An Epidemiological Study On The Interaction Between Genetic And Traditional Factors In Tuberculosis

Background:Numerous studies have confirmed that the incidence and development of tuberculosis may have an association with host genetic factors and environmental factors. A large number of genetic susceptibility gene (such as HLA, VDR, NRAMP1, SP110, IFN-y, TLR2, and IL-12RB1etc.) and traditional risk factors (smoking, economic status, ventilation, BCG vaccination history, history of exposure to the patient, etc.) associated with tuberculosis has been identified. Nevertheless, on the basis of modern epidemiology etiology models, gene-gene and gene-environment interactions rather than single gene or risk factor involve in the process of tuberculosis; Any single factor is insufficient to explain the etiology and pathogenesis of tuberculosis. However, the interactions between traditional and genetic factors in TB have been rarely investigated.Mycobacterium tuberculosis (Mycobacterium tuberculosis, MTB) can stimulate cellular immune in vivo. Macrophages are not only the host cells for MTB, but also the most important effect cells. Thus, macrophage activity and function may play a very crucial role in the immune response and outcome after MTB infection. Therefore, gene VDR, NRAMP1and SP110related with macrophage functions have received much attentions. Exploration of the interactions between these three genes and traditional factors may be of significance for understanding the etiology of tuberculosis.A large number of epidemiological studies and systematic reviews showed that genetic factors varied with regional and population differences. In the Chinese population, VDR-Fokl (ff) and NRAMP1-3’UTR (TGTG+-) have a strong association with tuberculosis (OR>2.0,95%CI lower limit greater than1). To date, the relationship between SP110gene and susceptibility to tuberculosis has been rarely reported and remains inconclusive. A systematic review failed to reveal a significant association between SP110gene and tuberculosis risk; this might be owing to insufficient number of the pooled studies, or the incomplete coverage of SNPs in SP110gene.In summary, in Part I, a case-control study was designed to clarify the association between SP110polymorphism and tuberculosis risk using high-resolution melting analysis with high sensitivity and specificity. In Part II, a case-case study was designed to explore the gene-environment interactions in etiology and mechanisms of tuberculosis.Part I A case-control study on SP110gene polymorphism and tuberculosis riskMethods:Newly diagnosed TB patients were continuously collected from the Institute of Tuberculosis Prevention and Treatment of Chongqing and Chongqing Shapingba District Center for Disease Control (excluding other infectious diseases, cancer and other chronic diseases). Healthy controls from blood donation centers, medical centers were matched to cases according to age and sex. Each subject was face-to-face interviewed to complete the questionnaire. The whole blood genomic DNA was extracted, and HRM20SP110gene polymorphism loci was detected using HRM methods. A total of198cases and195controls with specimens were included in the final analysis, respectively.Results and conclusions:Income (less with8000yuan), history of exposure to TB patients, smoking (passive smoking), per capita living space (less than10square meters), room no ventilation, work intensity (strong) might be the TB risk factors (OR value and OR95%CI lower limit greater than1);2. No significant association between BCG vaccination history, sleep duration and tuberculosis was observed (P>0.05).3. rs722555(G/G), rs1135791(C/T) and rs2114592(T/T) may be risk factors for tuberculosis (OR value and OR95%CI lower limit greater than1).4. rs722555(G/G), smoking, history of exposure to TB patients were involved into multivariate unconditional logistic regression model. The OR with95%CI from multivariate analysis were significantly different with the results from univariate analysis, indicating that these three factors may be independent risk factors for tuberculosis, meanwhile, the interactions among them might exist.Part Ⅱ A case-case study on the interactions between genetic and traditional factors in TBMethods:Newly diagnosed patients of TB who have lived in local area for more than10years were continuously collected from Institute of Tuberculosis Prevention and Treatment of Chongqing and Chongqing Shapingba District Center for Disease Control as cases for this study. Each case was collected for the major related factors (smoking, history of exposure to TB cases, often ventilated room, etc.) by a questionnaire. Polymorphisms of VDR-Fokl, NRAMP1-3’UTR and rs722555in SP110gene were tested by high-resolution melting analysis. Finally, a total of426cases were included for analysis. Cases with a certain genotype (or traditional factors) were classified as case group, while other cases were as control group. P value, OR and its95%CI were calculated to evaluate their possible interactions.Results and conclusions:1. The basic characteristics, such as age and sex, of426cases were similar to those of the general case.2. Genotype distributions of rs722555, VDR-Fok I and NRAMP1-3’UTR were consistent with Hardy-Weinberg equilibrium.3. rs722555(G/G) might interacted with smoking and history of exposure to tuberculosis; VDR-Fok I (ff) might interacted with smoking, no ventilation and tuberculosis exposure; NRAMP1-3’UTR (TGTG+/-) might interacted with smoking.4. rs722555interacted with VDR-Fok I, VDR-Fok I and NRAMP1-3’UTR, while no significant interactions between rs722555and NRAMP1-3’UTR were observed.This study further confirmed the interactions between the tuberculosis-related traditional factors and host genetic factors. The results might help understand the mechanisms of TB incidence and development.