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

Abstract

Objective: Chronic 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). Methods: A 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. Results: After 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. Conclusion: Genetic 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.