Identification of NR1I2 genetic variation using resequencing

Cristi R. King, Ming Xiao, Jinsheng Yu, Matthew R. Minton, Nicholas J. Addleman, Derek J. Van Booven, Pui Yan Kwok, Howard L. McLeod, Sharon Marsh

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)547-554
Number of pages8
JournalEuropean Journal of Clinical Pharmacology
Volume63
Issue number6
DOIs
StatePublished - Jun 1 2007

Keywords

  • NR1I2
  • PXR
  • Pharmacogenetics
  • RNA expression
  • Resequencing

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    King, C. R., Xiao, M., Yu, J., Minton, M. R., Addleman, N. J., Van Booven, D. J., Kwok, P. Y., McLeod, H. L., & Marsh, S. (2007). Identification of NR1I2 genetic variation using resequencing. European Journal of Clinical Pharmacology, 63(6), 547-554. https://doi.org/10.1007/s00228-007-0295-3