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Identification of NR1I2 genetic variation using resequencing

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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Acknowledgements

The authors wish to thank Robert Freimuth for his assistance with this study. This work was supported by R21 CA113491 and the NIH Pharmacogenetics Research Network (U01 GM63340).

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Authors and Affiliations

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

    Cristi R. King, Jinsheng Yu, Matthew R. Minton, Derek J. Van Booven, Howard L. McLeod & Sharon Marsh

  2. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Howard L. McLeod & Sharon Marsh

  3. Cardiovascular Research Institute, Department of Dermatology, University of California, San Francisco, CA, 94143, USA

    Ming Xiao, Nicholas J. Addleman & Pui-Yan Kwok

  4. UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Campus Box 7360–3203, Kerr Hall, Chapel Hill, NC, 27599, USA

    Derek J. Van Booven & Howard L. McLeod

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  1. Cristi R. King
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  2. Ming Xiao
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  3. Jinsheng Yu
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  4. Matthew R. Minton
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  6. Derek J. Van Booven
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  8. Howard L. McLeod
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  9. Sharon Marsh
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Corresponding author

Correspondence to Howard L. McLeod.

Additional information

The authors are members of the CREATE Pharmacogenetics Research Network.

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King, C.R., Xiao, M., Yu, J. et al. Identification of NR1I2 genetic variation using resequencing. Eur J Clin Pharmacol 63, 547–554 (2007). https://doi.org/10.1007/s00228-007-0295-3

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  • DOI: https://doi.org/10.1007/s00228-007-0295-3

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