TLR4/NF-κB signaling pathway gene single nucleotide polymorphisms alter gene expression levels and affect ARDS occurrence and prognosis outcomes

Abstract

Background: To study the occurrence and prognosis of acute respiratory distress syndrome (ARDS) using single nucleotide polymorphisms (SNPs) of TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci in the TLR4/NF-κB pathway. Methods: Genotypes were analyzed for TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci. Plasma TNF-α and IL-6 levels and MyD88 mRNA expression in peripheral blood mononuclear cells (PBMCs) of 300 ARDS patients and 300 non-ARDS patients (control group) were examined. The patients were followed up for 60 days, and the prognosis outcome was recorded. Results: The TNF-α rs1800629 locus A allele and the IL-6 rs1800796 locus G allele were found to be risk factors for ARDS (adjusted OR = 1.452, 95% CI: 1.211–1.689, P < .001 and adjusted OR = 1.205, 95% CI: 1.058–1.358, P = .005, respectively). The G allele at MyD88 rs7744 locus was a protective factor against ARDS (adjusted OR = 0.748, 95% CI: 0.631–0.876, P < .001). Compared with the other groups, homozygotes for TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci had higher expression levels, of which homozygotes for TNF-α rs1800629 and IL-6 rs1800796 loci had lower 60-day survival rates, while MyD88 rs7744 locus homozygotes had a higher 60-day survival rate. Conclusion: The effect of TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 SNPs on gene expression level is a likely cause of ARDS occurrence and poor prognosis.

Hydroxysafflor yellow A improves diabetes-induced renal fibrosis

“…This suggests that the inflammatory signalling pathway was activated and involved in kidney damage, which is consistent with the results of Garibotto et al [9]. The activation of TLR4 can lead to the translocation of NF-kB (p65) to the nucleus, thereby resulting in the activation of downstream NLRP3 protein [10][11][12][13] and inducing the inflammatory response. Some specific microRNAs play a crucial role in the fibrosis process of tissues [14,15].…”

Interleukin-6 gene polymorphisms and susceptibility to liver diseases

“…In the non-Asian group, GC and GG+GC genotype were risk factors for the development of liver diseases, which was in line with some studies showing the mRNA expressions of IL-6 was higher in the rs1800796 GG genotype compare with others. [45,53] rs1800797 (-579 G/A) is also another polymorphism located within the promoter region of IL-6 gene. Our overall, non-Asian subgroup analysis and the study of Chang et al, [42] showed GG and GA genotype may be risk factors for liver diseases, indicating patients with these genotypes may have higher IL-6 levels.…”

Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission

“…This effect leads to increased inflammatory gene expression and pro-survival gene expression, which may prolong the viral permanence in the infected cell [136]. (4) Upon recognition of viral particles and LPS from bacteria, TLR4-mediated signaling may lead to increased deleterious inflammation via NF-kB recruitment and p38 phosphorylation [105,106]. TLR4 polymorphism might explain the differential susceptibility to ARDS in COVID-19 patients [106].…”

“…During acute lung injury, the presence of TLR4 in macrophages acts as a key factor mediating the severity of the inflammation as well as tissue damage [105]. TLR4 polymorphisms have been also correlated to poor ARDS prognosis [106]. Many viruses, such as influenza and rhinoviruses, rely on strategies to silently surpass TLR-based warning signal in the airway epithelium, via inhibition of proteins such as RIG-1 and MDA5, components of TLR4 signaling and IRF-3, to drive IFN production [97].…”