title: Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population.
abstract: Toll-like receptor 4 (TLR4) is the central signaling receptor for lipopolysaccharide (LPS) in mammals. This study was designed to investigate the functional significance of the G11367C polymorphism, which is a novel variant we identified in the 3' untranslated region of TLR4 gene in Chinese Han population. Three hundred seventy healthy volunteers were selected. The TLR4/11367 polymorphism was genotyped using single-tube bidirectional allele-specific amplification method. The TLR4 protein expression on peripheral leukocytes and plasma tumor necrosis factor alpha levels were determined by means of flow cytometry and enzyme-linked immunosorbent assay. The post-transcriptional effect of the 11367 polymorphism was evaluated by means of reporter gene assay and real-time quantitative polymerase chain reaction. The G11367C polymorphism is a common allele in Chinese Han population, with minor allele frequency of 14.7%. In response to ex vivo LPS stimulation, the TLR4 expression on the surface of peripheral leukocytes and the plasma tumor necrosis factor alpha levels were significantly lower in carriers of 11367C variant allele than in carriers of 11367G allele. This association was allele dose dependent. We also found that the activity and the mRNA expression of luciferase was significantly smaller in human embryonic kidney 293 cells transfected with construct containing 11367C allele than in those transfected with construct containing 11367G allele. Together, these results suggest that the TLR4/11367 polymorphism may be a functional single nucleotide polymorphism, which could attenuate the LPS-induced transmembrane signaling through the alteration of post-transcriptional regulation of 3' untranslated region and target gene expression.
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Daping, Chongqing 400-042, China.
authors.forename: Zhao-xia
authors.initials: ZX
authors.lastname: Duan
authors.forename: Pei-fang
authors.initials: PF
authors.lastname: Zhu
authors.forename: Hong
authors.initials: H
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Ce
authors.initials: C
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Zheng-guo
authors.initials: ZG
authors.lastname: Wang
authors.forename: Jian-xin
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D002681:China; D005260:Female; D005828:Genetics, Population; D006801:Humans; D007962:Leukocytes / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4