李雨澤 侯紹英 陳向麗 張潔 褚光炎 劉玉琴 姜輝 李殿忠
·論著
Toll樣受體4基因多態(tài)性與2型糖尿病并發(fā)肺結(jié)核
患者發(fā)生糖尿病性下肢血管病變的關(guān)系研究
李雨澤 侯紹英 陳向麗 張潔 褚光炎 劉玉琴 姜輝 李殿忠
目的探索Toll樣受體4(Toll-like receptor 4,TLR4)基因多態(tài)性與2型糖尿病并發(fā)肺結(jié)核(type 2 diabetes mellitus complicated with pulmonary tuberculosis,T2DM-PTB)患者發(fā)生糖尿病性下肢血管病變(lower extremity arterial disease,LEAD)的關(guān)系。方法選取2013年9月至2015年6月期間,在黑龍江省傳染病防治院就診的T2DM-PTB發(fā)生LEAD的患者87例(觀察組)及T2DM-PTB未發(fā)生LEAD患者68例(對(duì)照組),所有患者于納入研究時(shí)采集基本信息及血液樣本。基因組DNA提取試劑盒提取血液DNA,采用實(shí)時(shí)熒光定量PCR技術(shù)(Taqman探針法)對(duì)TLR4基因的3個(gè)基因位點(diǎn)(rs7873784、rs1927911及rs1927914)進(jìn)行基因多態(tài)性檢測(cè)。結(jié)果觀察組和對(duì)照組的TLR4基因單核苷酸多態(tài)性(single nucleotide polymorphisms,SNPs)位點(diǎn)等位基因分布:rs7873784位點(diǎn)G等位基因兩組分別為91.38%(159/174)、91.18%(124/136),C等位基因兩組分別為8.62%(15/174)、8.82%(12/136),兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.00,P=0.950);rs1927911位點(diǎn)T等位基因兩組分別為59.20%(103/174)、61.76%(84/136),C等位基因兩組分別為40.80%(71/174)、38.24%(52/136),兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.21,P=0.646);rs1927914位點(diǎn)T等位基因兩組分別為59.77%(104/174)、64.71%(88/136),C等位基因兩組分別為40.23%(70/174)、35.29%(48/136),兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.79,P=0.374)。觀察組和對(duì)照組的TLR4基因SNP位點(diǎn)基因型分布:rs7873784位點(diǎn)GG基因型兩組分別為82.76%(72/87)、82.35 %(56/68),GC基因型兩組分別為17.24%(15/87)、17.65%(12/68),兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.00,P=0.947);rs1927911位點(diǎn)TT基因型兩組分別為32.18%(28/87)、35.30%(24/68),CT基因型兩組分別為54.02%(47/87)、52.94%(36/68),CC基因型兩組分別為13.80%(12/87)、11.76%(8/68),兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.24,P=0.887);rs1927914位點(diǎn)TT基因型兩組分別為33.33%(29/87)、42.65%(29/68),CT基因型兩組分別為52.87%(46/87)、44.12%(30/68),CC基因型兩組分別為13.80%(12/87)、13.23%(9/68),兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=1.49,P=0.475)。TLR4基因rs7873784位點(diǎn):與野生純合基因型GG相比,GC基因型的調(diào)整OR值為0.90(95%CI:0.39~2.06,P=0.80)。rs1927911位點(diǎn):與野生純合基因型TT相比,CT基因型及CC基因型的調(diào)整OR值分別為1.00(95%CI:0.51~1.97,P=1.00)和1.29(95%CI:0.46~3.66,P=0.63);rs1927914位點(diǎn):與野生純合基因型TT相比,CT基因型及CC基因型的調(diào)整OR值分別為1.27(95%CI:0.64~2.51,P=0.49)和1.24(95%CI:0.47~3.27,P=0.67)。3個(gè)基因位點(diǎn)各基因型間的差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值均>0.05)。結(jié)論TLR4基因rs7873784、rs1927911和rs1927914位點(diǎn)多態(tài)性與T2DMTB患者發(fā)生LEAD無(wú)關(guān)。
結(jié)核,肺; 糖尿病,2型; 共病現(xiàn)象; Toll樣受體4; 糖尿病血管病變; 因果律
2型糖尿病并發(fā)肺結(jié)核(type 2 diabetes mellitus complicated with pulmonary tuberculosis,T2DM-PTB)患者多表現(xiàn)為肺部病變重、病情進(jìn)展快、原發(fā)耐藥多和預(yù)后差。一旦T2DM-PTB患者發(fā)生糖尿病性下肢血管病變(lower extremity arterial disease,LEAD)會(huì)導(dǎo)致治療更加困難。2型糖尿病并發(fā)肺結(jié)核患者在體檢時(shí)發(fā)現(xiàn)并不是全部患者都會(huì)發(fā)生LEAD,其原因尚不明確。
自身免疫介導(dǎo)的炎癥反應(yīng)在2型糖尿病(type 2 diabetes, T2DM)及大血管病變的發(fā)生發(fā)展中具有重要作用,T2DM及大血管病變是自身免疫介導(dǎo)的炎癥性疾病。大血管病變主要是指動(dòng)脈粥樣硬化,Toll樣受體4(Toll-like receptor 4,TLR4)作為炎癥標(biāo)志物與動(dòng)脈粥樣硬化的發(fā)生和發(fā)展有著密切聯(lián)系。TLR4是機(jī)體天然免疫屏障中作用機(jī)制最明確的Toll樣家族相關(guān)受體,可在包括巨噬細(xì)胞、樹突狀細(xì)胞及胰島細(xì)胞等在內(nèi)的免疫和非免疫細(xì)胞中表達(dá),并在天然免疫防御中發(fā)揮關(guān)鍵作用[1-2]。TLR4水平的改變與健康人群T2DM或肺結(jié)核患病均相關(guān)[3-6]。因此,筆者進(jìn)行了T2DM-PTB血清中炎癥細(xì)胞因子TLR4的基因多態(tài)性與并發(fā)癥的關(guān)聯(lián)的研究。
一、研究設(shè)計(jì)
采用病例對(duì)照研究方法,將T2DM-PTB患者發(fā)生LEAD組設(shè)為觀察組,將T2DM-PTB患者未發(fā)生LEAD組設(shè)為對(duì)照組,分析TLR4基因的單核苷酸多態(tài)性(single nucleotide polymorphisms,SNPs)與T2DM-PTB并發(fā)LEAD之間的關(guān)系。
二、研究對(duì)象來(lái)源、納入和排除標(biāo)準(zhǔn)
選取2013年9月1日至2015年6月1日期間,在黑龍江省傳染病防治院就診的T2DM-PTB發(fā)生LEAD患者87例(觀察組)及T2DM-PTB未發(fā)生LEAD患者68例(對(duì)照組),所有患者進(jìn)行基因多態(tài)性分析。
觀察組的納入標(biāo)準(zhǔn):入院的中國(guó)漢族患者在符合2型糖尿病的診斷基礎(chǔ)上同時(shí)符合肺結(jié)核和LEAD的診斷標(biāo)準(zhǔn)。2型糖尿病以WHO 1999年的診斷標(biāo)準(zhǔn)進(jìn)行診斷,即有明顯的糖尿病典型癥狀(包括多飲、多食、多尿及體質(zhì)量下降),并滿足以下任意一項(xiàng)條件:任意時(shí)間血糖≥11.1 mmol/L,或空腹血糖≥7.0 mmol/L,或空腹血糖≥7.0 mmol/L囑患者口服75 g糖后2 h血糖≥11.1 mmol/L(葡萄糖耐量實(shí)驗(yàn)OGTT)。根據(jù)《肺結(jié)核診斷標(biāo)準(zhǔn)(WS 288-2008)》[7]進(jìn)行診斷,有咳嗽、咳痰、發(fā)熱等臨床癥狀,結(jié)合患者痰涂片及經(jīng)胸部X線攝影檢查陽(yáng)性發(fā)現(xiàn)即可確診為肺結(jié)核,具體標(biāo)準(zhǔn)參照肺結(jié)核診斷標(biāo)準(zhǔn)。雙下肢動(dòng)脈超聲診斷LEAD的標(biāo)準(zhǔn):根據(jù)患者的雙下肢動(dòng)脈超聲檢查結(jié)果對(duì)患者進(jìn)行診斷, 若患者雙下肢動(dòng)脈管腔狹窄程度在 30% 以上,存在彌漫性、多發(fā)或單發(fā)斑塊或內(nèi)膜增厚程度在1 mm 以上任一種情況,均可將其視為L(zhǎng)EAD[8]。
排除標(biāo)準(zhǔn):為防止研究對(duì)象存在可能與2型糖尿病及肺結(jié)核產(chǎn)生關(guān)聯(lián)的其他患病因素對(duì)研究結(jié)果產(chǎn)生影響,需要排除有HIV感染及乙型肝炎、丙型肝炎、梅毒、艾滋病的患者。同時(shí)排除并發(fā)腫瘤、結(jié)締組織病、除2型糖尿病以外的其他內(nèi)分泌疾病的患者。
三、研究?jī)?nèi)容
患者納入研究時(shí)采集外周血2 ml [乙二胺四乙酸(EDTA)抗凝],立即離心(1780×g離心15 min),將血清與血細(xì)胞分離,分別保存于-80 ℃冰箱。同時(shí)收集患者基本信息(信息來(lái)源于患者主訴及病歷記載),主要包括姓名、病歷號(hào)、性別、年齡、身高、體質(zhì)量等。黑龍江省第四醫(yī)院倫理委員會(huì)批準(zhǔn)本研究。患者本人同意并簽署了知情同意書。
四、實(shí)驗(yàn)方法
主要試劑和設(shè)備有定性PCR擴(kuò)增儀(7500 Fast型),美國(guó)Life公司;血液或細(xì)胞或組織基因組DNA提取試劑盒,北京天根生化科技有限公司。采用北京天根生化科技有限公司生產(chǎn)的血液(細(xì)胞或組織)基因組DNA提取試劑盒提取血液DNA,按照說(shuō)明書步驟進(jìn)行操作。采用實(shí)時(shí)熒光定量PCR技術(shù)(Taqman探針法)原理進(jìn)行基因多態(tài)性檢測(cè)。
五、統(tǒng)計(jì)學(xué)分析
基因多態(tài)性實(shí)驗(yàn)統(tǒng)計(jì)學(xué)方法:觀察組與對(duì)照組臨床資料及基因型頻率分布差異等采用χ2檢驗(yàn)。采用logistic回歸分析基因TLR4與T2DM-PTB的關(guān)系。所有統(tǒng)計(jì)檢驗(yàn)均為雙側(cè),以α=0.05為檢驗(yàn)水準(zhǔn)。應(yīng)用SPSS 20.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。
1.TLR4基因SNP位點(diǎn)等位基因在觀察組和對(duì)照組的分布:TLR4基因的3個(gè)基因位點(diǎn)rs7873784、 rs 1927911和 rs 1927914的等位基因在觀察組和對(duì)照組的分布差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值均>0.05)(表1)。
2.TLR4基因SNP位點(diǎn)各基因型的分布及Hardy-Weinberg平衡分析:TLR4基因的3個(gè)基因位點(diǎn)rs7873784、rs1927911和rs1927914的基因型在觀察組和對(duì)照組的分布差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值均>0.05)。Hardy-Weinberg平衡分析結(jié)果表明,對(duì)照組中TLR4各基因多態(tài)性位點(diǎn)各基因型頻率分布均滿足Hardy-Weinberg平衡(P>0.05),可以認(rèn)為數(shù)據(jù)來(lái)自同一群體(表2)。
表1 TLR4基因SNP位點(diǎn)等位基因在觀察組和對(duì)照組的分布
注T:胸腺嘧啶;C:胞嘧啶;G:鳥嘌呤
表2 TLR4基因SNP位點(diǎn)在兩組患者中的分布及基因型和Hardy-Weinberg平衡分析
注a:觀察組和對(duì)照組進(jìn)行3個(gè)基因位點(diǎn)基因型的χ2檢驗(yàn);b:觀察組和對(duì)照組進(jìn)行3個(gè)基因位點(diǎn)的Hardy-Weinberg平衡分析
表3 TLR4基因多態(tài)性與T2DM-PTB患者發(fā)生LEAD的關(guān)系a
注a:TLR4基因多態(tài)性與T2DM-PTB患者發(fā)生LEAD的關(guān)系采用非條件logistic回歸進(jìn)行法分析;b:為OR和95%CI在調(diào)整了年齡、BMI后得到的值;c:rs7873784位點(diǎn)CC基因型數(shù)目較少無(wú)法進(jìn)行計(jì)算,所以未列出該組數(shù)據(jù)
3.TLR4基因多態(tài)性與T2DM-PTB并發(fā)LEAD的關(guān)系:經(jīng)過統(tǒng)計(jì)學(xué)分析,TLR4各基因位點(diǎn)多態(tài)性與T2DM-PTB患者發(fā)生LEAD關(guān)系,觀察優(yōu)勢(shì)比(odds ratio,OR)和95%可信區(qū)間(confidence interval,CI),TLR4各基因位點(diǎn)多態(tài)性與T2DM-PTB患者發(fā)生LEAD無(wú)相關(guān)性(P>0.05)(表3)。
LEAD是一種常見的糖尿病慢性大血管病變類型,是造成糖尿病患者出現(xiàn)肢端壞疽的常見原因,致殘率和致死率較高[9]。由于機(jī)體持續(xù)處于高血糖與蛋白質(zhì)的非糖化狀態(tài),脂代謝紊亂等,使糖尿病患者的下肢動(dòng)脈容易發(fā)生血管病變,管壁增厚,管腔狹窄;糖尿病患者下肢血管病變?cè)缙诓灰妆淮_診,一旦出現(xiàn)下肢缺血癥狀,往往血管病變已較明顯,最終可導(dǎo)致患肢壞死,甚至截肢[10-12]。
在T2DM-PTB患者發(fā)生LEAD初期,患者往往無(wú)法分辨是由于LEAD還是抗結(jié)核藥物引起的下肢疼痛。經(jīng)過彩色多普勒超聲協(xié)助確定診斷后是否使用改善血液循環(huán)治療方案也成為棘手的問題,一方面LEAD需要進(jìn)行血液循環(huán)改善治療;另一方面在控制肺部結(jié)核病灶初期給予改善血液循環(huán)治療方案又擔(dān)心會(huì)加劇病灶的擴(kuò)散。所以,在早期排查T2DM-PTB患者易發(fā)生LEAD后,應(yīng)給予積極的抗結(jié)核藥物治療,在結(jié)核病情得到控制后盡早使用改善血液循環(huán)的治療方案。
在臨床工作中發(fā)現(xiàn),生活在相似飲食環(huán)境中的T2DM-PTB患者并未全部發(fā)生LEAD。但是飲食因素為重要的環(huán)境因素,使得我們不得不從基因水平方面考慮發(fā)病機(jī)制。
rs 7873784位點(diǎn):與野生純合基因型GG相比,突變雜合子GC基因型的粗OR值為0.96(95%CI:0.43~2.14,P=0.91),突變純合子CC基因型數(shù)量太少,無(wú)法進(jìn)行計(jì)算。通過調(diào)整OR值,得出該SNP位點(diǎn)各基因型與T2DM-PTB患者發(fā)生LEAD的發(fā)病風(fēng)險(xiǎn)無(wú)關(guān)系。
rs1927911位點(diǎn):與野生純合基因型TT相比,突變雜合子CT及突變純合子CC的粗OR值分別為1.15(95%CI:0.60~2.22,P=0.68)和1.32(95%CI:0.47~3.65,P=0.60),通過調(diào)整OR值,未發(fā)現(xiàn)該SNP位點(diǎn)各基因型與T2DM-PTB患者發(fā)生LEAD的發(fā)病風(fēng)險(xiǎn)有關(guān)系。
rs 1927914位點(diǎn):與野生純合基因型TT相比,突變雜合子CT及突變純合子CC的粗OR值分別為1.57 (95%CI:0.82~3.02,P=0.17)和1.35(95%CI:0.52~3.51,P=0.53)。通過調(diào)整OR值,未發(fā)現(xiàn)該SNP位點(diǎn)各基因型與T2DM-PTB患者發(fā)生LEAD的發(fā)病風(fēng)險(xiǎn)有關(guān)系。
本研究結(jié)果表明各基因位點(diǎn)與T2DM-PTB患者發(fā)生LEAD無(wú)關(guān)。其原因之一可能是樣本量不夠大。其次,基因多態(tài)性與人種有關(guān),筆者檢測(cè)的是中國(guó)漢族人群,本研究中發(fā)現(xiàn)TLR4基因多態(tài)性與T2DM-PTB患者發(fā)生LEAD無(wú)關(guān)聯(lián),并不代表在其他人種與其他地區(qū)TLR4基因多態(tài)性與T2DM-PTB患者發(fā)生LEAD無(wú)關(guān)。其次,本研究目的是為了尋找TLR4基因多態(tài)性與T2DM-PTB患者發(fā)生LEAD有無(wú)相關(guān)性,不是為了尋找TLR4基因多態(tài)性與健康人群患LEAD之間的關(guān)系;因此,本實(shí)驗(yàn)納入未發(fā)生LEAD的T2DM-PTB患者作為對(duì)照組人群,并沒有把健康人群作為對(duì)照組,更沒有進(jìn)一步比較TLR4基因多態(tài)性在T2DM-PTB患者、T2DM患者和健康人群之間的關(guān)系。由于T2DM-PTB也是T2DM并發(fā)癥的一種,T2DM患者可能已經(jīng)存在TLR4基因多態(tài)性,所以結(jié)果發(fā)現(xiàn)TLR4基因多態(tài)性與T2DM-PTB患者發(fā)生LEAD無(wú)相關(guān)性。這也符合一些對(duì)糖尿病的有關(guān)研究報(bào)道。有研究指出rs1927914基因多態(tài)性與糖尿病易并發(fā)糖尿病足潰瘍有關(guān)系[13],Singh等[14]的研究小組還發(fā)現(xiàn),TLR4基因SNPs位點(diǎn)rs10759931單核苷酸多態(tài)性(OR=1.50,P=0.05) 和TLR4基因SNPs位點(diǎn)rs1927914單核苷酸多態(tài)性 (OR=1.48,P=0.05) 均與糖尿病患者發(fā)生糖尿病視網(wǎng)膜病變有關(guān)。
經(jīng)過本研究對(duì)TLR4部分基因位點(diǎn)研究后,并未發(fā)現(xiàn)rs7873784位點(diǎn)、rs1927911位點(diǎn)和rs1927914位點(diǎn)與T2DM-PTB患者發(fā)生LEAD之間存在相關(guān)性。由于現(xiàn)階段并沒有關(guān)于T2DM-PTB患者并發(fā)其他疾病相關(guān)基因水平的研究,所以這是本研究的創(chuàng)新點(diǎn)。由于本次納入的患者樣本量比較少,可能會(huì)出現(xiàn)假陰性結(jié)果;筆者也并未對(duì)TLR4基因全部位點(diǎn)進(jìn)行檢測(cè)。所以,筆者在后期的相關(guān)研究中,將逐漸開展其余的TLR4基因位點(diǎn)來(lái)完善相關(guān)研究。從而為T2DM-PTB并發(fā)LEAD的遠(yuǎn)期預(yù)防,尤其是針對(duì)攜帶不同SNP患者的個(gè)體化預(yù)防提供依據(jù)。
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2017-09-18)
(本文編輯:范永德)
AssociationofToII-likereceptor4genepolymorphismwithdiabeticlowerextremityvasculardiseaseinpatientswithtype2diabetesmellituscomplicatedwithpulmonarytuberculosis
LIYu-ze*,HOUShao-ying,CHENXiang-li,ZHANGJie,CHUGuang-yan,LIUYu-qin,LIDian-zhong.
*InfectiousHospitalofHeilongjiangProvinceHarbin150500,China
s:LIUYu-qin,Email:liuyuqin_ssy@163.com;LIDian-zhong,Email:lidianzhong2010@163.com
ObjectiveTo investigate the relationship betweenTLR4gene polymorphism and LEAD in patients with T2DM-PTB.MethodsWe recruited 87 cases with T2DM-PTB patients complicated with LEAD and 68 cases with T2DM-PTB from Infectious Hospital of Heilongjiang Province between September 2013 and June 2015. The basic information of both T2DM-PTB patients complicated with LEAD and T2DM-PTB patients were collected. Meanwhile, peripheral blood was collected in order to undergo gene polymorphism analysis. DNA was extracted by genomic DNA extraction kits and genotyping was accomplished by using Real-time PCR (Taqman probe method). ThreeTLR4gene loci (rs 7873784, rs1927911, rs1927914) were tested.ResultsAllele distribution ofTLR4gene SNPs locus in the observation group and the control group: The G allele of rs7873784 were 91.38% (159/174) and 91.18% (124/136) in the two groups, and the C allele were 8.62% (15/174) and 8.82% (12/136) in the two groups, respectively. There was no significant difference between the two groups (χ2=0.00,P=0.950); The T allele of rs1927911 in two groups were 59.20% (103/174) and 61.76% (84/136), respectively, and the C allele were 40.80% (71/174) and 38.24% (52/136), respectively. There was no significant difference between the two groups (χ2=0.21,P=0.646); The T allele of rs1927914 in two groups were 59.77% (104/174) and 64.71% (88/136), respectively, and the C allele were 40.23% (70/174) and 35.29% (48/136), respectively. There was no significant difference between the two groups (χ2=0.79,P=0.374). Genotype distribution ofTLR4gene SNP locus in the observation group and the control group: The GG genotypes of rs7873784 were 82.76% (72/87) and 82.35% (56/68) in two group, and the GC genotype of the two groups were 17.24% (15/87) and 17.65% (12/68), respectively. The difference between the two groups was not statistically significant (χ2=0.00,P=0.947). The TT genotypes of rs1927911 were 32.18% (28/87) and 35.30% (24/68) in two groups, the CT genotype of the two groups were 54.02% (47/87) and 52.94% (36/68), and the CC genotype of the two groups were 13.80% (12/87), 11.76% (8/68), respectively. The difference between the two groups was not statistically significant (χ2=0.24,P=0.887). The TT genotypes of rs1927914 were 33.33% (29/87) and 42.65% (29/68) in two groups, the CT genotypes of two groups were 52.87% (46/87) and 44.12% (30/68), and the CC genotypes of two groups were 13.80% (12/87), 13.23% (9/68), respectively. The difference between the two groups was not statistically significant (χ2=1.49,P=0.475). Rs7873784 gene locus ofTLR4: compared with wild homozygous genotype GG, the adjustedORvalue of GC genotype was 0.90 (95%CI:0.39-2.06,P=0.80). Rs1927911 gene locus ofTLR4: compared with wild homozygous genotype TT, the adjustedORvalues of CT genotype and CC genotype were 1.00 (95%CI:0.51-1.97,P=1.00) and 1.29 (95%CI:0.46-3.66,P=0.63), respectively. Rs1927914 gene locus ofTLR4: compared with wild homozygous genotype TT, the adjustedORvalues of CT genotype and CC genotype were 1.27 (95%CI:0.64-2.51,P=0.49) and 1.24 (95%CI:0.47-3.27,P=0.67), respectively. There was no significant difference between the 3 genotypes at different loci (P>0.05).ConclusionThe polymorphisms of rs7873784, rs1927911 and rs1927914 inTLR4gene are not associated with LEAD in T2DM-PTB patients.
Tuberculosis, pulmonary; Diabetes mellitus, type 2; Comorbidity; Toll-like receptor 4; Diabetic angiopathies; Causality
10.3969/j.issn.1000-6621.2017.12.008
黑龍江省衛(wèi)生和計(jì)劃生育委員會(huì)科研項(xiàng)目(2017-524)
150500 哈爾濱,黑龍江省傳染病防治院 (李雨澤、張潔、褚光炎、劉玉琴、李殿忠);哈爾濱醫(yī)科大學(xué)公共衛(wèi)生學(xué)院(侯紹英);哈爾濱醫(yī)科大學(xué)地方病控制中心(陳向麗)
劉玉琴,Email:liuyuqin_ssy@163.com;李殿忠,Email:lidianzhong2010@163.com