Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy

Gastroenterology. 2007 Aug;133(2):507-16. doi: 10.1053/j.gastro.2007.05.015. Epub 2007 May 23.


Background and aims: Intrahepatic cholestasis of pregnancy (ICP) is characterized by liver impairment, pruritus, and elevated maternal serum bile acids. It can cause premature delivery and intrauterine death. Bile acid synthesis, metabolism, and transport are regulated by the bile acid sensor FXR, and we hypothesized that genetic variation in FXR confers susceptibility to ICP.

Methods: The coding regions and intron/exon boundaries of FXR were sequenced in 92 British ICP cases of mixed ethnicity. Subsequently, a case-control study of allele frequencies of these variants in 2 independent cohorts of Caucasian ICP patients and controls was performed. Variants were cloned into an FXR expression plasmid and tested in functional assays.

Results: We identified 4 novel heterozygous FXR variants (-1g>t, M1V, W80R, M173T) in ICP. W80R was not present in Caucasians and M1V was detected uniquely in 1 British case. M173T and -1g>t occur both in Caucasian cases and controls, and we found a significant association of M173T with ICP (OR, 3.2; 95% confidence interval, 1.1-11.2; P = .02) when the allele frequencies of both Caucasian cohorts were analyzed together. We demonstrate functional defects in either translation efficiency or activity for 3 of the 4 variants (-1g>t, M1V, M173T).

Conclusions: This is the first report of functional variants in FXR. We propose that these variants may predispose to ICP, and because FXR has a central role in regulating bile and lipid homeostasis they may be associated with other cholestatic and dyslipidemic disorders.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Bile Acids and Salts / metabolism*
  • Case-Control Studies
  • Cell Line
  • Cholestasis, Intrahepatic / genetics
  • Cholestasis, Intrahepatic / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Europe
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Odds Ratio
  • Phenotype
  • Polymorphism, Genetic*
  • Pregnancy
  • Pregnancy Complications / genetics
  • Pregnancy Complications / metabolism*
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Risk Assessment
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection


  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • farnesoid X-activated receptor