Research On The Association Of TLR2 And TIRAP Gene Polymorphism With Susceptibility To Tuberculosis In Chinese Han Population

Background:Tuberculosis, caused by the bacterium mycobacterium tuberculosis (MTB), is one of the most deadly infectious diseases. MTB is an intracellular pathogen that infects phagocytic antigen-presenting cells (APCs) in the lung, including alveolar macrophages, lung macrophages and dendritic cells (DCs). Development of active TB disease depends on a complex relationship between the bacterium and the host. Importantly, only about 10% of presumed immunologically normal individuals who are exposed to MTB will develop disease in their lifetime. Toll-like receptors (TLRs) play important roles in activating immune response against tuberculosis. Studies indicate that anti-tuberculosis immune response is mediated by TLR1,TLR2,TLR4,TLR6 and TLR9, especially TLR2.After ligand are recognized by TLRs, the bridging adaptor myeloid differentiation primary-response protein 88 (MyD88) and Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) are recruited to the'TLRs cytoplasmic domain. The macrophages are actived by TLR2 recognize the MTB composition, TIRAP trigger signaling cascade.In the end, the signaling transduction active Nuclear factor-kappa B (NF-κB). NF-κB induction of inflammatory cytokines transcription. TLR2 induces macrophage activation, anti-bacterial molecule production, and cell apoptosis that leads to the suppression of MTB proliferation. However, TLR2 signaling from MTB is also reported to facilitate MTB survival through decrease in MHC-II expression or antigen-processing activity. Clinic studies reveal associations between TB and single nucleotide polymorphisms (SNPs) with in TLR2 and TIRAP gene, suggesting a crucial role of TLR2 and TIRAP in the host defense against MTB.Objective:To detect specific polymorphisms in TLR2 and TIRAP gene for Chinese Han Population, and verify whether they are associated with susceptibility to tuberculosis. For the prevention, diagnosis and treatment of tuberculosis provide certain basis.Methods:Search TIRAP polymorphisms by sequencing in small sample; detect SNPs by ligase detection reaction technique in large sample;analyze whether polymorphisms are related to tuberculosis by statistic methods.Results:Six polymorphisms were present in the TLR2 promoter region and coding region: G-688T,T2121C,G2343A,T597C,INT+24 to+46 DEL and T1350C. We chose INT+24 to+46 DEL, T597C and T1350C that were detected SNPs in the large sample. In three polymorphisms, allelic and genotypic analysis showed that there were no significant differences between pulmonary tuberculosis patients and healthy controls (P>0.05), but they were related with gender and patient's condition. The male mutation frequencies was higher than female in healthy people. However, the female mutation frequencies was higher than male in TB patient. The SNP T1350C allelic frequencies had significant difference in statistic between heathy females and TB females (OR=1.713, P=0.044). In three polymorphisms, retreatment patients, sputum positive patients and lung cavitation patients'allelic frequencies were lower than first treatment patients, sputum negative patients and no lung cavitation patients respectively. Four polymorphisms were present in the TIRAP coding region:G164A, G303A,G394A and C539T.394A had higher frequencies in the TB group than the control. The SNP G394A allelic frequencies had significant difference in statistic between TB patients and controls (OR=3.19,P=0.043). The SNP G164A mutation related with TB patient's condition. Comparing to controls, retreatment patients'allelic frequencies had significant difference in statistic (OR=0.44, P=0.015), sputum positive patients and lung cavitation patients had lower 164A frequencies.Conclusion:TLR2 and TIRAP gene polymorphisms may be risk factors for TB occurrence and development in Chinese Han Population.