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This version published online on May 22, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0025
Molecular Endocrinology Vol. 0, No. 2007 200700251-
doi:10.1210/me.2007-0025
Copyright © 2007 by the Endocrine Society.
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Submitted on January 16, 2007
Accepted on May 18, 2007

A Common Polymorphism in the Bile Acid Receptor FXR is Associated with Decreased Hepatic Target Gene Expression

Catia Marzolini, Rommel G. Tirona, Guillermo Gervasini, Balasubramanian Poonkuzhali, Mahfoud Assem, Wooin Lee, Brenda F. Leake, John D. Schuetz, Erin G. Schuetz, and Richard B. Kim*

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Clinical Pharmacology, Department of Medicine, The University of Western Ontario, London, Ontario, Canada; Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada; Department of Pharmacology and Psychiatry, Medical School, University of Extremadura, Badajoz, Spain; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

* To whom correspondence should be addressed. E-mail: richard.kim{at}lhsc.on.ca.

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 carried out 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 in comparison to 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 (SHP) and organic anion transporting polypeptide (OATP) 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.
Key words: polymorphism • bile acid receptor • nuclear receptor • gene expression

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  FXRα



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