MTHFR C677T基因多態(tài)性與深靜脈血栓危險性Meta分析

宋秀婷，齊文彥，王　穎，喬丹丹，胡　瑩

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·預(yù)防醫(yī)學(xué)·

MTHFR C677T基因多態(tài)性與深靜脈血栓危險性Meta分析

宋秀婷1,2，齊文彥1，王穎1，喬丹丹1，胡瑩2,3

目的探討不同種族群體MTHFR-C677T多態(tài)性與深靜脈栓塞危險性的相關(guān)性。方法檢索關(guān)于MTHFR-C677T多態(tài)性與深靜脈栓塞危險性研究的文獻(xiàn)，把研究對象分為高加索人群和亞洲人群，以病例組與對照組比值比為效應(yīng)指標(biāo)，應(yīng)用Stata 11.0計算兩種人群的合并OR值及顯著性P值。結(jié)果納入文獻(xiàn)研究39篇，其中高加索人群20篇；亞洲人群研究19篇。MTHFR C677T基因多態(tài)性和深靜脈栓塞危險性有相關(guān)性，計算隱性模式高加索人群合并OR值為0.453，P值為0.0，異質(zhì)性檢測P值為0.0。加性模式亞洲人合并OR值為1.421，P值為0.0，異質(zhì)性P值為0.0；顯性模式亞洲人合并OR值為1.475，P值為0.001，異質(zhì)性P值為0.0；隱性模式亞洲人合并OR值為1.475，P值為0.0，異質(zhì)性P值為0.0；除顯性模式下亞洲人群有發(fā)表偏倚外，其他模式兩種人群均無發(fā)表偏倚。結(jié)論MTHFR C677T基因多態(tài)性與深靜脈栓塞危險性在高加索人群、亞洲人群均有相關(guān)性。

深靜脈栓塞；亞甲基四氫葉酸還原酶；基因多態(tài)性；Meta分析

靜脈栓塞癥(venous thromboembolism,VTE)包括肺栓塞(pulmonary thromboembolism,PE)和深靜脈血栓癥(deep venous thrombosis,DVT)，它們是同一種疾病的兩種不同表現(xiàn)形式[1]。目前在心腦血管疾病中成為第三大病因。靜脈血栓栓塞癥是復(fù)雜的多因子疾病，基因突變在靜脈血栓栓塞癥的發(fā)病中有不可忽視的作用，但是基因突變具有較高人種和區(qū)域特征，不同地區(qū)患者具有較大差異。因此，探討靜脈血栓栓塞癥的基因突變，為靜脈血栓栓塞癥預(yù)防、治療提供依據(jù)是今后血管疾病重要研究方向之一[2]。

亞甲基四氫葉酸還原酶(methylenetetrahydro-folate reductase,MTHFR)在同型半胱氨酸代謝過程中起到關(guān)鍵作用，能將N5,N10-亞甲基四氫葉酸還原為N5-甲基四氫葉酸，后者能夠維持血漿中同型半胱氨酸(Hcy)正常值，一旦MTHFR活性降低導(dǎo)致同型半胱氨酸甲基化障礙，造成高同型半胱氨酸血癥。其可破壞血管內(nèi)皮和改變血小板功能和血液凝固狀態(tài)，從而參與深靜脈血栓形成的發(fā)病過程。MTHFR基因在677位由堿基胞嘧啶(C)突變?yōu)樾叵汆奏?T)，使氨基酸發(fā)生錯譯，造成MTHFR活性下降，引起同型半胱氨酸水平升高。

近幾年國內(nèi)外關(guān)于MTHFR基因多態(tài)性與靜脈血栓栓塞癥危險性Meta分析較多。但他們的結(jié)論不一，有的甚至相反。于海東等[2]報道TT基因型分布在VTE組明顯高于對照組，由此其認(rèn)為TT基因型在深靜脈栓塞中可能是一個遺傳風(fēng)險因子。與高加索人群或者非洲美國人群相比，Gohil等[3]發(fā)現(xiàn)MTHFR/C677T在中國人群VTE中是一個顯著的危險因子，表明MTHFR C677T多態(tài)性與VTE危險性具有相關(guān)性。然而有國外學(xué)者實(shí)驗(yàn)表明MTHFR基因C677T突變不是靜脈血栓栓塞癥的獨(dú)立危險因子，沒有相關(guān)性。國外學(xué)者實(shí)驗(yàn)表明MTHFR基因C677T突變不是靜脈血栓栓塞癥的獨(dú)立危險因子[4-5]。造成結(jié)論不一的原因，可能是研究人群種族和地域分布差異、樣本量大小不同、研究方法不一致[6]。作者全面搜索文獻(xiàn)進(jìn)行Meta分析，以期發(fā)現(xiàn)MTHFR-C677T多態(tài)性與深靜脈栓塞危險性的相關(guān)性，為靜脈血栓栓塞癥的預(yù)防、治療提供理論依據(jù)。

1　材料和方法

1.1資料來源本研究采用的檢索策略為：外文數(shù)據(jù)庫中確定“MTHFR C677T”、“5,10-methylenetetrahydrofolate reductase”、“VTE”、“deep venous thrombosis”、 “pulmonary embolism”、“PE”為關(guān)鍵詞，在PUBMED、Ovid、Embase、Web of science、Cochrane database、Medline、Elsevier進(jìn)行檢索；中文數(shù)據(jù)庫中確定“亞甲基四氫葉酸還原酶”、“MTHFR”、“5,10-methylenetetrahydrofolate reductase”、“深靜脈栓塞”、“肺栓塞”、“肺動脈栓塞”為關(guān)鍵詞，在中國知網(wǎng)數(shù)據(jù)庫、萬方數(shù)據(jù)庫、中國生物醫(yī)學(xué)數(shù)據(jù)庫進(jìn)行檢索。對所有檢索文獻(xiàn)中提供的參考文獻(xiàn)進(jìn)行二次檢索，相關(guān)綜述、文章和會議的摘要均被檢索，以期發(fā)現(xiàn)可能的合格研究，重復(fù)檢索的研究，比對后作為同一研究對待。以上檢索策略的制定和檢索文獻(xiàn)工作由兩位研究者獨(dú)立完成，文獻(xiàn)檢索截止日期為2015年6月。

1.2文獻(xiàn)納入標(biāo)準(zhǔn)合格的研究必須滿足以下標(biāo)準(zhǔn)：①M(fèi)THFR C677T基因多態(tài)性和深靜脈栓塞(包括肺動脈栓塞)且排除病例組的病人應(yīng)排除視網(wǎng)膜深靜脈栓塞，門靜脈栓塞和中央靜脈栓塞，同時排除外科手術(shù)后導(dǎo)致的深靜脈栓塞或肺栓塞；②具有病例對照組的設(shè)計；③原始研究具有樣本量大小、等位基因的分布、其他明確的比值比(the odds ratio,OR)以及95%置信區(qū)間(95% confidence interval,95%CI)；④對照組應(yīng)是健康者或者沒有栓塞疾病的病人、基因相關(guān)栓塞疾病的對照組人群不同基因分布應(yīng)該符合Hardy-Weinberg遺傳平衡定律。

1.3提取匯總數(shù)據(jù)兩位研究者各自按照以下要求提取匯總數(shù)據(jù)：①基本信息：文獻(xiàn)第一作者、文獻(xiàn)發(fā)表的年份、研究對象種族和國籍、研究對象的性別和年齡范圍；②研究內(nèi)容信息：病例對照組各組人數(shù)和各組的等位基因、基因型分布情況，最后按照Meta分析的要求整理原始文獻(xiàn)并摘錄數(shù)據(jù)，對各研究對照組的基因分布進(jìn)行Hardy-Weinberg遺傳平衡檢驗(yàn)。

1.4統(tǒng)計學(xué)方法對各人群的研究進(jìn)行異質(zhì)性檢驗(yàn)，如果P<0.05，則認(rèn)為異質(zhì)性顯著；如果P>0.05，則認(rèn)為異質(zhì)性不顯著。各研究結(jié)果間無異質(zhì)性，則采用Mantel-Haenszel固定效應(yīng)模型進(jìn)行數(shù)據(jù)合并，計算合并OR及95%CI；若結(jié)果間存在異質(zhì)性，則選用Dersimonian-Laird隨機(jī)效應(yīng)模型計算。MTHFR C677T 多態(tài)性和深靜脈栓塞危險性用合并比值比和95%CI來評估，合并比值各組加性基因型、顯性基因型、隱性基因型來計算。去除樣本量最大的研究進(jìn)行敏感性分析，采用Egger法和Begg法對發(fā)表結(jié)果是否偏倚進(jìn)行評估。以上分析均通過統(tǒng)計分析軟件Stata11.0版進(jìn)行。

2　結(jié)果

2.1研究類型MTHFR-C677T多態(tài)性與深靜脈栓塞危險性的Meta分析，共39篇文獻(xiàn)按照納入標(biāo)準(zhǔn)進(jìn)入Meta分析，包含9 005例的病例組和13 229例的對照組，其中高加索人群研究納入病例組6 475例，對照組4 421例；亞洲人群研究納入病例組2 530例，對照組8 008例。按照納入標(biāo)準(zhǔn)的文獻(xiàn)的特征和深靜脈栓塞MTHFR C677T基因多態(tài)性的頻率分布各自總結(jié)在表1和表2，共19篇亞洲人群和20篇高加索人群，所有案例的病因都從診斷學(xué)上得到確認(rèn)，對照組主要按照性別、年齡和病例組進(jìn)行匹配。對照組基因多態(tài)性符合Hardy-Weinberg平衡。

2.2異質(zhì)性檢測表3顯示3種遺傳模式分析中異質(zhì)性檢驗(yàn)結(jié)果。高加索人群、亞洲人群中，均未見異質(zhì)性。

表1　Meta分析文獻(xiàn)的基本信息

(續(xù)表)

編號作者年份國家種族15Bezemer[20]2007荷蘭高加索人種16Lizbeth[21]2006德國高加索人種17于東海[2]2006中國亞洲人種18鄭紅[22]2006中國亞洲人種19Almawi[23]2005美國高加索人種20周玉斌[24]2003中國亞洲人種21葉艷平[25]2004中國亞洲人種22王美堂[26]2004中國亞洲人種23Lu[27]2002中國亞洲人種24Miranda[28]2002荷蘭高加索人種25Zalavras[29]2002希臘高加索人種26Gertrud[30]2002美國高加索人種27賀穎[31]2002中國亞洲人種28郭辰虹[32]2002中國亞洲人種29Maria[33]2001阿根廷高加索人種30Morelli[4]2001巴西高加索人種31NAOMI[34]2001美國高加索人種32Ray[35]2001加拿大高加索人種33HsuTS[36]2001中國亞洲人種34Gerald[37]2000澳大利亞高加索人種35Phillip[38]2000加拿大高加索人種36Hsu[39]2000中國亞洲人種37Toydemir[40]2000土耳其高加索人種38Koch[41]1999德國高加索人種39Martine[42]1999法國高加索人種

表2　Meta分析MTFHR C677T在病例組和對照組深靜脈血栓危險的基因多態(tài)性分布

(續(xù)表)

編號作者年份分組實(shí)驗(yàn)組對照組實(shí)驗(yàn)組對照組CCCTTTCCCTTT哈—溫平衡7Ben201226197206020600.7818Kupeli2011809749247492470.1459周為民20101011204226334226330.00010He200963751527211527210.92911OZMEN2009309016131161310.51612林壽榕200910310666316663160.10113Spiroski200863802033102033100.67914胡新華200863751527211527210.92915Bezemer2007437548562044189112044189110.39016Lizbeth20061201333158313158310.14817于東海20061032501857281857280.79818鄭紅20061031061857281857280.70819Almawi20051986978077418077410.02520周玉斌20057310993628936280.86221葉艷平200492922836282836280.00322王美堂200458581328171328170.24423Lu2002901431842301842300.35724Miranda20021714616790146790140.57925Zalavras20021763007082247082240.04926Gertrud2002133246446236446230.71027賀穎20021031061857281857280.70828郭辰虹2002638042633426330.36529Maria20011381444077214077210.54130Morelli200110110044389443890.06731NAOMI20011373295863165863160.50932Ray20011291294961197244130.11833HsuTS20018310448287482870.69734Gerald20001552986773156773150.55135PHILLIP200065642528122528120.25936Hsu20001071071004071004070.84337Toydemir20006010032226322260.25538Koch19991413456662136662130.00739Martine19992053989188269188260.364

表3　不同人群MTHFR C677T基同多態(tài)性與深靜脈血栓危險性Meta分析結(jié)果

2.3Meta分析結(jié)果表3列出了MTHFR C677T基因多態(tài)性和深靜脈栓塞危險性的結(jié)果，從表中可以看出，按照種群進(jìn)行分層分析，發(fā)現(xiàn)在隱性模式中，高加索人群MTHFR C677T基因多態(tài)性和深靜脈栓塞危險性有相關(guān)性，其結(jié)果如下：隱性基因型分析中，高加索人合并比值比(pool OR)為0.453，95%CI為0.397～0.518，P值為0.0，有相關(guān)性；在亞洲人群中，顯示加性基因模式、顯性基因模式、隱性基因模式與深靜脈栓塞危險性有相關(guān)性，結(jié)果分別為加性模式亞洲人合并比值比(pool OR)為1.421，95%CI為1.177～1.716，P值為0.0；顯性模式亞洲人合并比值比(pool OR)為1.475，95%CI為1.165～1.868，P值為0.001；隱性模式亞洲人合并比值比(pool OR)為1.475，95%CI為1.279～1.702，P值為0.00。

2.4發(fā)表偏倚在加性和隱性模式中，沒有發(fā)現(xiàn)高加索人群和亞洲人群關(guān)于MTHFR C677T基因多態(tài)性和深靜脈栓塞危險性的發(fā)表偏倚，漏斗圖的形狀對稱性分布說明無發(fā)表偏倚；但在顯性模式中，發(fā)現(xiàn)亞洲人群具有發(fā)表偏倚，而高加索人群無發(fā)表偏倚。

3　討論

VTE是一種復(fù)雜的多步驟、多個基因及基因—環(huán)境相互作用的疾病[43]。MTHFR基因在VTE中起到關(guān)鍵的作用，尤其是MTHFR 677位堿基C被T置換，導(dǎo)致原本編碼丙氨酸突變?yōu)槔i氨酸，使MTHFR編碼的酶活性下降，導(dǎo)致同型半胱氨酸水平升高，最終可能發(fā)展為深靜脈栓塞形成。Meta分析能將同一研究不同結(jié)果進(jìn)行綜合，在統(tǒng)計學(xué)上解決原始結(jié)果不穩(wěn)定的問題，增加統(tǒng)計效力，改善研究估值[44-45]。本次研究中共選擇39篇合格文獻(xiàn)納入Meta分析，其中包含9 005例的病例組和13 229例的對照組，此次研究納入大量研究對象且文獻(xiàn)來源范圍較廣，除Ben[12]和Ozmen[16]等的研究，大部分研究至少包含50例已確診深靜脈栓塞癥或者肺栓塞。因收集的信息不足，作者只對人群進(jìn)行分層，未查看性別、年齡等分層與MTHFR C677T多態(tài)性與深靜脈栓塞癥危險性的相關(guān)性。作者的結(jié)果顯示MTHFR C677T多態(tài)性與深靜脈栓塞危險性有相關(guān)性，且是在排除視網(wǎng)膜深靜脈栓塞、門靜脈栓塞和中央靜脈栓塞，同時排除外科手術(shù)后導(dǎo)致的深靜脈栓塞或肺栓塞的情況下。

異質(zhì)性問題是Meta分析中最值得關(guān)注的問題，也是解決異質(zhì)性原因的最重要目標(biāo)。研究發(fā)現(xiàn)3種模型均沒有異質(zhì)性，說明選擇的文獻(xiàn)質(zhì)量高，對于原始文獻(xiàn)采取研究方法、研究對象來源、基因分型等具有很好的統(tǒng)一性，是此次Meta分析未檢出異質(zhì)性的主要因素。

結(jié)果顯示MTHFR C677T多態(tài)性與深靜脈栓塞癥危險性有相關(guān)性，對于高加索人群分析，運(yùn)用隨機(jī)效應(yīng)模式計算顯性基因型合并OR值為0.453(95%CI：0.397～0.518)；在亞洲人群中，采用隨機(jī)效應(yīng)模式計算得到加性基因模式合并OR值為1.421(95%CI：1.177～1.716)，顯性基因模式合并OR值為1.475，(95%CI：1.165～1.868)、隱性基因模式合并OR值為1.475(95%CI：1.279～1.702)。Gohil等[3]發(fā)現(xiàn)MTHFR C677T多態(tài)性在隱性模型對于VTE是一個重要危險因子，雖然其Meta分析只包含10篇合格文獻(xiàn)，結(jié)果與其一致，且結(jié)果更加穩(wěn)定。Den Heijer等[46]Meta分析認(rèn)為，TT純合子基因型在高加索人群VTE危險性中較CC基因型更有相關(guān)性。而結(jié)果表明除MTHFR C677T顯性基因型有相關(guān)性外，并未發(fā)現(xiàn)其他基因模型有相關(guān)性。

采用漏斗圖圖形及Egger法對發(fā)表偏倚進(jìn)行評價，除發(fā)現(xiàn)亞洲人群在顯性模式下具有發(fā)表偏倚，未見其他模型有發(fā)表偏倚。顯性模式下亞洲人群的發(fā)表偏倚產(chǎn)生的主要原因，作者認(rèn)為是原始文獻(xiàn)中陽性結(jié)果更易于發(fā)表，而陰性結(jié)果較陽性結(jié)果較難發(fā)表，且此次研究中作者搜索中文和英文文獻(xiàn)庫，在接下來的研究中應(yīng)全面搜集相關(guān)文獻(xiàn)，以減少發(fā)表偏倚。

MTHFR基因C677T突變能導(dǎo)致同型半胱氨酸血癥，高同型半胱氨酸血癥在白種人和中國臺灣人中已被證實(shí)是靜脈血栓形成的獨(dú)立危險因素[24]。但有研究認(rèn)為MTHFR基因的3個位點(diǎn)突變包括C677T導(dǎo)致亞甲基四氫葉酸還原酶改變不是VTE的危險因素[35]。Brattstrom等[47]Meta分析認(rèn)為MTHFR C677T純合子和血管疾病沒有相關(guān)性。Zhang等[43]認(rèn)為MTHFR C677T在中國人群中與VTE危險性有相關(guān)性。不同研究結(jié)果不一致可能跟地區(qū)、人種、環(huán)境相關(guān)。MTHFR基因C677T多態(tài)性導(dǎo)致深靜脈栓塞癥其中還有很多過程，任何一個過程變化都會產(chǎn)生影響。所以此次Meta分析提供了一個統(tǒng)計學(xué)的證據(jù)，應(yīng)用于臨床還需進(jìn)一步研究。

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Association between MTHFR C677T Polymorphism and Venous Thromboembolism Risk:A Meta-analysis Study

SONG Xiu-ting1,QI Wen-yan,WANG Yin1,QIAO Dan-dan1,HU Yin2,3

(1.Department of Clinical Laboratory,Kunming 650101,China; 2.Department of Respiratory Diseases,Kunming 650101,China; 3.Yunnan Molecular diagnostics Research Center; Second Affiliated Hospital of Kunming Medical University,Kunming 650101,China)

ObjectiveTo discuss the relationship between MTHFR C677T polymorphism and deep vein thrombosis risk in the different ethnic groups.MethodsAll relevant studies were searched about MTHFR C677T polymorphism and the risk of DVT.Populations were divided into Caucasian population and Asian population,and the odds of case group and control group were acted as effect index.ORs and significant P value of populations were calculated by Stata 11.0 software .Results39 case-control studies were included in this analysis,20 studies in Caucasian population,and 19 studies in Asian.The association was found between of MTHFR C677T polymorphism and the dangers of deep vein thrombosis by calculating crude odds ratios with significant P value.The pooled ORs in Caucasian population was 0.453 with recessive model,P value was 0.0 and heterogeneity P value were 0.0; The ORs in Asian population was 1.421 with additive model,P value was 0.0 and heterogeneity P value were 0.0.Dominant model in Asian population ORs was 1.475,P value was 0.001 and heterogeneity P value was 0.0.Recessive model in Asian population ORs was 1.475，P value was 0.0 and heterogeneity P value was 0.0.Except Asian population in dominant model had publication bias,there was no publication bias in the other model of Caucasian and Asian population.ConclusionThe meta-analysis support the association between MTHFR C677T polymorphism and venous thromboembolism risk in Caucasia population and Asian population.

venous thromboembolism；methylenetetrahydro folate reductase；gene polymorphism；meta-analysis

1672-688X(2016)03-0209-07DOI：10.15926/j.cnki.issn1672-688x.2016.03.015

云南省衛(wèi)生科技計劃項目(2016NS246)

2016-03-24

1.昆明醫(yī)科大學(xué)第二附屬醫(yī)院呼吸內(nèi)科一病區(qū)，云南昆明 650101

2.云南省分子診斷研究中心，云南昆明 650101

3.昆明醫(yī)科大學(xué)第二附屬醫(yī)院檢驗(yàn)科，云南昆明 650101

宋秀婷(1990-)，女，湖北咸寧人，從事呼吸內(nèi)科基礎(chǔ)和臨床工作。

胡瑩，女，主治醫(yī)師，E-mail：hy2002@126.com

Q754;R543.6

A