本文選題：GSTT1 + GSTM1　； 參考：《南京醫(yī)科大學(xué)》2012年碩士論文

【摘要】：職業(yè)性噪聲聾(occupational noise-induced deafness)又稱噪聲性耳聾，其原因主要是由于長期暴露在損害性噪聲環(huán)境中所引起的緩慢的進(jìn)行性感音神經(jīng)性耳聾，是一種常見的職業(yè)病。在歐洲，有超過3500萬的工人存在患職業(yè)性噪聲聾的危險(xiǎn)，在工業(yè)化國家中約有超過10%的工人患有該疾病，，在一些發(fā)展中國家發(fā)病情況可能更為嚴(yán)重。職業(yè)性噪聲聾是一種可以預(yù)防的疾病，但是一旦發(fā)生就很難逆轉(zhuǎn)，因此降低其發(fā)病率已成為當(dāng)今職業(yè)病防治機(jī)構(gòu)面臨的一項(xiàng)非常重要的課題。 人群研究結(jié)果表明，職業(yè)性噪聲聾和累積噪聲暴露量呈正相關(guān)，噪聲愈強(qiáng)、噪聲暴露時(shí)間愈長，則聽力損失愈嚴(yán)重。除去噪聲外，其他環(huán)境影響因素包括高溫、振動(dòng)、有機(jī)溶劑、重金屬等。個(gè)體因素則包括年齡、性別、吸煙、高血壓、高血脂、服用耳毒性藥物(包括氨基糖苷類、氰化物等)、個(gè)體生活暴露以及遺傳因素等。嚴(yán)格控制條件的動(dòng)物實(shí)驗(yàn)證明了在相同暴露條件下，動(dòng)物的聽閾改變有較大差異。隨著近些年對(duì)職業(yè)性噪聲聾的研究不斷深入，在動(dòng)物模型中已經(jīng)證明某些基因可以影響動(dòng)物對(duì)噪聲的易感性。大樣本量的人群觀察發(fā)現(xiàn)在相同的噪聲暴露條件下，個(gè)體的聽閾改變也有很大差異，提示個(gè)體對(duì)噪聲的遺傳易感性存在著差異。 隨著近年來對(duì)職業(yè)性噪聲聾基因易感性研究的深入，目前已經(jīng)發(fā)現(xiàn)的職業(yè)性噪聲聾的可能易感基因有鈣粘蛋白23基因(CDH23)、質(zhì)膜Ca~(2+)-ATP酶2基因(PMCA2)、氧化性應(yīng)激基因家族(GSTT1、GSTM1、GSTP1、SOD1、SOD2、CAT等)、鉀離子循環(huán)有關(guān)基因(GJB2等)、熱休克蛋白70基因(HSP70)等。 研究職業(yè)性噪聲聾的易感基因?qū)β殬I(yè)性噪聲聾的一級(jí)預(yù)防具有很重要的意義，如果能確認(rèn)職業(yè)性噪聲聾的易感基因，就可以在接觸有害噪聲之前將對(duì)噪聲敏感的個(gè)體提前篩選出來，有效的減少職業(yè)性噪聲聾的發(fā)生，從而保護(hù)工人的健康。本課題組在較大樣本量的漢族人群中研究谷胱甘肽硫轉(zhuǎn)移酶(GST)的三個(gè)常見基因(GSTT1、GSTM1、GSTP1)與職業(yè)性噪聲聾易感性之間的關(guān)系，為進(jìn)一步研究這三個(gè)基因與職業(yè)性噪聲聾的易感性的關(guān)系提供理論依據(jù)，并為研究其他職業(yè)性噪聲聾的易感基因提供理論基礎(chǔ)和方法指導(dǎo)。目的：探討谷胱甘肽硫轉(zhuǎn)移酶(GST)的三個(gè)常見基因GSTT1(rs1049055)、GSTM1(rs10712361)、GSTP1(rs1695)的多態(tài)性與職業(yè)性噪聲聾易感性的關(guān)系，為職業(yè)性噪聲聾易感個(gè)體的篩檢提供理論支持，更好的預(yù)防職業(yè)性噪聲聾的發(fā)生。 方法： 1、研究對(duì)象的選擇 在中國漢族噪聲暴露人群中，采用病例對(duì)照的研究方法，根據(jù)GBZ49-2007，病例組為電測聽結(jié)果高頻聽閾大于等于40dB的工人，對(duì)照組為電測聽結(jié)果高頻聽閾小于40dB的同崗位輪班工人。 2、DNA的提取 采用天根試劑盒(非離心柱法)抽提外周血中的DNA。 3、基因型的測定 采用PCR-RFLP(聚合酶鏈?zhǔn)椒磻?yīng)-限制性片段長度多態(tài)性)測定基因型。參考相關(guān)文獻(xiàn)的報(bào)道來設(shè)計(jì)引物和設(shè)定實(shí)驗(yàn)條件。其中GSTT1和GSTM1的基因型測定需要Albumin(白蛋白內(nèi)參)為內(nèi)對(duì)照。 4、血漿中GST活性的測定GST活性的測定采用南京建成生物工程研究所研制的GST活性測試盒。 5、數(shù)據(jù)處理和統(tǒng)計(jì)分析 數(shù)據(jù)的錄入采用Epidate3.0，數(shù)據(jù)的統(tǒng)計(jì)分析使用SAS9.1.3軟件。年齡、工齡、聽閾等定量資料的兩組間比較采用雙側(cè)t檢驗(yàn)；年齡分層、工齡分層、噪聲暴露分層、基因型等定性資料的兩組間比較采用雙側(cè)2檢驗(yàn)；OR值和其95%的可信區(qū)間用Logistic多因素模型進(jìn)行分析計(jì)算，基因型和職業(yè)性噪聲聾的其他危險(xiǎn)因素的聯(lián)合作用采用Logistic多因素模型進(jìn)行分析。 結(jié)果： 1、病例組和對(duì)照組的一般情況 本次研究共收集符合條件的研究對(duì)象共計(jì)322例，其中病例組的工人161例，對(duì)照組的工人161例，兩組工人在年齡、性別、工齡、噪聲暴露強(qiáng)度、吸煙、飲酒方面均無統(tǒng)計(jì)學(xué)差異，而病例組工人的聽閾為53.3±10.0dB，對(duì)照組工人的聽閾為18.8±9.5dB，兩組之間比較有統(tǒng)計(jì)學(xué)差異(P0.001)。 2、GSTT1、GSTM1、GSTP1基因多態(tài)性與職業(yè)性噪聲聾易感性的關(guān)系 對(duì)161名病例組的工人和161名對(duì)照組的工人進(jìn)行GSTT1、GSTM1、GSTP1基因分型，結(jié)果表明：GSTM1缺失型在病例組和對(duì)照組的分布頻率分別為56.5%和41.0%，差異具有統(tǒng)計(jì)學(xué)意義(P0.001)，調(diào)整OR=1.8595%CI=(1.18-2.89)，說明攜帶GSTM1缺失型的噪聲暴露工人發(fā)生職業(yè)性噪聲聾的危險(xiǎn)性是攜帶GSTM1存在型的1.85倍；而GSTT1缺失型在病例組和對(duì)照組的分布頻率分別為49.1%和50.9%；GSTP1rs1695位點(diǎn)的AA、AG、GG基因型在病例組和對(duì)照組的分布頻率分別為57.1%，38.5%，4.4%和57.1%，37.3%，5.6%，GSTT1和GSTP1在病例組和對(duì)照組的分布差別均無統(tǒng)計(jì)學(xué)意義。 3、GSTM1多態(tài)性的分層分析和職業(yè)性噪聲聾易感性的關(guān)系 分層分析后發(fā)現(xiàn)當(dāng)GSTM1缺失型與噪聲作業(yè)工齡、噪聲暴露強(qiáng)度和吸煙等職業(yè)性噪聲聾的危險(xiǎn)因素結(jié)合后在統(tǒng)計(jì)學(xué)上可增加患職業(yè)性噪聲聾的危險(xiǎn)性，當(dāng)噪聲作業(yè)工齡大于二十年時(shí)，危險(xiǎn)性增大(OR=3.44)。工人的噪聲暴露強(qiáng)度≤85dB(A)時(shí)，OR=1.5195%CI=0.72-3.19，工人的噪聲暴露強(qiáng)度介于86-91dB(A)時(shí)，發(fā)生職業(yè)性噪聲聾的危險(xiǎn)性變大(OR=2.4295%CI=1.03-5.64)，但當(dāng)暴露強(qiáng)度≥92dB(A)時(shí)，未發(fā)現(xiàn)存在基因環(huán)境交互作用(OR=2.1595%CI=0.95-4.89)。吸煙作為職業(yè)性噪聲聾的危險(xiǎn)因素之一，與基因型可能也存在著交互作用，經(jīng)年齡、性別、飲酒等因素調(diào)整后，攜帶GSTM1缺失型并吸煙的工人發(fā)生職業(yè)性噪聲聾的危險(xiǎn)性是攜帶GSTM1存在型工人的2.06倍。 4、GSTT1、GSTM1、GSTP1的聯(lián)合基因多態(tài)性與職業(yè)性噪聲聾易感性的關(guān)系 對(duì)GSTT1、GSTM1、GSTP1的這三個(gè)位點(diǎn)的聯(lián)合分析后發(fā)現(xiàn)攜帶兩種危險(xiǎn)基因型的個(gè)體發(fā)生聽力損失的危險(xiǎn)性是不攜帶任何危險(xiǎn)基因型個(gè)體的1.98倍，其95%CI=1.03-3.81，但排除吸煙、飲酒等混雜因素后，未發(fā)現(xiàn)存在發(fā)生職業(yè)性噪聲聾的危險(xiǎn)性(OR=1.9595%CI=0.99-3.84)，Cochran-Armitage趨勢檢驗(yàn)發(fā)現(xiàn)病例組和對(duì)照組之間存在差異(P=0.024)。 5、GSTT1、GSTM1、GSTP1基因多態(tài)性與GST活性之間的關(guān)系 測定GST活性后發(fā)現(xiàn)病例組的活性低于對(duì)照組[14.5±5.1(U/ml) vs.15.9±6.3(U/ml), P=0.010]。在全部工人中[14.6±5.1(U/ml) vs.15.8±6.3(U/ml), P=0.021]和在對(duì)照組工人中[14.7±5.0(U/ml) vs.16.7±7.0(U/ml), P=0.012]，攜帶GSTM1缺失型工人的GST活性低于攜帶GSTM1存在型的工人，差異均有統(tǒng)計(jì)學(xué)意義。 結(jié)論： 1、GSTM1缺失型可能是漢族人群職業(yè)性噪聲聾的易感因素。 2、GSTT1和GSTP1的多態(tài)性可能不是職業(yè)性噪聲聾的易感因素。 3、GSTT1、GSTM1、GSTP1的三個(gè)多態(tài)性位點(diǎn)之間可能不存在有聯(lián)合作用。 4、GSTM1缺失型可能導(dǎo)致血漿中GST活性的下降從而影響機(jī)體的抗氧化能力，進(jìn)而可能導(dǎo)致噪聲暴露人群對(duì)職業(yè)性噪聲聾易感。
[Abstract]:Occupational noise deafness (occupational noise-induced deafness), also known as noise deafness, is mainly due to the slow onset of sensorineural deafness caused by long-term exposure to damaging noise environment. It is a common occupational disease. In Europe, more than 35 million workers are at risk of occupational noise and deafness. More than 10% of the workers in the industrialized countries are suffering from the disease and may be more serious in some developing countries. Occupational noise deafness is a preventable disease, but it is difficult to reverse once it occurs, so reducing its incidence has become a very important topic for the current occupational disease control institutions.
The results of the population study showed that occupational noise deafness was positively correlated with the amount of cumulative noise exposure, the stronger the noise and the longer the exposure to noise, the more serious the hearing loss. Other environmental factors included high temperature, vibration, organic solvents, heavy metals, etc. individual factors included age, sex, smoking, high blood pressure, hyperlipidemia, and high blood pressure. Ototoxic drugs (including aminoglycosides, cyanides, cyanide, etc.), individual life exposure, and genetic factors. Animal experiments with strict control conditions have proved that the hearing threshold changes of animals are greatly different under the same exposure conditions. With the study of occupational noise deafness in recent years, some genes have been proved in animal models. In order to affect the susceptibility of animals to noise, the population observation of large quantities found that under the same noise exposure conditions, the individual hearing threshold changes are also very different, suggesting that the individual genetic susceptibility to noise is different.
With the study of genetic susceptibility to occupational noise deafness in recent years, the possible susceptible genes for occupational noise deafness have been found to have the 23 gene (CDH23), the Ca~ (2+) -ATP enzyme 2 gene (PMCA2), the oxidative stress gene family (GSTT1, GSTM1, GSTP1, SOD1, SOD2, CAT, etc.), the genes of the potassium ion cycle related genes (GJB2, etc.), heat Shock protein 70 gene (HSP70) and so on.
The study of the susceptibility genes of occupational noise deafness is of great significance to the primary prevention of occupational noise deafness. If the susceptibility genes of occupational noise deafness can be identified, the noise sensitive individuals can be screened ahead of contact with harmful noise and effectively reduce the occurrence of occupational noise deafness, thus protecting the health of the workers. The research group studied the relationship between three common genes (GSTT1, GSTM1, GSTP1) of glutathione thiotransferase (GST) and occupational noise susceptibility in a large sample of Han population, providing a theoretical basis for further study of the relationship between the three genes and the susceptibility to occupational noise deafness, and for the study of other occupational noise. The predisposing genes of deafness provide theoretical basis and method guidance. Objective: To explore the relationship between the polymorphism of three common genes of glutathione thiotransferase (GST), GSTM1 (rs10712361), GSTP1 (rs1695) and the susceptibility of occupational noise deafness, to provide theoretical support for the screening of occupational noise deafness and easily susceptible individuals, and better preventive service. The occurrence of industrial noise deafness.
Method錛

本文編號(hào)：2021656