Identification of NR1I2 genetic variation using resequencing.
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.


CONCLUSIONS
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.
King
Cristi R
CR
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Xiao
Ming
M
Yu
Jinsheng
J
Minton
Matthew R
MR
Addleman
Nicholas J
NJ
Van Booven
Derek J
DJ
Kwok
Pui-Yan
PY
McLeod
Howard L
HL
Marsh
Sharon
S
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D044383:Black People; D003110:Colonic Neoplasms / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D012313:RNA / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044465:White People
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C000625852:NR1I2 protein, human; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012313:RNA; D051544:Cytochrome P-450 CYP3A