The genetics of complex cholestatic disorders

Gideon M Hirschfield, Roger W Chapman, Tom H Karlsen, Frank Lammert, Konstantinos N Lazaridis, Andrew L Mason

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)


Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.

Original languageEnglish
Pages (from-to)1357-74
Number of pages18
Issue number7
Publication statusPublished - Jun 2013


  • Cholangitis, Sclerosing
  • Cholestasis
  • Gallstones
  • Genome-Wide Association Study
  • Humans
  • Liver Cirrhosis, Biliary
  • Major Histocompatibility Complex


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