本文選題：結(jié)核 + 基因��； 參考：《中南大學(xué)》2014年博士論文

【摘要】：背景：結(jié)核病是嚴(yán)重危害公眾健康的全球性公共衛(wèi)生問題。據(jù)估計(jì),2012年,全球共有860萬人罹患結(jié)核病。中國是全球第二大結(jié)核病高負(fù)擔(dān)國家,2010年全國第五次結(jié)核病流行病學(xué)抽樣調(diào)查結(jié)果顯示：中國15歲及以上人群活動(dòng)性肺結(jié)核的患病率為459/10萬。目前很多研究都已經(jīng)證實(shí)吸煙、過度飲酒、廚房煙霧暴露是肺結(jié)核的危險(xiǎn)因素,實(shí)驗(yàn)室的證據(jù)發(fā)現(xiàn)茶葉中的EGCG可以通過抑制結(jié)核桿菌中烯酰基載體蛋白質(zhì)還原酶InhA的活性來抑制結(jié)核桿菌的生長繁殖。還可以通過抑制巨噬細(xì)胞內(nèi)TACO基因的轉(zhuǎn)錄,達(dá)到抑制結(jié)核桿菌在巨噬細(xì)胞內(nèi)存活的效果。研究顯示MBL基因在啟動(dòng)子區(qū)和結(jié)構(gòu)區(qū)的多態(tài)性影響MBL多聚體的形成和血漿MBL濃度。MBL多聚體形成減少,導(dǎo)致其與配體的結(jié)合力減弱,同時(shí)也更易被金屬蛋白酶降解。MASP-2基因的突變同樣影響著其編碼的蛋白(MASP2, Map19)血清含量的變化,并且導(dǎo)致其與MBL及ficolin分子結(jié)合的能力下降,從而阻礙補(bǔ)體活化的凝集素途徑,引起機(jī)體非特異性免疫系統(tǒng)功能障礙。 目的：本研究分析湖南省漢族人群MBL/MASP2基因的多態(tài)性與環(huán)境因素的作用,探討其對結(jié)核易感性的影響。 方法：病例的來源：采用多級抽樣原則,首先在湖南省14個(gè)市州隨機(jī)抽取3個(gè)市州(衡陽、岳陽、懷化),其次在這3個(gè)市州隨機(jī)抽取4個(gè)縣級疾病預(yù)防控制中心(祁東、岳陽樓區(qū)、岳陽縣、洪江市),最后從4個(gè)縣級疾病預(yù)防控制中心2009年新登記的所有肺結(jié)核病人中隨機(jī)抽取。所有病例均采用衛(wèi)生部結(jié)核病診斷標(biāo)準(zhǔn)被確診為肺結(jié)核病人。 健康對照的來源：采用多級抽樣方法,首先在長沙市開福區(qū)14個(gè)社區(qū)衛(wèi)生服務(wù)中心中應(yīng)用隨機(jī)數(shù)字表隨機(jī)抽取1個(gè)社區(qū)衛(wèi)生服務(wù)中心(新港社區(qū)衛(wèi)生服務(wù)中心),然后從新港社區(qū)衛(wèi)生服務(wù)中心管轄的6個(gè)社區(qū)中隨機(jī)抽取一個(gè)社區(qū)(新安寺社區(qū)),從新安寺社區(qū)常住居民中隨機(jī)抽取與病例等量的健康人群為對照,所有對象均為胸透無異常的健康人。 在研究對象簽署書面知情同意書之后,采用自制的調(diào)查問卷收集資料,并采用EDTA抗凝管采集5ml靜脈血液用來提取DNA。 基因的分型：本研究采用PCR-SSP技術(shù)對MBL基因rs7096206位點(diǎn)以及MASP-2基因rs2273346、rs6695096位點(diǎn)進(jìn)行分型。統(tǒng)計(jì)分析：采用Epidata3.0錄入數(shù)據(jù),采用SAS9.2進(jìn)行資料分析。分類資料的比較以及Hardy-Weinberg equilibrium檢驗(yàn)采用χ2檢驗(yàn),多因素分析采用Logistic回歸分析。加法交互作用采用Marginal Structural Linear Odds Models來對交互作用超額相對危險(xiǎn)度relative excess risk due to the interaction (RERI)進(jìn)行點(diǎn)估計(jì)和區(qū)間估計(jì)。RERI大于0,說明兩因素之間存在協(xié)同作用；若RERI小于0,說明兩因素之間存在拮抗作用。 結(jié)果：吸煙是肺結(jié)核的危險(xiǎn)因素,OR=1.605(1.121,2.296),P0.05。飲茶是肺結(jié)核的保護(hù)因素,OR=0.674(0.476,0.955),P0.05。MBL基因rs7096206位點(diǎn)GC基因型以及MASP-2基因rs2273346位點(diǎn)的TC基因型、rs6695096位點(diǎn)的TC基因型在肺結(jié)核病人組的分布高于健康對照組(P0.05),OR分別為1.427,1.379和1.396。MBL基因rs7096206與MASP-2基因rs2273346位點(diǎn)存在協(xié)同交互作用,交互作用超額相對危險(xiǎn)度(RERI)為0.7675(0.1521,1.3831),P0.05。MBL基因rs7096206與MASP-2基因rs6695096位點(diǎn)存在協(xié)同交互作用,交互作用超額相對危險(xiǎn)度(RERI)為1.0429(0.6556,1.4301),P0.05。MBL基因rs7096206位點(diǎn)與吸煙存在協(xié)同交互作用,交互作用超額相對危險(xiǎn)度(RERI)為0.5360(0.2996,0.7728), P0.05。MASP-2基因rs2273346位點(diǎn)與吸煙存在協(xié)同交互作用,交互作用超額相對危險(xiǎn)度(RERI)為0.4570(0.1522,0.7619),P0.05。MBL基因rs7096206位點(diǎn)與飲茶存在拮抗交互作用,交互作用超額相對危險(xiǎn)度(RERI)為-0.6530(-0.9830,-0.3230), P0.05。MASP-2基因rs2273346位點(diǎn)與飲茶存在拮抗交互作用,交互作用超額相對危險(xiǎn)度(RERI)為-0.2862(-0.5393,-0.03319), P0.05。MASP-2基因rs6695086位點(diǎn)與飲茶存在拮抗交互作用,交互作用超額相對危險(xiǎn)度(RERI)為-0.4907(-0.8356,-0.1455),P0.05。不吸煙人群中被動(dòng)吸煙(OR=1.51,95%C11.02-2.26)、烹調(diào)煙霧暴露(OR=2.78,95%CI1.81-4.28)是肺結(jié)核的危險(xiǎn)因素。不吸煙人群中MBL基因rs7096206位點(diǎn)與被動(dòng)吸煙和烹調(diào)煙霧暴露存在協(xié)同交互作用,交互作用超額相對危險(xiǎn)度(RERI)分別為1.857(0.594,3.150)和2.45(1.66,3.24),P0.05；MASP-2基因rs6695096位點(diǎn)與烹調(diào)煙霧暴露存在協(xié)同交互作用,交互作用超額相對危險(xiǎn)度(RERI)為2.60(1.57,3.61),P0.05。 結(jié)論：吸煙、被動(dòng)吸煙及廚房煙霧暴露都是肺結(jié)核的危險(xiǎn)因素,飲茶是肺結(jié)核的保護(hù)因素。MBL基因rs7096206位點(diǎn)GC基因型、MASP-2基因rs2273346位點(diǎn)TC基因型和rs6695096位點(diǎn)TC基因型均是肺結(jié)核的易感基因型。MBL基因rs7096206位點(diǎn)與MASP-2基因rs2273346、rs6695096位點(diǎn)均存在正交互作用。MBL基因rs7096206位點(diǎn)、MASP-2基因rs2273346位點(diǎn)與吸煙均存在正交互作用。MBL基因rs7096206位點(diǎn)、MASP-2基因rs6695086位點(diǎn)與飲茶均存在負(fù)交互作用。不吸煙人群中,MBL基因rs7096206位點(diǎn)與被動(dòng)吸煙存在正交互作用；MBL基因rs7096206位點(diǎn)及MASP-2基因rs6695096位點(diǎn)與烹調(diào)煙霧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 .

【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R52

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