Identification of NR1I2 genetic variation using resequencing.

Authors:
Cristi R King
Cristi R King
Washington University School of Medicine
United States
Ming Xiao
Ming Xiao
Nanjing Medical University
China
Jinsheng Yu
Jinsheng Yu
Washington University School of Medicine
Matthew R Minton
Matthew R Minton
Genome Technology Access Center
Pui-Yan Kwok
Pui-Yan Kwok
University of California
United States
Howard L McLeod
Howard L McLeod
University of North Carolina
United States

Eur J Clin Pharmacol 2007 Jun 3;63(6):547-54. Epub 2007 Apr 3.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Objective: The nuclear receptor NR1I2 (also called PXR or SXR) is primarily expressed in mouse and human liver and intestines. Direct activation of NR1I2 occurs in response to a range of xenobiotics, which causes the formation of a heterodimer with the RXR receptor. This heterodimer binds to the nuclear receptor response elements of downstream genes such as ABCB1, CYP2C, and CYP3A. This study determined the extent of NR1I2 variation in three world populations.

Methods: Variation in NR1I2 was identified by pooled resequencing in African, Asian, and European populations. Validation was performed in European and African populations using PCR and Pyrosequencing technology. RNA expression of NR1I2, ABCB1 and CYP3A4 was assessed using real-time PCR.

Results: Of 36 single nucleotide polymorphisms (SNPs) identified, 24 were in the untranslated region, 8 were intronic, and 4 exonic. Thirty-six percent were unique to the African population. In comparison with previously published data, we identified 13 novel polymorphisms. The NR1I2 -566A > C polymorphism was significantly associated with ABCB1 and CYP3A4 RNA expression in colon tumor (P = 0.04 in both cases), however, this polymorphism was not associated with NR1I2 expression.

Conclusion: With NR1I2 playing such a large role in the regulation of genes involved in drug metabolism and transport, genetic variation contributing to altered NR1I2 function may have an important clinical impact.

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June 2007
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References

(Supplied by CrossRef)
Article in Hum Mol Genet
MM Ameyaw et al.
Hum Mol Genet 1999
Article in Proc Natl Acad Sci U S A
G Bertilsson et al.
Proc Natl Acad Sci U S A 1998
Article in Genes Dev
B Blumberg et al.
Genes Dev 1998
Article in Eur J Clin Pharmacol
TM Bosch et al.
Eur J Clin Pharmacol 2006
Article in Hum Genet
JT Dunnen den et al.
Hum Genet 2001
Article in Gastroenterology
MM Dring et al.
Gastroenterology 2006
Article in Drug Metab Rev
SS Ferguson et al.
Drug Metab Rev 2002
Article in Hum Mutat
RR Freimuth et al.
Hum Mutat 2005
Article in Hum Mol Genet
RR Freimuth et al.
Hum Mol Genet 2005
Article in J Biol Chem
A Geick et al.
J Biol Chem 2001
Article in J Biol Chem
S Gerbal-Chaloin et al.
J Biol Chem 2002

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