A pharmacogenetic study of pregnane X receptor (NR1I2) in Han Chinese.
The pregnane X receptor (PXR/NR1I2) gene is a critical transcriptional regulator of a number of important drug metabolizing enzymes and transporters. This study was undertaken to determine the frequencies of single nucleotide polymorphisms (SNPs) and haplotypes and to detect yet unknown SNPs in the NR1I2 gene in 210 unrelated healthy Han Chinese in comparison with other ethnic groups. We also characterized the functional impact of two SNPs, -24622A>T in the 5'-untranslated region and -24446C>A in exon 1 of NR1I2, by constructing three recombinants and monitoring promoter activity using the dual luciferase reporter gene assay. Genomic DNA was isolated from peripheral leukocytes and subjected to polymerase chain reaction (PCR) amplification, followed by direct DNA sequencing. Sixteen SNPs in NR1I2 with frequencies of 0.3-90.3% were found in Han Chinese, two of which (-25439A>G in the 5'-untranslated region and 7637C>T in intron 5) are previously unknown. The mutant allelic frequencies varied from 0.3% to 90.3%. Most of the detected SNPs were located in introns. A total of 15 linkage disequilibriums were detected; and positive linkage disequilibriums were found between -24381A>C in exon 1 and -24113G>A in intron 1, and 252A>G in intron 2 and 275A>G in intron 2 (rho(2) = 1, P<0.001). A total of 42 haplotypes were inferred and the two most frequent haplotypes were H1 (TCAGGGGCCACC) and H2 (CCGAAAACTAAT) with a frequency of 15.1%. The activity of the recombinants with alleles containing the -24622A>T in the 5'-untranslated region or -24446C>A in exon 1 was 30-40% higher than that in the wild-type (reference genotype). These results indicate that there are marked ethnic differences in the frequency between Han Chinese and other ethnic groups and that alleles with -24622A>T in the 5'-untranslated region and -24446C>A in exon 1 of the NR1I2 gene result in an increased activity compared to the wild-type. Further studies are warranted to explore the clinical and toxicological impact of SNPs and haplotypes of NR1I2 in various ethnic groups.
Wang
Xue-Ding
XD
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Li
Jia-Li
JL
Su
Qi-Biao
QB
Deng
Xiao-Ying
XY
Lu
Yan
Y
Chen
Jie
J
Zhang
Jin-Xin
JX
Zhao
Li-Zi
LZ
Zuo
Zhong
Z
Chan
Eli
E
Chen
Xiao
X
Chowbay
Balram
B
Xue
Charlie Changli
CC
Huang
Min
M
Zhou
Shu-Feng
SF
D044466:Asian People / Q000208:ethnology / Q000235:genetics; D001483:Base Sequence; D005006:Ethnicity; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism*
C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid