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 journalArticle

86 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)1357-1374
Number of pages18
JournalGastroenterology
Volume144
Issue number7
DOIs
StatePublished - Jun 2013

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Sclerosing Cholangitis
Biliary Liver Cirrhosis
Genes
Gallstones
Liver Diseases
Interleukin-2 Receptors
Cholestasis
Interleukin-12
Major Histocompatibility Complex
Bile Acids and Salts
Phosphatidylcholines
Bile
Animal Models
Alleles
Cholesterol
Genome
Proteins

Keywords

  • γ-glutamyltransferase
  • AH
  • AMA
  • ancestral haplotype
  • antimitochondrial antibodies
  • genome-wide association studies
  • GGT
  • GWAS
  • IBD
  • IL
  • inflammatory bowel disease
  • interleukin
  • low phospholipid-associated cholelithiasis
  • LPAC
  • major histocompatibility complex
  • MHC
  • PBC
  • PDC-E2
  • PFIC
  • primary biliary cirrhosis
  • primary sclerosing cholangitis
  • progressive familial intrahepatic cholestasis
  • PSC
  • pyruvate dehydrogenase complex E2
  • T-helper
  • Th
  • TNF
  • tumor necrosis factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Hirschfield, G. M., Chapman, R. W., Karlsen, T. H., Lammert, F., Lazaridis, K. N., & Mason, A. L. (2013). The genetics of complex cholestatic disorders. Gastroenterology, 144(7), 1357-1374. https://doi.org/10.1053/j.gastro.2013.03.053

The genetics of complex cholestatic disorders. / Hirschfield, Gideon M.; Chapman, Roger W.; Karlsen, Tom H.; Lammert, Frank; Lazaridis, Konstantinos N; Mason, Andrew L.

In: Gastroenterology, Vol. 144, No. 7, 06.2013, p. 1357-1374.

Research output: Contribution to journalArticle

Hirschfield, GM, Chapman, RW, Karlsen, TH, Lammert, F, Lazaridis, KN & Mason, AL 2013, 'The genetics of complex cholestatic disorders', Gastroenterology, vol. 144, no. 7, pp. 1357-1374. https://doi.org/10.1053/j.gastro.2013.03.053
Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL. The genetics of complex cholestatic disorders. Gastroenterology. 2013 Jun;144(7):1357-1374. https://doi.org/10.1053/j.gastro.2013.03.053
Hirschfield, Gideon M. ; Chapman, Roger W. ; Karlsen, Tom H. ; Lammert, Frank ; Lazaridis, Konstantinos N ; Mason, Andrew L. / The genetics of complex cholestatic disorders. In: Gastroenterology. 2013 ; Vol. 144, No. 7. pp. 1357-1374.
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