title: Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population.
abstract: BACKGROUND
  Deregulated or excessive host immune responses contribute to the pathogenesis of sepsis. Toll-like receptor (TLR) signaling pathways and their negative regulators play a pivotal role in the modulation of host immune responses and the development of sepsis. The objective of this study was to investigate the association of variants in the TLR signaling pathway genes and their negative regulator genes with susceptibility to sepsis in the Chinese Han population.
  
  
  METHODS
  Patients with severe sepsis (n = 378) and healthy control subjects (n = 390) were enrolled. Five genes, namely TLR2, TLR4, TLR9, MyD88 and TOLLIP, were investigated for their association with sepsis susceptibility by a tag single nucleotide polymorphism (SNP) strategy. Twelve tag SNPs were selected based on the data of Chinese Han in Beijing from the HapMap project and genotyped by direct sequencing. The mRNA expression levels of TOLLIP were determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  Our results showed that the minor C-allele of rs5743867 in TOLLIP was significantly associated with the decreased risk of sepsis (Padj = 0.00062, odds ratio (OR)adj = 0.71, 95% confidence interval (CI) 0.59 to 0.86) after adjustment for covariates in multiple logistic regression analysis. A 3-SNP haplotype block harboring the associated SNP rs5743867 also displayed strong association with omnibus test P value of 0.00049. Haplotype GTC showed a protective role against sepsis (Padj = 0.0012), while haplotype GCT showed an increased risk for sepsis (Padj = 0.00092). After exposure to lipopolysaccharide (LPS), TOLLIP mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from homozygotes for the rs5743867C allele were significantly higher than in heterozygotes and homozygotes for the rs5743867T allele (P = 0.013 and P = 0.01, respectively). Moreover, the concentrations of TNF-α and IL-6 in culture supernatants were significantly lower in the subjects of rs5743867CC genotype than in CT and TT genotype subjects (P = 0.016 and P = 0.003 for TNF-α; P = 0.01 and P = 0.002 for IL-6, respectively).
  
  
  CONCLUSIONS
  Our findings indicated that the variants in TOLLIP were significantly associated with sepsis susceptibility in the Chinese Han population.
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, PR China.
authors.forename: Zhenju
authors.initials: Z
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Chenling
authors.initials: C
authors.lastname: Yao
authors.forename: Zhan
authors.initials: Z
authors.lastname: Sun
authors.forename: Mian
authors.initials: M
authors.lastname: Shao
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Tao
authors.forename: Peizhi
authors.initials: P
authors.lastname: Huang
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Tong
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000208:ethnology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis / Q000208:ethnology* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C410602:TOLLIP protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9