title: A functional variant of lipopolysaccharide binding protein predisposes to sepsis and organ dysfunction in patients with major trauma.
abstract: OBJECTIVE
  To determine the hypothesis that genetic variations of the lipopolysaccharide-binding protein (LBP) gene influence risk for the development of sepsis and multiple organ dysfunction (MOD) in patients with major trauma.
  
  
  BACKGROUND
  Lipopolysaccharide-binding protein plays a central role in innate immune response as the first line of defense and directing the microbial-induced activation of the inflammatory host response. Although a total of 112 single nucleotide polymorphisms (SNPs) have been identified so far within the entire LBP gene, only a few SNPs have been studied.
  
  
  METHODS
  Nine haplotype tagging SNPs (htSNPs) were selected from 51 SNPs with a minor allele frequency of ≥5% using the HapMap database for the Chinese Han population. Two independent cohorts of major trauma patients were recruited. The 9 htSNPs were genotyped using pyrosequencing method and analyzed in relation to the risk of development of sepsis and MOD, LBP production, and lipopolysaccharide (LPS)-induced activation of peripheral blood leukocytes. Moreover, the functionality of the rs2232618 polymorphism was assessed by the observation of its effects on the binding and activation of LPS and the LBP-CD14 interaction.
  
  
  RESULTS
  Among the 9 htSNPs, only the rs2232618 was significantly associated with higher susceptibility to sepsis and MOD in the 2 independent cohorts of major trauma patients recruited from southwest and eastern China. This SNP was also significantly associated with LPS-induced activation of peripheral blood leukocytes. In addition, the rs2232618 polymorphism could enhance LBP protein activities, showing significant increases in LPS binding to macrophages, LPS-induced cellular activation, and LBP-CD14 interaction at the presence of the variant LBP protein.
  
  
  CONCLUSIONS
  The rs2232618 polymorphism is a functional SNP and confers host susceptibility to sepsis and multiple organ dysfunction in patients with major trauma.
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: An-qiang
authors.initials: AQ
authors.lastname: Zhang
authors.forename: Mao
authors.initials: M
authors.lastname: Zhang
authors.forename: Lian-yang
authors.initials: LY
authors.lastname: Zhang
authors.forename: Ding-yuan
authors.initials: DY
authors.lastname: Du
authors.forename: Su-na
authors.initials: SN
authors.lastname: Huang
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics* / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001424:Bacterial Infections / Q000235:genetics* / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002681:China; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015601:Injury Severity Score; D007962:Leukocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D008875:Middle Aged; D008957:Models, Genetic; D009102:Multiple Organ Failure / Q000235:genetics* / Q000276:immunology*; D009104:Multiple Trauma / Q000276:immunology* / Q000601:surgery*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D018805:Sepsis / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein