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Xenobiotica
the fate of foreign compounds in biological systems
Volume 38, 2008 - Issue 10
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Research Article

Sequencing and functional assessment of hPXR (NR1I2) variants in intrahepatic cholestasis of pregnancy

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Pages 1289-1297 | Received 21 May 2008, Accepted 22 Aug 2008, Published online: 16 Oct 2008
 

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.

Acknowledgements

The present work was supported by Wellbeing of Women, the Lauren Page Trust, the Biotechnology and Biological Science Research Council (BBSRC), the Institute of Obstetrics and Gynaecology (IOG) Trust, the Biomedical Research Centre at Imperial College Healthcare NHS Trust, the Dutch Scientific Organization (NWO), and GlaxoSmithKline. The authors thank Sally Holt for her technical assistance.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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