Association Between TAP2,TNF-α Gene Polymorphisms And Tuberculosis In Tuberculosis-Prone Pedigrees

Objective1.To study the relationship between environmental factors and tuberculosis incidence in tuberculosis-prone families in Guangdong Province;Effects of environment and environment,gene and gene,gene and environment interaction on the occurrence of tuberculosis.MethodsThis study is based on TB-prone households,using a case-control study and a field epidemiological questionnaire to investigate the environmental risk factors for TB incidence among TB-prone households.Collect blood samples and extract DNA.Genotypes of rs241447,rs3819721 and TNF-αgene rs1800629 of TAP2 gene detected by Taq Man real-time PCR.Goodness of fit x² was used to test whether the distribution of target genotypes conformed to Hardy-Weinberg’s law of genetic equilibrium;using unconditional logistic regression to analyze associations of environmental factors,single genetic variation and susceptibility to tuberculosis;multivariate dimension reduction（MDR）was used to explore the environment-Environment,gene-gene interaction;the multiplicative interaction term of logistic regression model and binomial linear regression model were used to analyze the multiplicative and additive interaction of gene-environment.Results1.A total of 410 persons from 210 households were included in this study,96 households with 238 persons from tuberculosis-prone households,including 131 persons with tuberculosis,107 persons with close family contacts,and 172 persons from 114 households with healthy control.2.Among 131 tuberculosis patients and 172 healthy controls,the results of environmental factor association analysis showed that female,BMI≥18.5,college education level or above and living in urban areas were protective factors for tuberculosis incidence（OR=0.29,95%CI=0.16-0.50;OR=0.24,95%CI=0.11-0.54;OR=0.13,95%CI=0.05-0.31;OR=0.32,95%CI=0.19-0.52）,the risk of tuberculosis in the occupation of workers is higher than that of other occupations（OR=7.64,95%CI=1.43-40.98）,and smoking is a risk factor for tuberculosis（OR=2.02,95%CI=1.11-3.68）,the risk of tuberculosis in people without physical activity was 4.16 times that of those with physical activity（95%CI=2.52-6.86）,and the risk of tuberculosis in people with normal indoor lighting was 2.59 times higher than that in good lighting（95%CI=1.41-4.76）;indoor environment is generally a risk factor for tuberculosis（OR=2.43,95%CI=1.28-4.61）,and a three-order model of occupation-education level-fitness activity was obtained from the environment-environment MDR analysis was the combination with the strongest association with the risk of developing TB.The results of single genetic variation analysis showed that,after adjusting for relevant potential confounders,TAP2 gene rs3819721 in the co-dominant model,carrying AG and AA genotypes compared with GG genotype increased the risk of tuberculosis susceptibility（OR=3.83,95%CI=1.94-7.55;OR=5.18,95%CI=1.33-20.19）,in the dominant model,compared with the GG genotype,（AG+AA）genotype is associated with an increased risk of tuberculosis（OR=3.99,95%CI=2.88-7.66）,in the super-dominant model,the AG genotype was 3.26 times the risk of（AA+GG）tuberculosis（95%CI=1.68-6.32）;Compared with the AG haplotype carrying the AA haplotype,the risk of tuberculosis is reduced（OR=0.34,95%CI=0.18-0.64）.Gene-gene interaction results found that the third-order interaction of TAP2rs241447-TAP2rs3819721-TNF-αrs1800629 was the optimal model,the consistency of cross validation was 10/10,and the accuracy of test set was 0.6630,and the difference was statistically significant（P<0.001）.Gene-environment interaction showed that TAP2rs3819721 under the dominant model had multiplicative and additive interactions with smoking and indoor lighting on the occurrence of tuberculosis(P_mult=0.015,P_add=0.013;P_mult=0.03,P_add<0.001).3.Among 131 tuberculosis patients and 107 close contacts of healthy families,the results of environmental factor association analysis showed that female was a protective factor for the risk of tuberculosis（OR=0.33,95%CI=0.18-0.59）;other occupations were similar.Compared with students,the risk of tuberculosis was increased（P<0.05）;smoking was a risk factor for tuberculosis（OR=2.40,95%CI=1.18-4.85）;the risk of tuberculosis was higher among those without physical activity than those with physical activity.1.62 times（95%CI=1.02-2.56）;intermediate personality was a protective factor for tuberculosis compared with extroversion（OR=0.40,95%CI=0.23-0.68）.The environment-environment interaction results show that the optimal model is occupation-fitness activity,the test balance accuracy of this model is 0.6540,the cross-validation consistency is 9/10,and the P value of 1000 permutation tests is statistically significant（P<0.001）.Single genetic variant association analysis showed that after adjusting for potential confounders,the TAP2 gene rs3819721 locus in the dominant model,（AG+AA）genotype compared with GG genotype increased the risk of tuberculosis（OR=1.93,95%CI=1.05-3.54）.The gene-gene interaction showed that the third-order interaction of TAP2rs241447-TAP2rs3819721-TNF-αrs1800629 was the optimal model,the cross-validation consistency was 10/10,and the accuracy of test set was 0.6240,and the difference was statistically significant（P<0.001）.Gene-environment interaction showed that TAP2rs241447,TAP2rs3819721 and TNF-αrs1800629 had no statistically significant multiplicative and additive interactions with environmental factors under the dominant model（P>0.05）.Conclusions1.Compared with the general healthy population,it was found that female,BMI≥18.5,college education level or above,sleep time less than 7hours and living in urban areas are protective factors for tuberculosis incidence;workers occupation,smoking,no fitness activities,indoor lighting conditions General and indoor environmental conditions are generally risk factors for tuberculosis-prone households.Compared with close family contacts,female and intermediate personality were found to be protective factors for tuberculosis-prone family members,and smoking and lack of physical activity might be risk factors for tuberculosis-prone family members.2.The rs3819721 locus of the TAP2 gene is associated with tuberculosis susceptibility.Compared with the GG genotype,the AG and AA genotypes have a higher risk of tuberculosis,suggesting that the rs3819721 locus of TAP2 gene is a genetic variation affecting the susceptibility to tuberculosis.3.The third-order model of TAP2rs241447-TAP2rs3819721-TNF-αrs1800629 is the best gene-gene interaction model,which is the strongest combination with the risk of tuberculosis;TAP2 gene rs3819721 interacts with smoking and indoor lighting,respectively,and promotes the occurrence of tuberculosis.