models and human studies have suggested an association between environmental exposure and disease, as well as epigenetic modifications and disease pathogenesis.


• Despite associations between exposures and the risk of PSC, there have been no studies evaluating potential epigenetic changes that may be involved, thus this is an area that may expand our understanding of the pathogenesis of PSC, thereby opening doors to new treatment modalities.


 
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