【作者】 王建明； 唐少文； 沈洪兵；

【Author】 WANG Jian-ming,TANG Shao-wen SHEN Hong-bing.Department of Epidemiology and Biostatistics,School of Public Health,Nanjing Medical University,Nanjing 210029,China

【机构】 南京医科大学公共卫生学院流行病与卫生统计学系；

【摘要】 目的为探讨IL12-IFNG通路基因多态对结核病遗传易感性和预后的影响,选择中国人群开展了分子流行病学研究。方法共纳入530例肺结核病人和530例健康对照进行问卷调查。收集研究对象外周静脉血并分离DNA用于基因多态检测。IL12A rs2243115和rs568408、IL12B rs3212227三个多态位点基因型检测采用PCR-RFLP(restriction fragment length polymorphism)法。IFNG+874(rs2430561)多态位点基因型检测采用ARMS-PCR(amplification refractorymutational system PCR)法。IL12-IFNG通路基因多态在结核病遗传易感性中的效应分析采用多因素Logistic回归模型并用OR值及其95%CI表示。IL12-IFNG通路基因多态在结核病人预后方面的效应则采用Cox回归模型来估计并用HR(hazard ratio)及其95%CI表示。基因-基因、基因-环境间的高阶交互效应采用MDR(multifactor dimensionality reduction)分析。结果共有522例肺结核病例(男性:75.67%,女性:24.33%)和527例对照(男性:75.33%,女性:24.67%)纳入分析。病例和对照组的平均年龄分别是(55.20±16.56)岁和(54.93±16.71)岁。多因子回归模型分析发现,rs22431 15(IL12A)TG/GG基因型携带者患结核病的风险降低约30%(OR=0.70,95%CI:0.49～0.99),而rs2430561(IFNG+874)(AT/TT)携带者预后较佳,治疗失败的风险降低约82%(HR=0.18,95%CI:0.04～0.73)。MRD分析提示基因与基因、基因与环境间存在高阶交互效应,共同影响结核病遗传易感性和预后。结论 IL12-IFNG通路遗传多态可单独或通过联合作用影响结核病易感性和预后。更多还原

【Abstract】 Objective Cytokines are crucial in activation of the cell-mediated immunity required for eliminating pathogens and controlling intracellular growth of Mycobacterium tuberculosis(TB).Genetic variants in IL12-IFNG axis are hypothesized to be involved in the development and progression of TB. Methods This study included 530 pulmonary TB cases and 530 healthy controls.We chose SNPs for genotyping based on potentially functional SNPs selection strategy.The polymerase chain reaction(PCR) -restriction fragment length polymorphism(RFLP) assay was performed to detect three SNPs in IL12: rs2243115(T>G) and rs568408(G>A) in IL12A and rs3212227(A>C) in IL12B.Polymorphism of IFNG at +874(rs2430561) within intron 1 was identified using the amplification refractory mutational system PCR(ARMS-PCR).Multivariate unconditional Logistic regression model was applied to calculate OR and 95%CI) in analyzing the effects of selected SNPs on the risk of developing TB.Cox regression model was used to estimate hazard ratio(HR) and 95%CI of SNPs in the effect on the prognosis of TB patients.To explore higher order gene-gene and gene-environment interactions,we applied the multifactor dimensionality reduction(MDR) approach.Results 522 TB cases(male75.67%;female: 24.33%) and 527 controls(male:75.33%;female:24.67%) were included in the analysis.The mean (+SD) age for cases and controls was(55.20+16.56) years and(54.93+16.71) years,respectively (P=0.792).It was found that genetic variants TG/GG of rs2243115(IL12A) were associated with a decreased risk of TB,with OR(95%CI) of 0.70(0.49~0.99),whereas variant genotypes AT/TT of rs2430561(IFNG) conferred 82%less risk for treatment failure,with hazard ratio of 0.18(95%CI:0. 04～0.73).Cumulative effects analysis revealed that the risk of TB increased significantly with the number of unfavorable genotypes in IL12 genes.Furthermore,MDR analysis showed potential higher-order gene-gene,gene-environment interactions and indicated different outcomes based on distinct genotype profiles.Conclusions Results from this study demonstrate that genetic polymorphisms of IL12-IFNG pathway may independently or jointly contribute to the susceptibility to and prognosis of pulmonary TB.更多还原