title: Sequencing and functional assessment of hPXR (NR1I2) variants in intrahepatic cholestasis of pregnancy.
abstract: 1. The purpose of this study was to evaluate the role of coding variation in hPXR (NR1I2) in intrahepatic cholestasis of pregnancy (ICP) and to functionally asses the response of PXR variants to ligands of interest in ICP. 2. The coding region of hPXR was sequenced in a cohort of 121 Caucasian ICP patients and exon 2 was sequenced in an additional 226 cases. Reporter assays were used to evaluate the function of all known hPXR variants in response to the secondary bile acid lithocholic acid and therapeutic agents rifampicin, ursodeoxycholic acid and dexamethasone. 3. Two coding single nucleotide polymorphisms (C79T and G106A) were detected in the ICP cohort at frequencies consistent with healthy populations. These do not alter hPXR function in response to ligands of interest to ICP. Analysis of all known coding hPXR variants demonstrates that while subtle changes in experimental design mask or may unveil the functional effects of genetic variation, these are not maintained in a standard functional assay. 4. Coding genetic variation in hPXR does not contribute to the aetiology of ICP in Caucasian populations.
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.
authors.forename: B M
authors.initials: BM
authors.lastname: Owen
authors.forename: S W C
authors.initials: SW
authors.lastname: Van Mil
authors.forename: M
authors.initials: M
authors.lastname: Boudjelal
authors.forename: I
authors.initials: I
authors.lastname: McLay
authors.forename: W
authors.initials: W
authors.lastname: Cairns
authors.forename: E
authors.initials: E
authors.lastname: Elias
authors.forename: R
authors.initials: R
authors.lastname: White
authors.forename: C
authors.initials: C
authors.lastname: Williamson
authors.forename: P H
authors.initials: PH
authors.lastname: Dixon
mesh_terms: D001483:Base Sequence; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*
chemical_list: C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid