A Study On The Association And Interaction Between Environmental Factors And SNPs Of Susceptibility Gene To Tuberculosis In Chongqing

Background: Recently years,1/3people in global had infected MTB, but only5%-10%of them developed the disease (>80%PTB).At the same time, the epidemiological study andmonitoring suggested that Significant familial aggregation of tuberculosis were involved inpathogeny, the Host susceptibility genes plays a very important role in determining outcomesof exposure and infection with MTB.Now most people thought the tuberculosis infection,occurrence, prognosis and environmental factors closely related to the host genetic factors.The study report about interaction between them was very limited. The interaction betweenhost susceptibility and environmental factors needed further investigation. It helps us tounderstand the occurrence and development mechanism of tuberculosis, provide a scientificbasis to prevent and control the spread of the diseaseResults of epidemiological studies showed, environmental factors of TB include stress,living environment, income, smoking, TB patient around and complicating with otherinfections. Up to now, people have found many susceptibility genes to tuberculosis such asHLA, VDR, NRAMP1,IFN—γ,IFNGRl,MHC,IL-12RBl and TLR2.The bacterial cell immunity is the main immune reaction after the invasion of mycobac-teria and macrophages is the important ingredient in cell immunity makes an important contri-bution to occurrence of tuberculosis.Either of SP110, VDR and NRAMP1has influence on the function and activity ofmacrophages. It affects the survival, growth and infection of the outcome in macrophages.Epidemiological studies demonstrated that the polymorphisms of SP110,VDR andNRAMP1Closely related to TB susceptibility. But different research and system evaluationor Meta analysis found the relation was unsteady, even contradiction. The main reason mightbe relate to sample size, race and region. Chongqing is a high incidence area of TB. It isimportant significance to reveal the molecular mechanisms of the development of suscepti- bility genes to tuberculosis.Part1Association between gene polymorphisms of VDR and pulmonarytuberculosis susceptibility: a meta-analysisMethod: We comprehensive collected all the studies on the association betweenpolymorphisms of VDR and TB susceptibility, through literature retrieval, review and manualsearch.The studies which met criteria were chosen. The following information was extractedfrom the study: first author, publishing year, sample size, ethnicity of subjects, mean age,male-female ratio, source of controls, distribution of genotypes in case and control groups.Choosing OR value as a combined statistics, assessed the data from Hardy-Weinbergequilibrium and heterogeneity test. According to RevMan5.0, pooled OR by fixed effectmodel or random effect model. In order to assessed the association between polymorphismsof VDR and TB susceptibility.Results and Conclusion:(1)17case-control studies were selected finally. Publicationbiases were assessed by funnel plot and Egger. The funnel plot appeared to be approximatelysymmetrical. It suggested that biases from publications and other factors may not have asignificant influence on the result（st=-0.39, P=0.71）.（2）The study on meta-analysis of FokIpolymorphism of VDR gene and TB susceptibility showed: allele comparison (f vs F),OR=1.12，OR95%CI=(1.02,1.23),thus it can be concluded that allele f might have anassociation with susceptibility of PTB. It showed the comparison (ff vs FF), OR=1.12，OR95%CI=（1.10,1.77),we could also conclude that genotype ff have an association withsusceptibility of PTB.（3）For TaqI polymorphisms, association of the allele(t vs T) andgenotype with PTB were estimated using dominant (TT vs Tt+tt),additive(tt vs TT)，recessive(tt vs Tt+TT) genetic models showed no association was found between TaqIpolymorphisms and susceptibility of PTB.（4）For ApaI polymorphisms, association of theallele(a vs A) and genotype with PTB were estimated using additive (aa vs AA), recessive (aavs Aa+AA)，recessive(aa+Aa vs AA) genetic models showed no association was foundbetween ApaI polymorphisms and susceptibility of PTB.（5）For BsmI polymorphisms,association of the allele(b vs B) and genotype with PTB were estimated using dominant (BBvs bb+Bb),additive(bb vs BB)，recessive(bb vs Bb+BB) genetic models showed no associationwas found between BsmI polymorphisms and susceptibility of PTB. Part2Association and interaction between TB susceptibility genes andenvironmental factorsMethod: Using case-control study, we have identified198PTB cases meeting tostandard coming from Chongqing dispensary and Shapingba CDC.195health people werefrom blood donation center and Physical examination center of triple A hospital were selectedas controls. Epidemiological data of cases and controls were collected by traininginterviewers according to the constructed questionnaire. About5ml whole blood of eachpatient and control was collected. According to the reference, we adopted the HRM to testSNPs. By comparing the different gene of cases and controls, analyzing the gene-environmental interaction in the progress of TB, and calculating odds ratios、95%confidenceintervals and chi-squares, we detected the association between SNPs and susceptibility totuberculosis.Results and Conclusion:（1）There is no difference between the patient and the controlgroup about age and sex by chi-square test.（2）one-factor analysis: It showed the highhousing area per capita and large salary were the protect factors(OR and OR95%CL <1).While TB patients around, smoking，low housing area per capita, atmosphere draught-freeand labor-intensive were the major environment risk of TB(OR and OR95%CL>1).（3）Thefrequencies of rs722555G/G and rs1135791C/T genotypes had statistically significantdifference between the patient and the control group. That means the people with thers722555G/G and rs1135791C/T genotypes had a significant risk of tuberculosis.（4）Thefrequencies of NRAMP1INT4G/C,3’UTR TGTG/deficiency and D543N G/A genotypeshad statistically significant difference between the patient and the control group. Thesegenotypes had a significant increased risk of tuberculosis.（5）The frequencies of genotypefor FokI with FF, Ff and ff in tuberculosis were34.8%、42.9%and22.2%.Among them,people with the ff genotype had2.21times risk of TB than the one without ff genotype. Thefrequencies of genotype for FokI with TT, tt and ff in patient group were79.3%and2.0%.They had no statistically significant difference. But the polymorphism of genotype forTaq I had no susceptibility to tuberculosis.（6）Multivariate unconditional Logistic regressionanalysis of Gene and environmental factors showed the major risk factors of tuberculosiswere TB patients around(OR=3.0295%CI=1.99-4.57)、 smoking （OR=2.0395%CI=1.33-3.10)、passive smoking（OR=1.9295%CI=1.28-2.87)、labor-intensive（OR=1.895%CI=1.21-2.71)、atmosphere draught-free（OR=1.795%CI=1.12-2.57). The interaction between gene and environmental factors showed the significant interaction was observed withsmoking，low housing area per capita, Fok I–ff, INT4G/C、D543N G/A and rs722555G/G.It is further confirmed the host genetic factors are important factors in the pathogenesisof tuberculosis. Association existed between the polymorphisms of SP110, VDR andNRAMP1and environmental factors. The results of study will help us further understand theoccurrence and development mechanism of tuberculosis, but also provides scientific basis forthe prevention and controlling occurrence of the disease...