| Tuberculosis (TB) remains a major global health problem. With the popularity of modern TB control strategy in the past twenty years, China has made remarkable achievements in TB prevention and control. However, as one of the22high TB burden countries, TB epidemic condition is still serious in China. Therefore, finding efficient way to control TB and lower the incidence rate and mortality of TB is the top priority. There are many bottleneck problems in diagnosis, prevention and treatment of TB:too many drug resistant patients but too few achievements in drug development; Bacillus Calmette-Guerin remains the only option of TB vaccination which immuno logical protection is not stable; current diagnosis method cannot meet clinical demand. Biomarks with our own intellectual-property rights will not only be essential for the development of new drugs, vaccines and diagnosis methods, but also provide extra clues for studing mechanism underlying TB development. In the present case-control study, we explored the potential relation of Mycobacterium tuberculosis (MTB) infection and active TB development with host single nucleotide polymorphisms (SNPs) and circulating miRNA levels, and searched for potential host biomarks in MTB infection and TB development process.In the first case-control study,44candidate SNPs were examined in a total of600participants from3groups (pulmonary TB patients, LTBI controls and healthy controls without MTB infection). The two groups of controls were frequency matched on gender and age with pulmonary TB patients. Genotyping was carried out by the Illumina Golden Gate assay. When comparing pulmonary TB patients with LTBI controls but not healthy controls without MTB infection, significant associations with disease development were observed for TLR91174A/G, TLR91635A/G and IFNG2109G/A. A significant association was observed for GG genotype carriers of TLR91174A/G when compared with the more frequent A allele carriers (OR=1.87,95%CI:1.08-3.23, P=0.027). A significantly increased risk of pulmonary TB development was observed for TLR91635AA genotypes carrying cases compared with G allele carriers (OR=1.90,95%CI:1.09- 3.31, P=0.025). The GG genotype of IFNG2109G/A was found to be associated with decreased risk of disease development when compared with AA genotype (OR=0.54,95%CI:0.30-0.98, P=0.042). A combined effect of the genotypes associated with increased risk of pulmonary TB (i.e. TLR91174G/G and IFNG2109A/A) was found when comparing pulmonary TB patients with LTBI controls. None of the other selected SNPs was found to be significantly related to pulmonary TB with respect to LTBI controls or healthy controls without MTB infection. These epidemiological findings provided clue for further studies to explore the potential role of TLR9/IFN-y pathway in human immune responses to MTB infection and active disease development.In the second case-control study,1887miRNAs were examined in a total of34participants from3groups (pulmonary TB patients, LTBI controls and healthy controls without MTB infection) using Agilent human miRNA microarray. The two groups of controls were frequency matched on gender and age with pulmonary TB patients. Differently expressed miRNAs between the3groups identified by chip were then verified by real-time qPCR. Then, miRNAs which passed qPCR verification were used for target gene prediction and miRNA-gene network construction. The result showed that expression levels of hsa-let-7b-5p and hsa-miR-30b-5p were up-regulated in pulmonary TB patients when compared with LTBI controls and healthy controls without MTB infection (Fold Change>4, P<0.01). These two miRNAs may play the role as regulator in MTB infection and TB development. These epidemiological findings provided clue for further studies of potential regulation effect in TB development of circulating miRNAs in plasma, and value assessment of miRNA as host biomarker for TB diagnosis. |
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