Functional variations of the TLR4 gene in association with chronic obstructive pulmonary disease and pulmonary tuberculosis

Abstract

ObjectiveChronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis (PTB) share a number of common risk factors, including innate immunity-related genetic factors. In the present study, we compared the role of genetic variations of the TLR4 gene in susceptibility to COPD and PTB and illuminated the underlying molecular mechanism of functional single-nucleotide polymorphisms (SNPs).MethodsA population-based case control study was performed in a Chinese Han population and included 152 COPD cases, 1601 PTB cases and 1727 controls. Five SNPs in the TLR4 gene (rs10759932, rs2737190, rs7873784, rs11536889, and rs10983755) were genotyped using TaqMan allelic discrimination technology. We estimated the effects of SNPs using the odds ratio (OR) together with 95% confidence interval (CI). Dual-luciferase reporter vectors expressing different genotypes of SNPs were constructed and transfected into the human HEK 293 T cell line to explore their effects on potential transcription activity.ResultsAfter Bonferroni correction, the genetic polymorphisms of all five SNPs remained significantly associated with COPD, while rs10759932 and rs2737190 were also associated with PTB. Compared with rs10759932-TT, individuals carrying TC (OR: 0.42, 95% CI: 0.28–0.64) or CC (OR: 0.24, 95% CI: 0.09–0.63) had a significantly reduced risk of COPD. However, individuals carrying TC (OR: 1.28, 95% CI: 1.11–1.49) or CC (OR: 1.26, 95% CI: 0.98–1.62) had an increased risk of PTB. The OR (95% CI) for allele rs10759932-C was 0.45 (0.32–0.62) for COPD and 1.18 (1.07–1.32) for PTB. For rs2737190, heterozygous AG was related to a decreased risk of COPD (OR: 0.32, 95% CI: 0.21–0.49) and an increased risk of PTB (OR: 1.30, 95% CI: 1.11–1.52). The dual-luciferase reporter assay showed decreased transcription activity caused by rs10759932-C and rs2737190-G.ConclusionGenetic polymorphisms of rs10759932 and rs2737190 in TLR4 are significantly related to both COPD and PTB but with inverse effects. The altered transcription activity caused by mutations in these two loci may partly explain the observed relationship.

Increased HSP70 and TLR2 Gene Expression and Association of HSP70 rs6457452 Single Nucleotide Polymorphism with the Risk of Chronic Obstructive Pulmonary Disease in the Croatian Population

“…TLR2 and TLR4 polymorphisms were associated with various conditions such as asthma [40], pulmonary tuberculosis [32,41], Helicobacter pylori infection [42], as well as alterations in levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides [36]. They were also associated with susceptibility to COPD [25], the level and decline of lung function, an increased number of inflammatory cells in induced sputum of COPD patients [24], and an increased risk of COPD in smokers [43] or an earlier stage of COPD [44]. However, the ethnic context of polymorphisms as well as sample size should be considered regarding the results of the genetic association studies.…”

“…Furthermore, the HSP70 rs1061581 variant was associated with COPD in the Croatian population [22]. Genetic polymorphisms in TLR2 and TLR4 genes were also significantly related to altered risk of COPD [23][24][25] as well as to reduced lung function and an increased number of inflammatory cells in the sputum of COPD patients [24].…”

<p>The Role of Toll-Like Receptors 2 and 4 in the Pathogenesis of Chronic Obstructive Pulmonary Disease</p>

“…27 A number of other genetic studies have also revealed a relationship between TLR2 and TLR4 gene polymorphism and the risk of developing COPD. 28,29 Haw et al have found that the mRNA levels of TLR2, TLR4, and their coreceptors (TLR1, TLR6, CD14, and MD2) were increased in the airway epithelium of patients with mild and moderate COPD. However, the expression of these receptors was decreased in lung parenchymal cores from patients with severe COPD.…”

Gene expression and pathway bioinformatics analysis detect a potential predictive value of MAP3K8 in thyroid cancer progression

“…All the mentioned above pathways are respectively depicted in Figure 2, 3 and 4. Moreover, single nucleotide polymorphisms among various TLR genes have been identified, and their association with susceptibility/resistance to certain infections like pulmonary tuberculosis and other inflammatory diseases has been reported [11].…”