Genetic Susceptibility To Acute Lung Injury/acute Respiratory Distress Syndrome In Chinese Han Population

PART I Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injuryBackground: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 subjects (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 the Han Chinese population. However, the association needs to be replicated in independent studies. PART?An association study of TLRs signaling pathway genetic variants and susceptibility to ALI/ARDS in the Chinese Han populationBackground:Deregulated or excessive host immune responses contribute to the pathogenesis of ALI/ARDS. TLRs signaling pathways and their negative regulators play a pivotal role in the modulation of host immune responses and the development of ALI/ARDS. 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 ALI/ARDS in the Chinese Han population.Methods:720 critically ill patients with risk factors for ALI/ARDS admitted to the ICUs from 2006 to 2010. Cases were 336 patients who developed ALI/ARDS and controls were 384 subjects who did not developed ALI/ARDS. Four genes, namely IRAKI, TRAF6, SIGIRR and IRAK3, were investigated for their association with ALI/ARDS susceptibility by a tag SNP strategy. Seventeen tag SNPs were selected based on the data of Chinese Han in Beijing from the HapMap project and genotyped by the SNPstream system. The differences of allele and genotype distributions between two groups were compared with the chi-square test or Fisher's exact test when appropriate. Multivariate logistic regression was used to adjust for potential confounding factors and Bonferroni method was used to correct for multiple comparisons.Results:All of the 17 tag SNPs were genotyped successfully and all of the genotype distributions were consistent with Hardy-Weinberg equilibrium. Single SNP analyzing showed rs4755453 in TRAF6 is associated with susceptibility to ALI/ARDS. The allele and genotype distributions of rs4755453 in TRAF6 were significantly different between ALI/ARDS and control groups (p=0.0000187, p=0.00015). The allele frequency of rs4755453C was associated with a decreased risk of ALI/ARDS (OR= 0.52,95%CI 0.38-0.70). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. The allele and genotype distributions of rsl370128 and rs2289314 in 1RAK3 were also significantly different between ALI/ARDS and control groups. But this difference disappeared after adjustment for covariates in multiple logistic regression analysis and after Bonferroni correction. Two haplotype blocks were indentified in the IRAK3 region. But no association was found between these two blocks and the susceptibility to ALI/ARDS.Conclusions:These results indicated that genetic variants in the TRAF6 gene might be associated with susceptibility to ALI/ARDS in the Han Chinese population. However, the association needs to be replicated in independent studies. PART IIIAn association study of TNF-a signaling pathway genetic variants and susceptibility to ALI/ARDS in the Chinese Han populationBackground:The pleiotropic cytokine tumour necrosis factor-a (TNF-a) is an important pro-inflammatory cytokine involved in the pathogenesis and development of ALI/ARDS. TNF-a binds directly to tumor necrosis factor receptors (TNFR) and induces the inflammatory response. A20, the product of the TNFAIP3 gene, is a key negative regulator of NF-?B activity downstream of TNF-a. The objective of this study was to investigate the association of variants in the TNF-a signaling pathway genes with susceptibility to ALI/ARDS in the Chinese Han population.Methods:TNF-a, TNFRSF1A, TNFRSF1B and TNFAIP3 were investigated for their association with ALI/ARDS susceptibility. Fourteen SNPs were genotyped in 336 ALI/ARDS patients and 384 controls. The differences of allele and genotype distributions between two groups were compared with the chi-square test or Fisher's exact test when appropriate. Multivariate logistic regression was used to adjust for potential confounding factors and Bonferroni method was used to correct for multiple comparisons.Results:All of the 14 SNPs were genotyped successfully and all of the genotype distributions were consistent with Hardy-Weinberg equilibrium. Single SNP analyzing showed rs661561 in TNFAIP3 is associated with susceptibility to ALI/ARDS. There was significant difference of the allele and genotype distributions in ALI/ARDS patients compared with those of control subjects (p= 0.0002, p= 0.001). The minor allele frequency of rs661561T was associated with a decreased risk of ALI/ARDS (OR= 0.52,95% CI 0.36-0.74). A 2-SNP haplotype block harboring rs661561 and rs610604 also displayed strong association with ALI/ARDS risk. Haplotype GT and TG frequencies in ALI/ARDS patients were significantly different from that control subjects (p= 0.00039, OR= 1.87,95% CI 1.32-2.65; p= 0.029, OR = 0.63,95% CI 0.42-0.96, respectively). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. No association was found between TNF-a, TNFRSF1A, TNFRSF1B variants and the susceptibility to ALI/ARDS.Conclusions:These results indicated that genetic variants in the TNFAIP3 gene might be associated with susceptibility to ALI/ARDS in the Han Chinese population. However, the association needs to be replicated in independent studies.