湖南省汉族人群MBL与MASP2基因多态性与相关因素对结核易感性的综合影响研究

发布时间：2018-04-18 03:39

本文选题：结核 + 基因　；参考：《中南大学》2014年博士论文

【摘要】：背景：结核病是严重危害公众健康的全球性公共卫生问题。据估计,2012年,全球共有860万人罹患结核病。中国是全球第二大结核病高负担国家,2010年全国第五次结核病流行病学抽样调查结果显示：中国15岁及以上人群活动性肺结核的患病率为459/10万。目前很多研究都已经证实吸烟、过度饮酒、厨房烟雾暴露是肺结核的危险因素,实验室的证据发现茶叶中的EGCG可以通过抑制结核杆菌中烯酰基载体蛋白质还原酶InhA的活性来抑制结核杆菌的生长繁殖。还可以通过抑制巨噬细胞内TACO基因的转录,达到抑制结核杆菌在巨噬细胞内存活的效果。研究显示MBL基因在启动子区和结构区的多态性影响MBL多聚体的形成和血浆MBL浓度。MBL多聚体形成减少,导致其与配体的结合力减弱,同时也更易被金属蛋白酶降解。MASP-2基因的突变同样影响着其编码的蛋白(MASP2, Map19)血清含量的变化,并且导致其与MBL及ficolin分子结合的能力下降,从而阻碍补体活化的凝集素途径,引起机体非特异性免疫系统功能障碍。目的：本研究分析湖南省汉族人群MBL/MASP2基因的多态性与环境因素的作用,探讨其对结核易感性的影响。方法：病例的来源：采用多级抽样原则,首先在湖南省14个市州随机抽取3个市州(衡阳、岳阳、怀化),其次在这3个市州随机抽取4个县级疾病预防控制中心(祁东、岳阳楼区、岳阳县、洪江市),最后从4个县级疾病预防控制中心2009年新登记的所有肺结核病人中随机抽取。所有病例均采用卫生部结核病诊断标准被确诊为肺结核病人。健康对照的来源：采用多级抽样方法,首先在长沙市开福区14个社区卫生服务中心中应用随机数字表随机抽取1个社区卫生服务中心(新港社区卫生服务中心),然后从新港社区卫生服务中心管辖的6个社区中随机抽取一个社区(新安寺社区),从新安寺社区常住居民中随机抽取与病例等量的健康人群为对照,所有对象均为胸透无异常的健康人。在研究对象签署书面知情同意书之后,采用自制的调查问卷收集资料,并采用EDTA抗凝管采集5ml静脉血液用来提取DNA。基因的分型：本研究采用PCR-SSP技术对MBL基因rs7096206位点以及MASP-2基因rs2273346、rs6695096位点进行分型。统计分析：采用Epidata3.0录入数据,采用SAS9.2进行资料分析。分类资料的比较以及Hardy-Weinberg equilibrium检验采用χ2检验,多因素分析采用Logistic回归分析。加法交互作用采用Marginal Structural Linear Odds Models来对交互作用超额相对危险度relative excess risk due to the interaction (RERI)进行点估计和区间估计。RERI大于0,说明两因素之间存在协同作用；若RERI小于0,说明两因素之间存在拮抗作用。结果：吸烟是肺结核的危险因素,OR=1.605(1.121,2.296),P0.05。饮茶是肺结核的保护因素,OR=0.674(0.476,0.955),P0.05。MBL基因rs7096206位点GC基因型以及MASP-2基因rs2273346位点的TC基因型、rs6695096位点的TC基因型在肺结核病人组的分布高于健康对照组(P0.05),OR分别为1.427,1.379和1.396。MBL基因rs7096206与MASP-2基因rs2273346位点存在协同交互作用,交互作用超额相对危险度(RERI)为0.7675(0.1521,1.3831),P0.05。MBL基因rs7096206与MASP-2基因rs6695096位点存在协同交互作用,交互作用超额相对危险度(RERI)为1.0429(0.6556,1.4301),P0.05。MBL基因rs7096206位点与吸烟存在协同交互作用,交互作用超额相对危险度(RERI)为0.5360(0.2996,0.7728), P0.05。MASP-2基因rs2273346位点与吸烟存在协同交互作用,交互作用超额相对危险度(RERI)为0.4570(0.1522,0.7619),P0.05。MBL基因rs7096206位点与饮茶存在拮抗交互作用,交互作用超额相对危险度(RERI)为-0.6530(-0.9830,-0.3230), P0.05。MASP-2基因rs2273346位点与饮茶存在拮抗交互作用,交互作用超额相对危险度(RERI)为-0.2862(-0.5393,-0.03319), P0.05。MASP-2基因rs6695086位点与饮茶存在拮抗交互作用,交互作用超额相对危险度(RERI)为-0.4907(-0.8356,-0.1455),P0.05。不吸烟人群中被动吸烟(OR=1.51,95%C11.02-2.26)、烹调烟雾暴露(OR=2.78,95%CI1.81-4.28)是肺结核的危险因素。不吸烟人群中MBL基因rs7096206位点与被动吸烟和烹调烟雾暴露存在协同交互作用,交互作用超额相对危险度(RERI)分别为1.857(0.594,3.150)和2.45(1.66,3.24),P0.05；MASP-2基因rs6695096位点与烹调烟雾暴露存在协同交互作用,交互作用超额相对危险度(RERI)为2.60(1.57,3.61),P0.05。结论：吸烟、被动吸烟及厨房烟雾暴露都是肺结核的危险因素,饮茶是肺结核的保护因素。MBL基因rs7096206位点GC基因型、MASP-2基因rs2273346位点TC基因型和rs6695096位点TC基因型均是肺结核的易感基因型。MBL基因rs7096206位点与MASP-2基因rs2273346、rs6695096位点均存在正交互作用。MBL基因rs7096206位点、MASP-2基因rs2273346位点与吸烟均存在正交互作用。MBL基因rs7096206位点、MASP-2基因rs6695086位点与饮茶均存在负交互作用。不吸烟人群中,MBL基因rs7096206位点与被动吸烟存在正交互作用；MBL基因rs7096206位点及MASP-2基因rs6695096位点与烹调烟雾暴露均存在正交互作用。
[Abstract]:Background : Tuberculosis is a global public health problem which seriously endangers public health . It is estimated that in 2012 , there are 8.6 million people suffering from tuberculosis . China is the second largest country in the world . In 2010 , the prevalence of active pulmonary tuberculosis in China is 459 / 100000 . It is also found that the inhibition of the transcription of TACO gene in the population can inhibit the growth and reproduction of Mycobacterium tuberculosis .

Objective : To study the effect of polymorphisms and environmental factors on the gene polymorphism and environmental factors in Han population in Hunan Province .

Methods : The source of the cases : The multi - level sampling principle was adopted . First , three cities ( Hengyang , Yuyang , Huaihua ) were randomly selected from 14 cities in Hunan Province . Four county - level disease prevention control centers ( Qidong , Yuyang , Yuyang and Hongjiang ) were randomly selected in the three cities . All cases were randomly selected from four newly registered tuberculosis patients in 2009 . All cases were diagnosed as pulmonary tuberculosis by the tuberculosis diagnostic criteria of the Ministry of Health .

A multi - stage sampling method was used to randomly extract 1 community health service center ( Xingang Community Health Service Center ) from 14 community health service centers in Changsha , Changsha , and then randomly selected a community ( Xinan temple community ) from 6 communities under the jurisdiction of the community health service center in Changsha . All the subjects were randomly selected from the community of Xin ' an Temple community as the control , and all the subjects were healthy persons with no abnormal breast cancer .

After the written informed consent form was signed by the study object , the data was collected using a self - made questionnaire and 5 ml of venous blood was collected using EDTA anticoagulant to extract DNA .

Genetic typing : PCR - SSP technique was used to classify the rs7096206 locus and rs123346 of the MASP - 2 gene . The statistical analysis showed that the data was recorded by using the data of Epidata 3.0 . The data were analyzed by SAS9.2 . The comparison of the classification data and the Hardy - equilibrium test were analyzed by Logistic regression . The multivariate analysis was performed using Logistic regression analysis . The additive interaction was performed on the relative excess risk due to the interaction ( RERI ) . The RERI was greater than 0 , indicating the synergy between the two factors .
If RERI is less than 0 , there is an antagonistic effect between the two factors .

Results : Smoking is a risk factor for pulmonary tuberculosis , OR = 1.605 ( 1.121 , 2.296 ) , P0.05 . There is a synergistic interaction between the locus of rs7096206 and MASP - 2 gene rs7096206 . The interaction of the interaction excess relative risk ( RERI ) is 0.7675 ( 0.2996 , 0.7619 ) , P0.05 . The interaction excess relative risk ( RERI ) is 0.7675 ( 0.2996 , 0.7619 ) , P0.05 . The interaction excess relative risk ( RERI ) is 0.7675 ( 0.2996 , 0.7619 ) , P0.05 . The interaction excess relative risk ( RERI ) is 0.7675 ( 0.2996 , 0.7619 ) , P0.05 . The interaction excess relative risk ( RERI ) is 0.7675 ( 0.2996 , 0.7619 ) , P0.05 . The interaction excess relative risk ( RERI ) is 0.7675 ( 0.2996 , 0.7619 ) , P0.05 .
There was a synergistic interaction between the MASP - 2 gene and the exposure of cooking fumes . The interaction excess relative risk ( RERI ) was 2.60 ( 0.57 , 3.61 ) , P0.05 .

Conclusion : Smoking , passive smoking and exposure to kitchen fumes are the risk factors of pulmonary tuberculosis .
There was positive interaction between the rs7096206 locus and the MASP - 2 gene rs66996 and the exposure to cooking fumes .

【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R52

【参考文献】