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Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injury.

ABSTRACT: BACKGROUND: Toll like receptors (TLRs) signaling pathways, including the adaptor protein Mal encoded by the TIRAP gene, play a central role in the development of acute lung injury (ALI). Recently, the TIRAP variants have been described association with susceptibility to inflammatory diseases. The aim of this study was to investigate whether genetic variants in TIRAP are associated with the development of ALI. METHODS: A case-control collection from Han Chinese of 298 healthy subjects, 278 sepsis-associated ALI and 288 sepsis alone patients were included. Three tag single nucleotide polymorphisms (SNPs) of the TIRAP gene and two additional SNPs that have previously showed association with susceptibility to other inflammatory diseases were genotyped by direct sequencing. The differences of allele, genotype and haplotype frequencies were evaluated between three groups. RESULTS: The minor allele frequencies of both rs595209 and rs8177375 were significantly increased in ALI patients compared with both healthy subjects (odds ratio (OR) = 1.47, 95% confidence interval (CI):1.15-1.88, P = 0.0027 and OR = 1.97, 95% CI: (1.38-2.80), P = 0.0001, respectively) and sepsis alone patients (OR = 1.44, 95% CI: 1.12-1.85, P = 0.0041 and OR = 1.82, 95% CI: 1.28-2.57, P = 0.00079, respectively). Haplotype consisting of these two associated SNPs strengthened the association with ALI susceptibility. The frequency of haplotype AG (rs595209A, rs8177375G) in the ALI samples was significantly higher than that in the healthy control group (OR = 2.13, 95% CI: 1.46-3.09, P = 0.00006) and the sepsis alone group (OR = 2.24, 95% CI: 1.52-3.29, P = 0.00003). Carriers of the haplotype CA (rs595209C, rs8177375A) had a lower risk for ALI compared with healthy control group (OR = 0.69, 95% CI: 0.54-0.88, P = 0.0003) and sepsis alone group (OR = 0.71, 95% CI: 0.55-0.91, P = 0.0006). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. CONCLUSIONS: These results indicated that genetic variants in the TIRAP gene might be associated with susceptibility to sepsis-associated ALI in Han Chinese population. However, the association needs to be replicated in independent studies.

SUBMITTER: Song Z

PROVIDER: S-EPMC3001691 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injury.

Song Zhenju Z Tong Chaoyang C Sun Zhan Z Shen Yao Y Yao Chenling C Jiang Jinjun J Yin Jun J Gao Lei L Song Yuanlin Y Bai Chunxue C

BMC medical genetics 20101130

<h4>Background</h4>Toll like receptors (TLRs) signaling pathways, including the adaptor protein Mal encoded by the TIRAP gene, play a central role in the development of acute lung injury (ALI). Recently, the TIRAP variants have been described association with susceptibility to inflammatory diseases. The aim of this study was to investigate whether genetic variants in TIRAP are associated with the development of ALI.<h4>Methods</h4>A case-control collection from Han Chinese of 298 healthy subject ...[more]

PMID: 21118491

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Project description:BackgroundRecent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population.MethodsFourteen tag single nucleotide polymorphisms (tagSNPs) in MyD88, IRAK1, IRAK4 and TRAF6 were genotyped in samples of sepsis-induced ALI (n = 272) and sepsis alone patients (n = 276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS) ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA).ResultsThe association analysis revealed that rs4755453, an intronic SNP of TRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P = 0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37-0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. TRAF6 mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P = 0.012 and P = 0.003, respectively) as well as after LPS stimulation (P = 0.009 and P = 0.005). Moreover, the concentrations of TNF-α and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases.ConclusionsOur findings indicated that common genetic variants in TRAF6 were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role for TRAF6 in ALI.

Project description:BackgroundRecent studies reported the association between the changes in gut microbiota and sepsis, but there is unclear for the gut microbes on aged sepsis is associated acute lung injury (SALI), and metformin treatment for the change in gut microbiota. This study aimed to investigate the effect of metformin on gut microbiota and SALI in aged rats with sepsis. It also explored the therapeutic mechanism and the effect of metformin on aged rats with SALI.MethodsAged 20-21 months SD rats were categorized into three groups: sham-operated rats (AgS group), rats with cecal ligation and puncture (CLP)-induced sepsis (AgCLP group), and rats treated with metformin (100 mg/kg) orally 1 h after CLP treatment (AgMET group). We collected feces from rats and analyzed them by 16S rRNA sequencing. Further, the lung samples were collected for histological analysis and quantitative real-time PCR (qPCR) assay and so on.ResultsThis study showed that some pathological changes occurring in the lungs of aged rats, such as hemorrhage, edema, and inflammation, improved after metformin treatment; the number of hepatocyte death increased in the AgCLP group, and decreased in the AgMET group. Moreover, metformin relieved SALI inflammation and damage. Importantly, the gut microbiota composition among the three groups in aged SALI rats was different. In particular, the proportion of E. coli and K. pneumoniae was higher in AgCLP group rats than AgS group rats and AgMET group rats; while metformin could increase the proportion of Firmicutes, Lactobacillus, Ruminococcus_1 and Lactobacillus_johnsonii in aged SALI rats. Moreover, Prevotella_9, Klebsiella and Escherichia_Shigella were correlated positively with the inflammatory factor IL-1 in the lung tissues; Firmicutes was correlated negatively with the inflammatory factor IL-1 and IL-6 in the lung tissues.ConclusionsOur findings suggested that metformin could improve SALI and gut microbiota in aged rats, which could provide a potential therapeutic treatment for SALI in aged sepsis.

Project description:ObjectivesAcute respiratory distress syndrome occurring in the setting of direct versus indirect lung injury may reflect different pathobiologies amenable to different treatment strategies. We sought to test whether a panel of plasma biomarkers differed between children with sepsis-associated direct versus indirect acute respiratory distress syndrome. We hypothesized that a biomarker profile indicative of endothelial activation would be associated with indirect acute respiratory distress syndrome.DesignObservational cohort.SettingAcademic PICU.SubjectsPatients less than 18 years old with sepsis-associated direct (pneumonia, n = 52) or indirect (extrapulmonary sepsis, n = 46) acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsOf 58 biomarkers examined, 33 differed by acute respiratory distress syndrome subtype. We used classification and regression tree methodology to examine associations between clinical and biochemical markers and acute respiratory distress syndrome subtype. The classification and regression tree model using only clinical variables (age, sex, race, oncologic comorbidity, and Pediatric Risk of Mortality-III score) performed worse than the classification and regression tree model using five clinical variables and 58 biomarkers. The best classification and regression tree model used only four endothelial biomarkers, including elevated angiopoietin-2/angiopoietin-1 ratio, vascular cell-adhesion molecule, and von Willebrand factor, to identify indirect acute respiratory distress syndrome. Test characteristics were 89% (80-97%) sensitivity, 80% (69-92%) specificity, positive predictive value 84% (74-93%), and negative predictive value 86% (76-96%).ConclusionsIndirect lung injury in children with acute respiratory distress syndrome is characterized by a biomarker profile indicative of endothelial activation, excess inflammation, and worse outcomes. A model using four biomarkers has the potential to be useful for more precisely identifying patients with acute respiratory distress syndrome whose pathobiology may respond to endothelial-targeted therapies in future trials.

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Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injury.

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Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injury.

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