Abstract
BackgroundToll 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.MethodsA 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.ResultsThe 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.ConclusionsThese 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.
Highlights
Toll like receptors (TLRs) signaling pathways, including the adaptor protein Mal encoded by the TIR domaincontaining adaptor protein (TIRAP) gene, play a central role in the development of acute lung injury (ALI)
Characteristics of the study population From February 2006 to August 2009, a total of 278 sepsis-associated ALI (103 ALI, 175 acute respiratory distress syndrome (ARDS)) and 288 sepsis alone patients were enrolled in this study
There was no significant difference in age, gender, body mass index (BMI), diabetes, liver cirrhosis and history of smoking between ALI patients and sepsis alone patients (P > 0.05)
Summary
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). 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. Emerging evidence has suggested that the severity and outcome of ALI depend significantly on systemic inflammatory response [11]. TLRs recognize a diverse array of pathogens and initiate intracellular signaling via their Toll/interleukin-1 receptor domains, leading to an inflammatory host response [12]. Accumulating evidence has demonstrated that inappropriate activation of TLRs signaling pathways plays an important role in the pathogenesis of ALI [13]. We considered the TIRAP a robust candidate gene for ALI susceptibility
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