title: A pharmacogenetic study of pregnane X receptor (NR1I2) in Han Chinese.
abstract: 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.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xue-Ding
authors.initials: XD
authors.lastname: Wang
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Li
authors.forename: Qi-Biao
authors.initials: QB
authors.lastname: Su
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Deng
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Jin-Xin
authors.initials: JX
authors.lastname: Zhang
authors.forename: Li-Zi
authors.initials: LZ
authors.lastname: Zhao
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
authors.forename: Eli
authors.initials: E
authors.lastname: Chan
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.forename: Charlie Changli
authors.initials: CC
authors.lastname: Xue
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: 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*
chemical_list: C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid