title: A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression.
abstract: The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, The University of Western Ontario, London Health Sciences Centre, University Hospital, London, Ontario, Canada N6A 5A5.
authors.forename: Catia
authors.initials: C
authors.lastname: Marzolini
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gervasini
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Poonkuzhali
authors.forename: Mahfoud
authors.initials: M
authors.lastname: Assem
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Leake
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Erin G
authors.initials: EG
authors.lastname: Schuetz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001647:Bile Acids and Salts / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated