【作者】 范红敏；

【导师】 张孔来； 袁聚祥；

【作者基本信息】 中国协和医科大学 ， 流行病与卫生统计学， 2007， 博士

【摘要】 肺结核是尘肺主要的并发症,也是尘肺患者死亡的主要原因之一。大量的流行病学资料表明,尘肺患者是发生肺结核的高危人群。尘肺结核是多因素共同作用引起的疾病。这些因素包括环境因素、当地矿区和居民结核的流行情况、尘肺结核的控制措施、尘肺患者的遗传因素、感染的结核杆菌的菌型特征等。本研究应用现况调查研究方法,在国有煤矿中选取6个煤矿的所有存活尘肺患者进行问卷调查,采集血液标本、收集结核菌株,分析煤工尘肺结核流行的现状和分布特征；采用现况调查和访谈的方式分析煤工尘肺结核控制的现状,存在的问题,提出有针对性的尘肺结核的控制策略和措施；采用1：1配比的病例对照研究方法,应用限制性片断长度多态性聚合酶链反应方法(PCR-RFLP)检测TNF-α-238G/A、-308G/A的基因多态性,分析遗传因素和环境因素的交互作用；采用MIRU分型方法分析尘肺结核菌株的基因型特征和影响因素；从而为尘肺结核的防制提供理论依据。本研究的主要结果如下：1.6个煤矿煤工尘肺结核的合并率为13.63%。不同地区煤矿煤工尘肺结核的合并率不同(P<0.0001),安徽C矿尘肺结核的合并率最高,达23.26%；其次是辽宁D矿、北京B矿、山东F矿和河北A矿,其尘肺结核的合并率分别为17.47%、17.02%、10.99%、8.90%；河南E矿的尘肺结核合并率最低为1.41%。影响尘肺合并结核的因素有人均月收入、人均居住面积、尘肺发病的病程、结核接触史、工种、尘肺期别、煤矿别、开始接尘年代。2.煤工尘肺患者结核病知识／意识差；煤工尘肺结核患者以被动发现为主；煤矿企业的职防与结防机构防治尘肺结核的工作有待改善,职防与结防工作人员学历偏低,非专业人员挤占专业岗位。3.病例组中,TNF-α-308位点GG、GA、AA三种基因型频率分别为53.10%、40.71%和6.19%；对照组中这三种基因型频率分别为68.14%、28.32%和3.54%,两组人群基因型频率差异无显著性(x2=5.44,P=0.07)。病例组和对照组携带TNF-α-308A等位基因的频率分别为26.55%和17.70%,病例组比对照组高,差异有显著性(x2=5.14,P=0.02)。病例组中,TNF-α-238位点GG、GA、AA三种基因型频率分别为87.61%、10.62%和1.77%,对照组中这三种基因型频率分别为92.92%、7.08%和0,两组基因型频率分布差别无统计学意义(x2=1.81,P=0.19)。病例组和对照组携带TNF-α-238A等位基因的频率分别为7.08%和3.54%,病例组比对照组高,但差异无显著性(x2=2.82,P=0.09)。经年龄、体质指数、卡介苗接种史、结核接触史、开始接尘年龄、接尘工龄等因素调整后,携带TNF-α-238GA/AA型者发生肺结核的危险性与携带TNF-α-238GG型者发生肺结核的危险性差异无显著性(OR=4.295,x2=1.27,P=0.2598)；TNF-a-308GA/AA发生肺结核的危险性是TNF-a-308GG型的3.959(95%CI：1.297-12.086)倍,呈明显的等位基因效应关系。以TTNF-a-238GG和TNF-a-308GG为参照组,TNF-a-238GG和TNF-a-308GA发生肺结核的风险是参照组的1.98(95%CI：1.06-3.71,P=0.0118)倍；其他组合与参照组比较,差异无显著性(P>0.05)。基因与环境交互作用的病例对照研究设计分析结果表明以BMI<20和TNF-a-308GG基因型为参照组,BMI≥20和TNF-a-308GA或AA基因型共同存在时,交互作用产生的ORint为26.85,提示此基因变异与BMI之间存在正交互作用(似然比检验,P=0.0024)。TNF-a-238位点和TNF-a-308位点与卡介苗接种史及结核接触史存在负交互作用。4.结核杆菌临床分离株按是否成簇分为两型。成簇菌株可根据聚类分型的结果分为10型。在成簇菌株中,以Ⅲ、Ⅳ、Ⅴ、Ⅶ型所占比例较大。北京B矿收集到的菌株多聚集在Ⅲ型(7／42)、Ⅳ型(6／42)和Ⅶ型(7／42)；安徽C矿收集到的菌株多聚集在第V型(9／18)和Ⅳ型(4／18)。尘肺患者结核菌株多聚集在Ⅳ型(7／20)；非尘肺患者结核菌株多聚集在Ⅲ型(5／40)、Ⅴ型(9／40)和Ⅶ型(5／40)。北京B矿和安徽C矿的研究菌株基因型分布差异无显著性；尘肺结核菌株与非尘肺结核菌株基因型分布差异亦无显著性。结核分枝杆菌MIRU分型的结果显示菌型成簇与否在尘肺患者、煤矿、文化程度、吸烟、结核接触史、初治／复治情况、耐药与否等因素间分布差异无显著性(P＞0.05)。结论1.6个煤矿煤工尘肺结核的合并率为13.63%。不同地区煤矿煤工尘肺结核的合并率不同；影响尘肺合并结核的因素有人均月收入、人均居住面积、尘肺发病的病程、结核接触史、工种、尘肺期别、煤矿别、开始接尘年代。2.煤工尘肺患者结核病知识／意识差；煤工尘肺结核患者以被动发现为主；煤矿企业的职防与结防机构防治尘肺结核的工作有待改善,职防与结防工作人员学历偏低,非专业人员挤占专业岗位；3.TNF-a-308位点基因多态性与尘肺结核发生有关,携带TNF-a-308GG基因型的不易感染结核,携带TNF-a-308GA或AA基因型者感染结核的危险性增加。本研究未发现TNF-a-238位点基因多态性与尘肺结核发生有关。TNF-a-238位点和TNF-a-308位点基因与卡介苗接种史、结核接触史、BMI间存在交互作用；4.尘肺结核菌株与非尘肺结核菌株基因型之间未见差异,结核杆菌的基因型未发现不同地区煤矿分布的差异,说明结核菌株可能有相同的来源。更多还原

【Abstract】 Tuberculosis harmed health of human being seriously, and is one of the serious diseases of control in our country and is also the concerned problem to public health and society all over the world. Coal worker’s pneumoconiosis (CWP) is a disease that pulmonary tissue occurred fibrosis because of inhaling powder and dust for a long time and a law occupational diseases of harming physical and mental health of coal miners. Occupational epidemiology data showed that CWP patients were the high risk population of tuberculosis. How to control effectively CWP complicated with tuberculosis has become an important problem to public health and society. At present, studies on CWP complicated with tuberculosis were very limited. And there is no sweeping investigation in our country after the reform in 1998. So we selected CWP patients of six main coal mines all over the country as subjects and made an analysis of the prevalence and risk factors, control measure, susceptibility to tuberculosis and genotype character of mycobacterium of tuberculosis of CWP patients so as to provide theory basis for prevention and control of CWP complicated with tuberculosis. The results of the study are as follows:1. The total prevalence of CWP complicated with tuberculosis was 13.63%. The prevalence of PTB varied with the different region (P＜0.0001). The prevalence of PTB in Anhui was the highest (23.26%), and that of Henan was the lowest (1.41%). We made an analysis of the prevalence of CWP combined with tuberculosis and discovered significant difference between the prevalence of CWP of years, type of work, exposure dusty time, cumulative exposure time, sicken years, sicken area, education years, and so on (P<0.05). There was no significant difference between the prevalence of CWP combined with tuberculosis of the inoculation history (P>0.05). Average income monthly every person, average housing area every person, the attack period of CWP, the contact of tuberculosis, type of work, the stage of CWP, the different coal mine and the begin time of exposure were determinants factors by non-condition logistic regression analysis.2. TB knowledge and awareness in CWP is poor, attitude to TB or TB patients is not right and. And it is short of the therapy and management to CWP TB patients. Most of pneumoconiosis patients complicated with tuberculosis were detected by the passive way. 52.24% patients were detected because they had some symptoms to see a doctor. Most of the education years of medical staff were short in institute of Prevention and Control of occupational disease and tuberculosis, and non-professional personnel hold professional post. 3.60 clinical separated strains were classified into two types according to the situation of cluster, including cluster type and non-cluster type. TheⅢ,Ⅳ,Ⅴ,Ⅶgenotype families was most among the cluster type which were classified into 10 types. The main genotype families of tuberculosis strains from CWP and non-CWP was respectivelyⅣandⅤ. The main genotype of families of tuberculosis strains from Anhui and Beijing was respectivelyⅤ,ⅢandⅦ. The distribution nof genotype of strains of CWP complicated with tuberculosis has no significant difference between the different districts after years, marriage status, the situation of therapy and so on (P>0.05). There was significant difference in the genotype between tuberculosis strains of CWP and non-CWP (P＜0.05), but there was no significant difference between them after adjusting years, culture, smoking, the situation of therapy and so on. There were no significant difference in the association of district, years, gender, marriage status, culture, the history of tuberculosis contact, the situation of therapy, the pathological part, the symptoms and the genotype (P>0.05).4. The frequency of TNF-a-308GG, GA, AA genotype in the case group and control group was respectively 53.10%,40.71%,6.19% and 68.14%,28.32%,3.54%. There was no significant difference of TNF-a-308 locus genotype frequency between the case group and the control group (χ2=5.44,P=0.07). There was significant difference of TNF-a-308 A allele frequency between the case and control group and, A allele frequency of case group was higher than that of the control group (χ2=5.14, P=0.02). There was no significant difference of TNF-a-238 locus genotype frequency and allele frequency between the case and control group (P=0.23 and P=0.09). There was no association of polymorphism of TNF-a-238(G→A) and TNF-a-308(G→A) with CWP complicated with tuberculosis (P>0.05). TNF-a-308GG and AA were demonstrated to be risk of factors of tuberculosis (OR=3.959,95%CI: 1.297-12.086), while TNF-a-238GG and AA not to be risk of factors of tuberculosis (OR=4.295,χ2=1.27, P=0.2598) after years, body mass index, the contact history of tuberculosis, the start exposure time of dust and cumulative exposure time were adjusted by logistic regression analysis. It was found that multivariate-adjusted odds ratio (OR; 95% confidence interval) for TNF-a-238GG and.TNF-a-308GA compared with the combination of TNF-a-238GG and TNF-a-308GG were 1.98(1.06-3.71). While there was no significant association between other combination compared with the combination of TNF-a238GG and TNF-a-308GG (P>0.05). A case-control study was used to analyze gene-environment interactions in the CWP complicated with tuberculosis and the pneumoconiosis. There was positive interaction between TNF-a-308GG genotype and body mass index (ORint=26.85). While there was negative interactions between TNF-a-308 GG genotype and the inoculating history of BCG vaccine or the contact history of tuberculosis, and so was between TNF-α-238GG genotype and the mark of BCG vaccine or the contact history of tuberculosis. Conclusions1. The prevalence of CWP complicated with tuberculosis was 13.63% in six coal mines. The prevalence of CWP complicated with tuberculosis varied with the stage of CWP, type of coal mine and type of work and so on. Average income monthly every person, average housing area every person, the attack period of CWP, the contact of tuberculosis, type of work, the stage of CWP, the different coal mine and the begin time of exposure were determinant factors.2. TB knowledge and awareness in CWP is poor, attitude to TB or TB patients is not right and. And it is short of the therapy and management to CWP TB patients. Systematic measures for CWP TB patients and health service providers like strengthening health education and improving TB related health service are necessary. The manage model of CWP tuberculosis is that the special institute of prevention and control of tuberculosis manages tuberculosis..3. The subjects with TNF-α-308 A alleles are associated with susceptibility to pneumoconiosis complicated with tuberculosis, whije TNF-α-238 A alleles are not discovered an association with susceptibility to CWP complicated with tuberculosis. Interaction was found that TNF-α-238GG or TNF-α-308GG and the inoculating history of BCG vaccine or the contact history of tuberculosis or body mass index.4 There is no significant difference in the genotype between the isolated tuberculosis strains from CWP and non-CWP. There is no significant difference in the genotype between the isolated strains from Beijing and Anhui. There were no significant difference in the proportion of genotype cluster of tuberculosis strains between district, years, marriage status, culture, the history of tuberculosis contact, the situation of therapy, the pathological part, the symptoms and the genotype.更多还原