The association of Toll-like receptor 4 gene polymorphisms with the development of emphysema in Japanese subjects: a case control study

Abstract

BackgroundThe principal role of Toll-like receptor 4 (TLR4) is the induction of immune responses to lipopolysaccharides. Previously, mice deficient in the TLR4 gene exhibited up-regulation of the NADPH oxidase system in the lungs. This resulted in increased oxidant generation and elastolytic activity, which led to pulmonary emphysema. It was suggested that TLR4 might maintain constitutive lung integrity by modulating oxidant generation. We investigated whether single nucleotide polymorphisms (SNPs) in the TLR4 gene were associated with the emphysema phenotype in Japanese subjects with chronic obstructive pulmonary disease (COPD).ResultsSeven SNPs in the TLR4 gene (rs10759930, rs1927914, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953) were genotyped with allelic discrimination assays. The frequencies of SNPs were compared between 106 patients with the emphysema phenotype of COPD and 137 healthy smokers. We found that the positivity of the individuals with the major G allele of rs11536889 was significantly less in the emphysema group than the control group (p = 0.019). The frequencies of the minor C allele and the distribution of the CC genotype as well as the frequency of the major haplotype that carried the minor C allele of rs11536889 were all significantly higher in the emphysema group than the control group (p = 0.0083, 0.019, and 0.004, respectively). Furthermore, the strength of the association of the CC genotype with the emphysema phenotype was in an odds ratio of 2.60 with 95% confidence intervals from 1.17 to 5.78. However, these significances were not apparent after adjust for age and smoking history by logistic regression. No associations were observed between the rs11536889 and the low attenuation area score, the forced expiratory volume, and the carbon monoxide diffusion capacity in the emphysema group.ConclusionsThe minor C allele of the rs11536889 SNP in the TLR4 gene is likely associated with the risk of developing emphysema in the Japanese population.

Genetic association of Toll-like receptor 4 gene and coronary artery disease in a Chinese Han population

“…The SNP rs1156889 is located in the 3′-UTR of the TLR4 gene, where the sequence may influence mRNA stability, translation and localization and thereby regulate expression of the gene and interfere with the host immune system. In previous studies, the rs11536889 C was showed to be significantly associated with a high risk of emphysema (Ito et al 2012 ) and prostate cancer (Kim et al 2012 ). However, our study did not find any significant association between this SNP and CAD, relating to allele, genotype and haplotype analysis.…”

Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms

“…did not find a change in frequency of TLR4(Asp299Gly) in COPD, while a later investigation described decreased frequency of this allele in COPD [ 15 , 17 ]. TLR4 polymorphism (rs11536889) was also associated with COPD in a Japanese population [ 31 ]. Others have found increased frequency of TLR4(T399I) and TLR9(T1486C) in COPD [ 16 , 18 ].…”

Genetic diversity of TLR2, TLR4, and VDR loci and pulmonary tuberculosis in Moroccan patients

“…This might impair function of the TLR4 molecule and interfere with the host innate immunity. Interestingly, this allele was previously demonstrated to be associated with the risk of developing emphysema [35], severe periodontitis [36], and gastric atrophy in Helicobacter pylori-seropositive subjects [37]. However, this variant was not associated with autoimmune pancreatitis [38] or sarcoidosis-related uveitis [39].…”