Identification of NR1I2 genetic variation using resequencing

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 recept...

Full description

Saved in:
Bibliographic Details
Published in:European journal of clinical pharmacology 2007-06, Vol.63 (6), p.547-554
Main Authors: KING, Cristi R, MING XIAO, JINSHENG YU, MINTON, Matthew R, ADDLEMAN, Nicholas J, VAN BOOVEN, Derek J, KWOK, Pui-Yan, MCLEOD, Howard L, MARSH, Sharon
Format: Article
Language:English
Subjects:
Adult
African Continental Ancestry Group
Aged
Aged, 80 and over
Asian Continental Ancestry Group
ATP Binding Cassette Transporter, Sub-Family B
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
Biological and medical sciences
Colonic Neoplasms - metabolism
Cytochrome P-450 CYP3A - biosynthesis
Cytochrome P-450 CYP3A - genetics
European Continental Ancestry Group
Female
Gene expression
Gene Frequency
Genetic Variation
Genotype
Humans
Large intestine
Liver
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Polymorphism
Polymorphism, Single Nucleotide
Population genetics
Receptors, Steroid - biosynthesis
Receptors, Steroid - genetics
RNA - biosynthesis
Sequence Analysis, DNA
Small intestine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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. 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.
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-007-0295-3