謝敏娟 徐石張 傅小一

血管緊張素轉(zhuǎn)換酶基因多態(tài)性與兒童原發(fā)性腎病綜合征關(guān)聯(lián)性的系統(tǒng)評(píng)價(jià)和Meta分析

謝敏娟1徐石張2傅小一1

目的 系統(tǒng)評(píng)價(jià)血管緊張素轉(zhuǎn)換酶(ACE)基因多態(tài)性與兒童原發(fā)性腎病綜合征(PNS)的關(guān)聯(lián)。方法 計(jì)算機(jī)檢索PubMed、EMBASE、Wiley Online Library、Cochrane圖書館、Science Citation Index、Google Scholar、中國(guó)期刊全文數(shù)據(jù)庫(kù)、萬方數(shù)據(jù)庫(kù)、中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)和維普數(shù)據(jù)庫(kù)，檢索時(shí)間為2000年1月1日至2014年5月31日，納入ACE基因多態(tài)性與兒童PNS關(guān)聯(lián)的病例對(duì)照研究。提取PNS組和對(duì)照組基因型和等位基因頻率，計(jì)算各納入文獻(xiàn)對(duì)照組Hardy-Weinberg平衡(HWE)，并進(jìn)行文獻(xiàn)偏倚評(píng)價(jià)。采用Stata 12.0軟件，對(duì)PNS組和對(duì)照組ACE基因DD、DI、II基因型和D、I等位基因頻率的差異行Meta分析。結(jié)果 14篇文獻(xiàn)進(jìn)入Meta分析，共納入2 849例研究對(duì)象，其中PNS組1 264例，對(duì)照組1 585例。14篇文獻(xiàn)偏倚風(fēng)險(xiǎn)較大。①D等位基因頻率PNS組高于對(duì)照組(OR=1.277，95%CI 1.080～1.509，P=0.004)；I等位基因頻率PNS組低于對(duì)照組(OR=0.811，95%CI 0.738～0.892，P<0.001)。②DD基因型頻率PNS組高于對(duì)照組(OR=1.505，95%CI 1.136～1.994，P=0.004)；II基因型頻率PNS組低于對(duì)照組(OR=0.746，95%CI 0.634～0.877，P<0.001)；DI基因型頻率PNS組與對(duì)照組差異無統(tǒng)計(jì)學(xué)意義(OR=0.932，95%CI 0.805～1.079，P=0.347)。③6篇文獻(xiàn)對(duì)照組不符合HWE，剔除后8篇文獻(xiàn)行敏感性分析，結(jié)果無明顯變化；④DD基因型和D等位基因的文獻(xiàn)間具有異質(zhì)性，對(duì)照人群的來源、種族可解釋部分的異質(zhì)性，HWE與否不是異質(zhì)性的原因。結(jié)論ACE基因DD基因型和D等位基因與兒童PNS的關(guān)聯(lián)性不確定，如果有關(guān)聯(lián)，強(qiáng)度可能較低。

血管緊張素轉(zhuǎn)換酶； 基因多態(tài)性； 兒童； 腎病綜合征； Meta分析

隨著分子生物學(xué)技術(shù)的廣泛應(yīng)用，某些與原發(fā)性腎病綜合征(PNS)發(fā)病相關(guān)的致病基因陸續(xù)被發(fā)現(xiàn)，其中包括較為常見的血管緊張素轉(zhuǎn)換酶(ACE)基因[1,2]。有研究發(fā)現(xiàn)，ACE基因的第16內(nèi)含子中存在287 bp片段的缺失(D)與插入(I)，主要表現(xiàn)為缺失純合子DD，并能影響血液中ACE水平[3,4]。之后多項(xiàng)研究發(fā)現(xiàn)ACE基因的D或I等位基因與多種腎臟病(如糖尿病腎病、IgA腎病)存在關(guān)聯(lián)[5～7]。ACE基因多態(tài)性與PNS是否存在聯(lián)系，目前仍無明確結(jié)論。Zhou等[8，9]曾對(duì)ACE基因多態(tài)性與兒童PNS的關(guān)聯(lián)性行系統(tǒng)評(píng)價(jià)，但該研究未能對(duì)不同種族ACE基因多態(tài)性與PNS的關(guān)聯(lián)性進(jìn)行分析，尤其缺乏中國(guó)兒童PNS的數(shù)據(jù)。本文在已發(fā)表相關(guān)Meta分析的基礎(chǔ)上，進(jìn)一步檢索和納入中國(guó)PNS患兒的文獻(xiàn)，探討ACE基因多態(tài)性與PNS的關(guān)聯(lián)性。

1 方法

1.1 文獻(xiàn)納入標(biāo)準(zhǔn) ①ACE基因與PNS關(guān)聯(lián)性的病例對(duì)照研究；②文獻(xiàn)中有關(guān)于PNS診斷標(biāo)準(zhǔn)的描述；③PNS組年齡<18歲，對(duì)照組為健康成人或兒童；④采用PCR技術(shù)行ACE基因檢測(cè)，PCR引物序列根據(jù)Rigat等[3]采用的ACE基因序列設(shè)計(jì)；⑤文獻(xiàn)中提供了兩組ACE各基因型或等位基因的例數(shù)；⑦中文和英文文獻(xiàn)。

1.2 文獻(xiàn)排除標(biāo)準(zhǔn) 重復(fù)發(fā)表的文獻(xiàn)。

1.3 文獻(xiàn)檢索策略

1.3.1 數(shù)據(jù)庫(kù) 計(jì)算機(jī)檢索PubMed、EMBASE、Wiley Online Library、Cochrane圖書館、Science Citation Index、Google Scholar、中國(guó)期刊全文數(shù)據(jù)庫(kù)、萬方數(shù)據(jù)庫(kù)、中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)和維普數(shù)據(jù)庫(kù)。檢索起止時(shí)間均為2000年1月至2014年5月。并回溯檢索到相關(guān)文獻(xiàn)的參考文獻(xiàn)。

1.3.2 檢索式 中文檢索詞：血管緊張素、血管緊張素轉(zhuǎn)換酶、基因、多態(tài)性、兒童、小兒、腎病綜合征等；英文檢索詞：angiotensin converting enzyme、ACE、nephrotic syndrome、NS、gene、polymorphism、childen、pediatric、idiopathic。以PubMed數(shù)據(jù)庫(kù)為例，英文檢索式：“angiotensin converting enzyme” (MeSH) OR pediatric (MeSH) OR “nephritic syndrome” (MeSH)；以CBM數(shù)據(jù)庫(kù)為例，中文檢索式：血管緊張素轉(zhuǎn)換酶 AND 兒童 AND 腎病綜合征。

1.4 文獻(xiàn)篩選、資料提取和偏倚評(píng)價(jià) 由謝敏娟、徐石張完成，如遇分歧由傅小一決定。

1.4.1 文獻(xiàn)篩選和資料提取 閱讀文題和摘要排除明顯不相關(guān)的文獻(xiàn)，對(duì)可能符合納入標(biāo)準(zhǔn)的文獻(xiàn)閱讀全文決定是否納入。提取項(xiàng)目包括：第一作者、發(fā)表時(shí)間、國(guó)家、語種、對(duì)照人群類型、樣本量、樣本來源、實(shí)驗(yàn)方法、PNS組和對(duì)照組ACE各基因型(DD、DI、II)的例數(shù)和等位基因的頻數(shù)。對(duì)納入文獻(xiàn)對(duì)照組行Hardy-Weinberg平衡(HWE)檢驗(yàn)。

1.5 統(tǒng)計(jì)學(xué)分析 采用Stata 12.0軟件行Meta分析，采用比值比(OR)作為效應(yīng)量行Meta分析。行文獻(xiàn)間異質(zhì)性檢驗(yàn)，P<0.1為文獻(xiàn)間存在統(tǒng)計(jì)學(xué)異質(zhì)性，采用隨機(jī)效應(yīng)模型；P≥0.1為文獻(xiàn)間具同質(zhì)性，采用固定效應(yīng)模型合并結(jié)果。對(duì)于存在顯著統(tǒng)計(jì)學(xué)異質(zhì)性的文獻(xiàn)，采用亞組分析和回歸分析行異質(zhì)性原因分析。發(fā)表偏倚檢驗(yàn)采用漏斗圖和Begg檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 文獻(xiàn)檢索結(jié)果 依據(jù)本文文獻(xiàn)檢索策略獲得270篇文獻(xiàn)，14篇文獻(xiàn)[10～23]符合納入和排除標(biāo)準(zhǔn)進(jìn)入本文系統(tǒng)評(píng)價(jià)(圖1)。14篇文獻(xiàn)共納入2 849例研究對(duì)象，其中PNS組為1 264例，對(duì)照組為1 585例。文獻(xiàn)[12～15]以健康成人為對(duì)照組，余文獻(xiàn)以健康兒童作為對(duì)照組；中國(guó)人群的研究7篇[17～23]。納入14篇文獻(xiàn)的一般情況和ACE基因型、等位基因數(shù)據(jù)見表1。

圖1 文獻(xiàn)篩選流程圖

Fig 1 Flow chart of aricle screening and selection process

2.2 文獻(xiàn)偏倚風(fēng)險(xiǎn)評(píng)價(jià) 圖2顯示，14篇文獻(xiàn)條目1、4、6、8～10、12～14符合率為0，條目2、3符合率為92.9%，條目7的符合率為57.1%，條目5的符合率為21.4%，條目11的符合率為14.3%。

2.3 發(fā)表偏倚 對(duì)14篇納入文獻(xiàn)的DD基因型行發(fā)表偏倚檢驗(yàn)，漏斗圖對(duì)稱(圖3)，Begg檢驗(yàn)P=0.743，提示發(fā)表偏倚可能性不大。

表1 納入14篇文獻(xiàn)的基本情況(n)

Notes HWE: Hardy-Weinberg equilibrium; HC: healthy children; HA: healthy adult

圖2 納入14篇文獻(xiàn)的偏倚風(fēng)險(xiǎn)評(píng)價(jià)結(jié)果

Fig 2 Quality of 14 included studies

Notes 1:power;2:controls characterization;3:case characterization;4: LD exploration;5:polymorphism identification;6:genotyping error check;7:Hardy-Weinberg equilibrium;8: blinding;9:multiple testing ;10:covariate adjusment;11:risks;12:population stratification adjustment;13:replication;14:functional study

2.4 Meta分析結(jié)果

2.4.1 D和I等位基因與PNS的關(guān)聯(lián)性 報(bào)道D等位基因文獻(xiàn)的異質(zhì)性檢驗(yàn)I2=61.2%，有統(tǒng)計(jì)學(xué)異質(zhì)性，采用隨機(jī)效應(yīng)模型合并結(jié)果。Meta分析結(jié)果顯示，D等位基因頻率PNS組高于對(duì)照組，OR=1.277，95%CI 1.080～1.509，P=0.004(圖4)。

報(bào)道I等位基因文獻(xiàn)的異質(zhì)性檢驗(yàn)I2=8.5%，無統(tǒng)計(jì)學(xué)異質(zhì)性，采用固定效應(yīng)模型合并結(jié)果。Meta分析結(jié)果顯示，I等位基因頻率PNS組低于對(duì)照組，OR=0.811，95%CI 0.738～0.892，P<0.001(圖4)。

2.4.2 不同基因型與PNS的關(guān)聯(lián)性 報(bào)道DD基因型文獻(xiàn)間存在統(tǒng)計(jì)學(xué)異質(zhì)性(P=0.013，I2=51.6%)，采用隨機(jī)效應(yīng)模型合并結(jié)果，Meta分析結(jié)果顯示，DD基因型頻率PNS組高于對(duì)照組，OR=1.505，95%CI 1.136～1.994，P=0.004(圖5) 。

圖3 DD基因型發(fā)表偏倚的漏斗圖

Fig 3Funnel plot of D allele

報(bào)道II和DI基因型文獻(xiàn)間具同質(zhì)性(I2分別為18.8%和7.6%)，固定效應(yīng)模型的Meta分析結(jié)果顯示，II基因型頻率PNS組低于對(duì)照組，OR=0.746，95%CI 0.634～0.877，P<0.001(圖5)，DI基因型頻率PNS組與對(duì)照組差異無統(tǒng)計(jì)學(xué)意義，OR=0.932，95%CI 0.805～1.079，P=0.347(圖5,6)。

2.5 敏感性分析 本文6篇文獻(xiàn)對(duì)照組不符合HWE，剔除后8篇文獻(xiàn)行敏感性分析，Meta分析結(jié)果顯示，D等位基因頻率PNS組高于對(duì)照組，OR=1.521，95%CI: 1.273～1.820；DD基因型頻率PNS組亦高于對(duì)照組，OR=2.083，95%CI：1.542～2.805(表3)，與原結(jié)果相比無明顯變化。

2.6 異質(zhì)性原因分析 DD基因型和D等位基因文獻(xiàn)間具顯著異質(zhì)性，以對(duì)照人群來源、國(guó)家、HWE行異質(zhì)性原因分析，表3顯示，DD基因型非中國(guó)人群、成人對(duì)照的文獻(xiàn)間無統(tǒng)計(jì)學(xué)異質(zhì)性，D等位基因成人對(duì)照的文獻(xiàn)間無統(tǒng)計(jì)學(xué)異質(zhì)性。HWE與否不是異質(zhì)性的原因。

圖4 D、I等位基因與PNS關(guān)聯(lián)性的Meta分析

圖5 DD、II基因型與PNS關(guān)聯(lián)性的Meta分析

圖6 DI基因型與PNS關(guān)聯(lián)性的Meta分析

Fig 6 Meta analysis of relationship between DI genotype and PNS

3 討論

本文Meta分析納入14篇ACE基因與兒童PNS的遺傳關(guān)聯(lián)性研究，行14個(gè)條目的文獻(xiàn)質(zhì)量評(píng)價(jià)顯示，9/14個(gè)條目的符合率為0，僅2個(gè)條目的符合率>90%，2個(gè)條目的符合率<25%，且有6篇文獻(xiàn)對(duì)照組不符合HWE，提示本文Meta分析納入的文獻(xiàn)具有局限性。14篇文獻(xiàn)的發(fā)表偏倚可能性不大。本Meta分析的證據(jù)強(qiáng)度低。

Lee等研究發(fā)現(xiàn)，42%的DD基因型患者進(jìn)展為終末期腎病(ESRD)，而在II基因型中僅有25%的患者最終發(fā)展為ESRD[24]。Frishberg等[25]研究顯示，近50%攜帶D等位基因的患者隨訪過程中出現(xiàn)腎功能損害，II基因型者腎功能均正常。Luther等發(fā)現(xiàn)2/21例基因型II患者出現(xiàn)腎功能損害，50例攜帶等位基因D的患者中，超過60%出現(xiàn)腎功能損害[26]。存在等位基因D的患兒更易進(jìn)展為局灶性節(jié)段性腎小球硬化[24,27]，提示ACE基因多態(tài)性可能與PNS相關(guān)。

表3 等位基因D與基因型DD的亞組分析

本文ACE基因多態(tài)性的Meta分析結(jié)果提示， DD基因型和D等位基因與PNS的發(fā)生存在統(tǒng)計(jì)學(xué)關(guān)聯(lián)，但文獻(xiàn)間存在統(tǒng)計(jì)學(xué)異質(zhì)性，以對(duì)照人群來源、國(guó)家行亞組分析，能部分解釋異質(zhì)性的來源。同時(shí)本文納入的14篇文獻(xiàn)中有6篇(42.9%)對(duì)照組不符合HWE，提示ACE基因可能不是一個(gè)特異性的PNS相關(guān)的基因，異質(zhì)性來源與HWE無關(guān)，進(jìn)一步對(duì)HWE或非HWE文獻(xiàn)的敏感性分析顯示，結(jié)果無明顯變化。

本文Meta分析結(jié)果效應(yīng)值的95%CI下限接近無效值1，行亞組分析后更為明顯，特別是中國(guó)人群DD基因型與PNS的關(guān)聯(lián)性差異無統(tǒng)計(jì)學(xué)意義，結(jié)果存在顯著的不精確性，提示ACE基因DD基因型和D等位基因與兒童PNS的關(guān)聯(lián)性不確定，如果有關(guān)聯(lián)，強(qiáng)度可能較低。

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(本文編輯：丁俊杰)

Relationship between ACE gene polymorphisms and pediatric idiopathic nephrotic syndrome: a meta-analysis

XIEMin-juan1,XUShi-zhang2,FUXiao-yi1

(1DepartmentofPathology,YichunUniversity,Yichun336000; 2DepartmentofNephrology,YichunPeople'sHospital,JiangxiProvince,Yichuan336000,China)

FU Xiao-yi，E-mail:1059139963@qq.com

ObjectiveTo assess the relationship between angiotensin converting enzyme (ACE) gene polymorphism and pediatric idiopathic nephrotic syndrome (PNS).MethodsCase-control studies searched from the database of PubMed, EMBASE, Wiley Online Library, Cochrane Library, Science Citation Index, Google Scholar, China National Knowledge Infrastucture, Wanfang Data, China Biology Medicine, China science and technology journal were recruited to summarize the association betweenACEgene polymorphisms with PNS from January 2000 to May 2014. Meta-analysis of the frequency of D, I alleles and DD, DI, II genotypes between PNS group and the control group were performed by Stata 12.0 software.Results Fourteen literatures including 2 849 subjects (1 264 in PNS group and 1 585 in the control group) were recruited. ① The frequency of D allele in PNS group was higher than that in the control group (OR=1.277，95%CI 1.080-1.509，P=0.004)and the frequency of I allele in PNS group was lower than that in the control group (OR=0.811，95%CI 0.738-0.892，P<0.001). ② The frequency of DD genotype in PNS group was higher than that in the control group (OR=0.746，95%CI 0.634-0.877，P<0.001), the frequency of II genotype in PNS group was lower than that in the control group (OR=0.746，95%CI 0.634-0.877，P<0.001) and there was no significant difference of the frequency of DI genotype between PNS and the control groups. ③ Six literatures did not meet Hardy-Weinberg equilibrium, but it did not bias the study by sensitive analysis. ④ The articles reported D allele and DD genotype showed significant heterogeneity. The control group and race could explain partial heterogeneity, but Hardy-Weinberg equilibrium was not the cause of heterogeneity.ConclusionThe relation about DD gene and D allele with PNS was not indubitable. The strength of the association about ACE gene and PNS gene was possibly lower.

Angiotensin converting enzyme; Gene polymorphism; Pediatrics; Nephritic syndrome; Meta-analysis

10.3969/j.issn.1673-5501.2015.05.009

1 江西省宜春學(xué)院病理教研室 宜春，336000；2 江西省宜春市人民醫(yī)院腎內(nèi)科 宜春，336000

傅小一，E-mail:1059139963@qq.com

2015-01-24

2015-07-12)