| Objective Tuberculosis(TB)is one of the top 10 causes of death in the world and poses a serious threat to human health.The situation has become increasingly critical as the new coronavirus has ravaged the world in the last two years and the huge health needs during the epidemic have greatly reduced the ability to diagnose and treat TB.It is necessary to determine the relationship between environmental factors,host genetic variation and environment-genetic interactions and susceptibility to tuberculosis in order to gain a comprehensive understanding of the pathogenesis of Mycobacterium tuberculosis infection and to provide a scientific basis for accurate prevention and treatment of tuberculosis.1.To explore the environmental risk factors for TB incidence in TB-prone family lines in Guangdong.2.To conduct a case-control study based on family lines to investigate the association between single SNPs of TAP1 gene and interleukin-10 gene and TB susceptibility,and to further analyze the association between multiple SNPs and TB susceptibility on the basis of single SNPs.3.To explore the effects of multiplicative and additive interactions between gene-gene and gene-environment on the development of pulmonary tuberculosis.Methods This study used a family-based case-control study method to recruit TB-prone family lines and healthy control family lines in Guangdong Province from January 2017 to January 2020.Questionnaires were collected through an on-site epidemiological survey of the study population,which included traditional environmental factors associated with the occurrence of TB such as demographic indicators,living and living environment,lifestyle living habits,history of disease and exposure to infectious diseases,and history of BCG vaccination.Two ml of whole blood from the elbow vein of the case and control family groups were collected and stored in a low temperature refrigerator at-80°C.DNA extraction kit was used to extracted DNA,and the three loci of the TAP1 and IL-10 genes were genotyped by Taq Man probe method.The Hardy-Weinberg law of genetic equilibrium for each locus was verified using the chi-square goodness-of-fit test.The association between environmental risk factors and SNPs in the TAP1 and IL-10 genes and susceptibility to tuberculosis was analyzed using chi-square tests and unconditional logistic regression models.After linkage disequilibrium analysis,haplotypes were constructed for haplotype analysis,and the association between the cumulative genetic effect of the three loci and TB incidence was analyzed by genetic risk score.Multifactorial interactions between genes and environment were analyzed using the generalized multifactor dimensionality reduction(GMDR)method.Results 1.164 family lines included a total of 413 study subjects,of whom 222(53.8%)were male and 191(46.2%)were female,with a mean age of 40.45 ± 16.97 years;82 TB family lines included a total of 193 subjects,of whom 141(73.1%)were male and 52(26.9%)were female,with a mean age of 38.58 ± 18.43 years,and 82 There were 220 control family lines,of which 81(36.8%)were male and 139(63.2%)were female,with a mean age of 42.09±15.44 years.There was a statistical difference in the gender distribution of the two study groups(P<0.05),while there was no statistical difference in the age distribution(P>0.05).2.Men were at higher risk of developing TB than women(OR=3.99,95%CI=2.18-7.33);higher education was a protective factor for TB incidence(OR=0.44,95%CI=0.23-0.85);the risk of TB incidence was0.24 times higher for a BMI of 18.5-23.9 than for a BMI less than 18.5(OR=0.24,95%CI=0.10-0.56);monthly income levels of 5001-7500RMB(OR=0.61,95%CI=0.32-0.72)and more than 7500 RMB(OR=0.67,95%CI=0.35-0.83)were protective factors for TB incidence;the risk of TB incidence was 1.83 times higher in those with a history of smoking than in those without a history of smoking(OR=1.83,95%CI=1.02-3.27);2.16 times the risk of TB among those without daily physical exercise(OR=2.16,95%CI=1.22-3.80);no history of BCG vaccination(OR=2.22,95%CI=1.23-4.00),indoor humidity(OR=4.13,95%CI=2.16-7.90),poor indoor hygiene(OR=2.42,95%CI=1.16-5.03)and crowded bedrooms(OR=2.41,95%CI=1.34-4.34)were all risk factors for TB incidence3.For the rs1135216 locus of the TAP1 gene,in the co-dominant model: those carrying the CT genotype(OR=3.48,95%CI=1.83-6.61)and those carrying the CC genotype(OR=5.51,95%CI=1.31-23.20)had an increased risk of developing TB;in the dominant model: those carrying the CT-CC genotype had a 3.72 times higher risk of developing TB than the TT genotype(OR=3.72,95%CI=2.02-6.83).In the dominant model:the risk of TB in those carrying the CT-CC genotype was 3.72 times higher than that of the TT genotype(OR=3.72,95%CI=2.02-6.83);in the super-dominant model,the risk of TB in those carrying the CT genotype was 3.89 times higher than that of the TT-CC genotype(OR=3.89,95%CI=0.94-16.09).For the IL-10 gene rs1800896 locus,in the co-dominant model: those carrying the AG genotype(OR=3.36,95%CI=1.83-6.16)and those carrying the GG genotype(OR=3.15,95%CI=0.92-10.82)had an increased risk of developing TB;in the dominant model: those carrying the AG-GG genotype had a 3.33 times higher risk of developing TB than those carrying the AA genotype.(OR=3.33,95%CI=1.86-5.97);in the super-dominant model,those carrying the AG genotype had 2.98 times the risk of developing TB as compared to the AA-GG genotype(OR=2.98,95%CI=1.65-5.39).For the rs1057141 locus of the TAP1 gene,no association was found between it and TB incidence in any of the genetic models(P<0.05).4.There was some degree of linkage disequilibrium between the two loci at rs1135216,rs1057141 and rs1800896,with the CT and CC haplogroups constituted by the rs1135216 and rs1057141 loci having a2.89-fold and 3.97-fold higher risk of TB incidence than the TT haplogroup,respectively;the rs1135216 and rs1135216 and rs1800896 haplogroups CA and CG have a 2.15-fold and 17.57-fold risk of nodule incidence,respectively,compared to haplogroup TA;rs1057141 and rs1800896 haplogroups CG have a 4.06-fold risk of nodule incidence compared to haplogroup TA;there is also a degree of linkage disequilibrium at the three loci,with rs1135216,rs1057141 and rs1800896 haplogroups having a higher risk of nodule incidence than haplogroup TA.There was also a degree of linkage disequilibrium at three loci,with haplogroup TCG and haplogroup CTG at loci rs1135216,rs1057141 and rs1800896 having a 3.36-fold and 14.39-fold higher risk of TB incidence than haplogroup TTA,respectively.Genetic risk score analysis revealed that the OR for the risk of TB incidence was 3.15(OR=3.15,95%CI=1.76-5.65)for individuals with GRS scores of 2-3 and8.52(OR=8.52,95%CI=1.99-36.60)for individuals with GRS scores of4-6 compared to individuals with GRS scores of 0-2.The GMDR analysis found that the BMI,smoking history,and rs1135216 third-order interaction model was the optimal model,which had a cross-validation consistency coefficient(CVC)of 10/10 and a test set precision of 0.7366,with some interaction between the three.Conclusions 1.males,low education,BMI below 18.5,low monthly income,history of smoking,no physical activity,no history of BCG vaccination,indoor dampness,poor indoor hygiene,and crowded bedrooms are risk factors for the development of TB in TB-prone families.2.genetic variants at the rs1135216 locus of the TAP1 gene and the rs1800896 locus of the IL-10 gene are associated with susceptibility to TB and may be candidate loci for TB pathogenesis in TB-prone families.3.the cumulative effect of genetic variants in the TAP1 and IL-10 genes increases the risk of tuberculosis development.4.BMI and smoking history synergize with the rs1135216 locus variant to increase the risk of TB incidence. |
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