腎素-血管緊張素系統(tǒng)基因多態(tài)性與兒童青少年高血壓易感關(guān)聯(lián)的系統(tǒng)評(píng)價(jià)和Meta分析

葉冰冰 蘇丹艷 劉冬立 覃素元 勞金泉 龐玉生

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·論著·

腎素-血管緊張素系統(tǒng)基因多態(tài)性與兒童青少年高血壓易感關(guān)聯(lián)的系統(tǒng)評(píng)價(jià)和Meta分析

葉冰冰 蘇丹艷 劉冬立 覃素元 勞金泉 龐玉生

目的 評(píng)價(jià)腎素-血管緊張素系統(tǒng)中的血管緊張素轉(zhuǎn)換酶(ACE)基因插入/缺失(I/D)、血管緊張素原(ANG)基因M235T和血管緊張素Ⅱ受體-1(AT1R)基因A1166C多態(tài)性與兒童青少年高血壓易感的關(guān)聯(lián)。方法 計(jì)算機(jī)檢索EMBASE、PubMed、HUGE、中國(guó)知網(wǎng)、維普數(shù)據(jù)庫(kù)、萬方數(shù)據(jù)庫(kù)和中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)，檢索時(shí)間均為建庫(kù)至2015年11月27日，納入3個(gè)基因多態(tài)性與兒童青少年高血壓關(guān)聯(lián)的病例對(duì)照研究。提取高血壓組和對(duì)照組基因型和等位基因頻率，行文獻(xiàn)偏倚風(fēng)險(xiǎn)評(píng)價(jià)。采用Stata 12.0軟件，分別以隱性、顯性、共顯性、相加和等位基因模型對(duì)高血壓組和對(duì)照組上述3個(gè)基因多態(tài)性與高血壓的關(guān)聯(lián)行Meta分析。根據(jù)對(duì)照組人群和種族行亞組分析。結(jié)果 7篇文獻(xiàn)進(jìn)入Meta分析，病例組824例，對(duì)照組1 731例。7篇文獻(xiàn)存在中等偏倚風(fēng)險(xiǎn)。①納入6篇文獻(xiàn)的ACE基因I/D多態(tài)性在隱性模型下與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)(OR=1.405, 95%CI：1.073～1.840,P=0.013)。②上述5種分析模型，ANG基因M235T和AT1R基因A1166C多態(tài)性(分別納入3和2篇文獻(xiàn))與兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)均無關(guān)聯(lián)。③亞組分析結(jié)果顯示，2篇文獻(xiàn)肥胖人群的ACR基因I/D多態(tài)性在隱性、相加和等位基因模型下顯著增加兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)(隱性模型:OR=1.564 , 95%CI:1.054～2.321,P=0.026；相加模型：OR=2.017， 95%CI:1.137～3.576，P=0.016; 等位基因模型：OR=1.406， 95%CI： 1.076～1.838，P=0.013)。；對(duì)一般兒童青少年人群的高血壓發(fā)病風(fēng)險(xiǎn)無影響，且與種族和高血壓分類方法無關(guān)。結(jié)論ANG基因M235T、AT1R基因A1166C多態(tài)性與兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)無關(guān)聯(lián)，ACE基因I/D多態(tài)性可能與肥胖兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)。

基因多態(tài)性； 腎素-血管緊張素系統(tǒng)； 高血壓； 兒童青少年； Meta分析； 系統(tǒng)評(píng)價(jià)

近年來，高血壓在兒童青少年中的患病率呈逐年增高趨勢(shì)[1, 2]。多種族流行病學(xué)研究證實(shí)兒童青少年高血壓的發(fā)病率為2%～3%[3, 4]。兒童期血壓水平可影響其成年后的血壓水平[5]。有研究表明，在總體人群的血壓變異原因中，遺傳因素占30%～50%[6]，高血壓的易感基因是近年來關(guān)注的熱點(diǎn)問題。腎素-血管緊張素系統(tǒng) (RAS)通過其效應(yīng)激素血管緊張素原Ⅱ(AⅡ)在調(diào)節(jié)血壓的穩(wěn)態(tài)中起重要作用[7]，其中血管緊張素轉(zhuǎn)換酶(ACE)、血管緊張素原(ANG)、血管緊張素Ⅱ受體-1(AT1R)以及腎素作為RAS的重要組成部分,參與了原發(fā)性高血壓的發(fā)生[8, 9]。血漿中ACE和ANG的升高可引起AⅡ的升高，提示RAS的基因多態(tài)性在高血壓的發(fā)生和發(fā)展中起重要作用。關(guān)于RAS基因多態(tài)性和兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)的研究不多且樣本量不大，結(jié)果也不一致，因此有必要對(duì)RAS基因多態(tài)性與兒童青少年高血壓的關(guān)聯(lián)行Meta分析，以明確和豐富高血壓的易感基因。

1 方法

1.1 高血壓定義 按照2004年美國(guó)高血壓教育項(xiàng)目工作組制定的兒童青少年高血壓標(biāo)準(zhǔn)[1]，以SBP和(或)DBP≥同性別、同年齡兒童血壓P95診斷為高血壓；以SBP和(或)DBP在同性別、同年齡兒童血壓P90～P95為高血壓前期。

1.2 文獻(xiàn)納入標(biāo)準(zhǔn) ①病例對(duì)照研究，高血壓和(或)高血壓前期為病例組，血壓正常為對(duì)照組；②研究對(duì)象為<18歲的兒童青少年[10]；③研究的目的基因?yàn)锳CE(I/D)，ANG(M235T)和AT1R(A1166C)多態(tài)性;④能夠直接或間接提供不同基因型、等位基因頻率的數(shù)據(jù)。

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

1.4 文獻(xiàn)檢索策略 數(shù)據(jù)庫(kù)：EMBASE、PubMed、哈特福德用戶組交流(HUGE)數(shù)據(jù)庫(kù)、中國(guó)知網(wǎng)，萬方數(shù)據(jù)庫(kù)和中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)，并回溯納入文獻(xiàn)的參考文獻(xiàn)，檢索起止時(shí)間均為建庫(kù)至2015年11月27日。

英文檢索詞：angiotensin-converting enzyme，angiotensinogen，angiotensinogen Ⅱ type-1 receptor，renin-angiotensin system, ACE, ANG, AT1R, RAS, gene polymorphism, hypertension,high blood pressure。

以PubMed數(shù)據(jù)庫(kù)為例檢索式為：(angiotensin-converting enzyme OR angiotensinogen OR angiotensinogen Ⅱ type-1 receptor OR Renin-Angiotensin System OR ACE OR ANG OR AT1R OR RAS)AND (gene polymorphism)AND (hypertension OR high blood pressure) AND (children OR adolescence)。

中文檢索詞：血管緊張素轉(zhuǎn)換酶、血管緊張素原、血管緊張素Ⅱ受體-1、腎素-血管緊張素系統(tǒng)、基因多態(tài)性、高血壓、兒童青少年。

以中國(guó)知網(wǎng)為例檢索式：(血管緊張素轉(zhuǎn)換酶 OR 血管緊張素原 OR 血管緊張素Ⅱ受體-1 OR 腎素-血管緊張素系統(tǒng)) AND 基因多態(tài)性 AND 高血壓 AND 兒童青少年。

1.5 文獻(xiàn)篩選、資料提取和偏倚風(fēng)險(xiǎn)評(píng)估 均由葉冰冰和蘇丹艷完成，如遇分歧與龐玉生討論決定。

1.5.1 文獻(xiàn)篩選和資料提取 首先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。提取文獻(xiàn)中第一作者、發(fā)表時(shí)間、國(guó)家、語種、種族、樣本量、樣本來源、實(shí)驗(yàn)方法和各基因型在病例組和對(duì)照組的例數(shù)，并對(duì)納入文獻(xiàn)行Hardy-Weinberg平衡檢驗(yàn)。

1.6 統(tǒng)計(jì)學(xué)分析 采用Stata 12.0軟件行Meta分析，采用OR作為效應(yīng)量行Meta分析。異質(zhì)性檢驗(yàn)P<0.10采用隨機(jī)效應(yīng)模型，P≥0.10采用固定效應(yīng)模型合并結(jié)果。分別采用隱性、顯性、共顯性、相加和等位基因模型分析基因多態(tài)性與高血壓發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián)。對(duì)于存在顯著統(tǒng)計(jì)學(xué)異質(zhì)性的文獻(xiàn)，采用亞組分析異質(zhì)性原因。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 文獻(xiàn)檢索一般情況 初步檢索到228篇文獻(xiàn)，7篇文獻(xiàn)[12～18]符合本文納入標(biāo)準(zhǔn)進(jìn)入Meta分析(圖1)，英文5篇，中文1篇，韓文1篇。高血壓組824例，對(duì)照組1 731例。6篇文獻(xiàn)[13～18]研究ACE基因I/D多態(tài)性，3篇文獻(xiàn)[12,15,17]研究AT1R基因A1166C多態(tài)性，2篇文獻(xiàn)[15,17]研究ANG基因M235T多態(tài)性。各基因型和等位基因分布情況如表2所示。3篇文獻(xiàn)病例組為原發(fā)性高血壓[15,17,18]；余4篇文獻(xiàn)中未嚴(yán)格限定為原發(fā)性高血壓。3篇文獻(xiàn)[12,17,18]研究對(duì)象為亞洲人群；3篇為歐洲人群[14～16]；文獻(xiàn)[13]為混合種族背景。6篇研究ACE基因I/D多態(tài)性的文獻(xiàn)中，文獻(xiàn)[13, 16]的病例組和對(duì)照組均為肥胖的兒童青少年人群；余4篇[14,15,17,18]為一般兒童青少年人群。納入7篇文獻(xiàn)的一般情況見表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，納入的7篇文獻(xiàn)均未行連鎖不平衡檢測(cè)、多態(tài)性鑒定、計(jì)算錯(cuò)誤率、多重檢驗(yàn)校正及功能驗(yàn)證性實(shí)驗(yàn)；7篇文獻(xiàn)均未描述是否采用盲法；6篇文獻(xiàn)的病例組和對(duì)照組均來自同一人群；均描述了病例組人口學(xué)及臨床信息；對(duì)各研究基因型分布的Hardy-Weinberg遺傳平衡檢驗(yàn)發(fā)現(xiàn)，6篇文獻(xiàn)的對(duì)照組符合Hardy-Weinberg平衡，文獻(xiàn)[15]對(duì)照組不符合Hardy-Weinberg平衡(P<0.05)。

2.3ACE基因I/D多態(tài)性與兒童青少年高血壓關(guān)聯(lián)Meta分析 6篇文獻(xiàn)報(bào)道了ACE基因I/D多態(tài)性與兒童青少年高血壓的關(guān)聯(lián)，病例組539例，對(duì)照組829例，分別采用5種模型分析。表2所示，ACE基因I/D多態(tài)性隱性模下與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)有統(tǒng)計(jì)學(xué)意義(OR=1.405, 95%CI：1.073～1.840,P=0.013)。異質(zhì)性存在于顯性模型，相加模型和等位基因模型中(顯性模型：I2=51.6%；相加模型：I2=60.8%；等位基因模型：I2=61.6%)

表1 7篇文獻(xiàn)的基本情況(n)

Notes HWE: Hardy-Weinberg equilibrium;ACED/I: angiotensin converting enzyme gene I/D polymorphism;AT1RA1166C: angiotensin II type 1 receptor gene A1166C polymorphism;ANGM235T: angiotensinogen gene M235T polymorphi

圖2 7篇文獻(xiàn)的偏倚風(fēng)險(xiǎn)評(píng)價(jià)結(jié)果

Fig 2 Quality of 7 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

2.4AT1R基因A1166C多態(tài)性與兒童青少年高血壓關(guān)聯(lián)的Meta分析 3篇文獻(xiàn)病例組149例，對(duì)照組578例，如表2所示，無論何種模型，AT1R基因A1166C多態(tài)性與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)均關(guān)聯(lián)無統(tǒng)計(jì)學(xué)意義，隱性模型結(jié)果見圖3。在所有模型中，各研究間異質(zhì)性均無統(tǒng)計(jì)學(xué)意義。

2.5ANG基因M235T多態(tài)性與兒童青少年高血壓關(guān)聯(lián)的Meta分析 2篇文獻(xiàn)病例組136例，對(duì)照組324例。如表2所示，合并效應(yīng)量結(jié)果顯示所有模型ANG基因M235T多態(tài)性與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)均無統(tǒng)計(jì)學(xué)意義，隱性模型結(jié)果見圖3。異質(zhì)性存在顯性模型和共顯性模型中(顯性模型：I2=78.9%；共顯模型：I2=89.3%)。

表2ACED/I,AT1RA1166C和ANGM235T多態(tài)性與兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)的Meta分析結(jié)果

Tab2ResultsofthepooleddataofACED/I, AT1RA1166C, ANGM235Tpolymorphismandhypertensioninpediatricpatientsinmeta-analysis

Geneticmod-elACED/IOR(95%CI)PI2/%AT1RA1166COR(95%CI)PI2/%ANGM235TOR(95%CI)PI2/%Recessive1.405(1.073-1.840)0.01336.91.736(0.403-7.481)0.45900.643(0.281-1.471)0.2969.0Dominant1.254(0.847-1.855)0.25851.61.255(0.753-2.094)0.38344.51.180(0.316-4.404)0.80678.9Additive1.444(0.826-2.524)0.19760.82.292(0.512-10.255)0.27801.170(0.419-3.267)0.7650Co-domi-nant0.964(0.768-1.211)0.75301.218(0.731-2.030)0.44941.11.302(0.292-5.814)0.72989.3Allele1.208(0.921-1.584)0.17261.61.202(0.782-1.847)0.40128.40.862(0.614-1.208)0.3880

Notes VV: variant homozygous; WV: heterozygous; WW: wild homozygous. Recessive model: VVvsWV+WW; dominant model: VV+WVvsWW; additive model: VVvsWW; co-dominant model: WVvsVV+WW; allele model: VvsW

圖3 隱性模型下ACEI/D,ANGM235T和AT1RA1166C多態(tài)性與兒童青少年高血壓易感關(guān)聯(lián)的Meta分析

Fig3ForestplotsoftherelationshipbetweenACE (I/D), ANG (M235T), AT1R(A1166C) polymorphisms and hypertension in overall pediatric patients

2.6 亞組分析 報(bào)道ACE基因I/D多態(tài)性與兒童青少年高血壓關(guān)聯(lián)的6篇文獻(xiàn)中，有2篇文獻(xiàn)的病例組和對(duì)照組均為肥胖的兒童青少年人群[13, 16]，行亞組分析。如表3所示，在肥胖人群中，ACE基因I/D多態(tài)性在隱性、相加和等位基因模型下顯著增加兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)(隱性模型:OR=1.564 , 95%CI:1.054～2.321,P=0.026；相加模型：OR=2.017， 95%CI:1.137～3.576，P=0.016; 等位基因模型：OR=1.406， 95%CI： 1.076～1.838，P=0.013)。在一般人群中，5種模型ACE基因I/D多態(tài)性與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)均無統(tǒng)計(jì)學(xué)意義。

以種族、高血壓分類在一般人群中行亞組分析顯示(表4)，不同種族、高血壓分類ACE基因I/D多態(tài)性與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)均無關(guān)聯(lián)。

3 討論

本文納入7篇病例對(duì)照設(shè)計(jì)的遺傳關(guān)聯(lián)性研究，文獻(xiàn)偏倚風(fēng)險(xiǎn)的評(píng)價(jià)結(jié)果提示：7篇文獻(xiàn)在研究設(shè)計(jì)、病例組及對(duì)照組來源、一般信息、實(shí)驗(yàn)方法、統(tǒng)計(jì)學(xué)方法等條目的符合率較低。6/7篇文獻(xiàn)對(duì)照組符合Hardy-Weinberg平衡。由于納入文獻(xiàn)數(shù)量少，未行發(fā)表偏倚檢驗(yàn)。本文Meta分析的證據(jù)強(qiáng)度為中等。

RAS是復(fù)雜的內(nèi)分泌和旁分泌系統(tǒng)，其組成成分介導(dǎo)了血壓穩(wěn)態(tài)的調(diào)節(jié)。因此，RAAs基因編碼的組件是高血壓遺傳研究的重要候選基因。ACE基因定位于17q23，其第16個(gè)內(nèi)含子第287個(gè)堿基的插入和(或)缺失多態(tài)性與高血壓有關(guān)。ANG基因位于1q42-43，當(dāng)編碼ANG的外顯2區(qū)域核苷酸704處胸腺嘧啶T被胞嘧啶C替代， 導(dǎo)致基因編碼產(chǎn)物第235號(hào)氨基酸由蛋氨酸M變異為蘇氨酸T，即M235T分子變異[19]。同時(shí)發(fā)現(xiàn)AT1R基因位于1166處的胸腺嘧啶A變異為胞嘧啶C，會(huì)出現(xiàn)3種基因型，AA, AC和CC，并與高血壓的發(fā)生有關(guān)[8]。ACE基因I/D 和ANG基因M235T 多態(tài)性被證實(shí)與血漿中ACE和ANG的水平有關(guān)[20,21]。而ACEⅡ則是通過AT1R發(fā)揮作用。ACE基因作為RAS的重要組成部分，其多態(tài)性將會(huì)導(dǎo)致血管收縮反應(yīng)，打破循環(huán)穩(wěn)態(tài)。有研究報(bào)道在成人中ACE基因 DD 基因型和高水平的ACE有關(guān)[22,23]。Ajala等[24]在巴西兒童中發(fā)現(xiàn)攜帶DD 基因型兒童有更高ACE水平及活性。這種效應(yīng)在韓國(guó)兒童中也有同樣的發(fā)現(xiàn)[25]。提示，ACE基因多態(tài)性通過影響ACE的水平及活性，最終影響血壓水平。

表3ACED/I 多態(tài)性和兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)的人群分層Meta分析結(jié)果

Tab 3 Subgroup analysis of association betweenACED/I polymorphism and risk of hypertension in pediatric patients stratified by population in meta-analysis

GeneticmodelGroupsStudiesOR(95%CI)PI2/%RecessivemodelOverall61.405(1.073-1.840)0.01336.9Obesepopulation21.564(1.054-2.321)0.0260Generalpopulation41.227(0.704-2.138)0.47152.8DominantmodelOverall61.254(0.847-1.855)0.25851.6Obesepopulation21.625(0.972-2.716)0.06421.6Generalpopulation41.150(0.683-1.934)0.59962.8AdditivemodelOverall61.444(0.826-2.524)0.19760.8Obesepopulation22.017(1.137-3.576)0.01644.2Generalpopulation41.272(0.581-2.784)0.54769.3Co-dominantmodelOverall60.964(0.768-1.211)0.7530Obesepopulation20.885(0.611-1.282)0.5170Generalpopulation41.016(0.761-1.356)0.9150AllelemodelOverall61.208(0.921-1.584)0.17261.6Obesepopulation21.406(1.076-1.838)0.01333.4Generalpopulation41.135(0.764-1.685)0.53171.2

Notes VV: variant homozygous; WV: heterozygous; WW: wild homozygous. Recessive model: VVvsWV+WW; dominant model: VV+WVvsWW; additive model: VVvsWW; co-dominant model: WVvsVV+WW; allele model: VvsW

表4ACED/I 多態(tài)性和兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)在一般人群中的亞組Meta分析結(jié)果

Tab 4 Stratification analyses of the relationship betweenACED/I polymorphism and hypertension in general population in meta-analysis

GeneticmodelGroupsStudiesOR(95%CI)PI2/%RecessivemodelAll41.227(0.704-2.138)0.47152.8Asian21.640(0.633-4.249)0.30971.3European20.878(0.498-1.549)0.6530Essentialhypertention31.375(0.677-2.795)0.37959.7DominantmodelAll41.150(0.683-1.934)0.59962.8Asian21.539(0.740-3.200)0.24871.3European20.833(0.494-1.405)0.49475.0Essentialhypertention31.153(0.561-2.370)0.69862.8AdditivemodelAll41.272(0.581-2.784)0.54769.3Asian21.994(0.561-7.087)0.28680.0European20.796(0.414-1.531)0.4940Essentialhypertention31.383(0.474-4.032)0.55377.6Co-dominantmodelAll41.016(0.761-1.356)0.9150Asian21.061(0.738-1.527)0.7480European20.942(0.584-1.518)0.8060Essentialhypertention30.973(0.703-1.347)0.8690AllelemodelAll41.135(0.764-1.685)0.53171.2Asian21.425(0.763-2.663)0.26782.0European20.885(0.631-1.241)0.4770Essentialhypertention31.180(0.693-2.010)0.54279.3

Notes VV: variant homozygous; WV: heterozygous; WW: wild homozygous. Recessive model: VVvsWV+WW; dominant model: VV+WVvsWW; additive model: VVvsWW; co-dominant model: WVvsVV+WW; allele model: VvsW. EH: essential hypertension

本文Meta分析發(fā)現(xiàn)，ANG基因M235T和AT1R基因A1166C多態(tài)性，在任意一種模型下與兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)均無統(tǒng)計(jì)學(xué)關(guān)聯(lián)。ACE基因I/D多態(tài)性在隱性模型下與高血壓的發(fā)病風(fēng)險(xiǎn)有統(tǒng)計(jì)學(xué)關(guān)聯(lián)(OR=1.405, 95%CI: 1.073～1.840)，但效應(yīng)值的95%CI下限接近無效值1，結(jié)果具有顯著的不精確性。有研究顯示，肥胖引起的兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)為1.7～7.2[26～29]，本文分層分析顯示，ACE基因I/D多態(tài)性在隱性、相加和等位基因模型下可顯著增加肥胖兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)，但結(jié)果仍具顯著的不精確性；在一般人群中，ACE基因I/D多態(tài)性與兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)均無統(tǒng)計(jì)學(xué)關(guān)聯(lián)；提示ACE基因I/D多態(tài)性對(duì)個(gè)體血壓水平的影響可能通過肥胖介導(dǎo)。有研究顯示ACE基因I/D多態(tài)性與肥胖相關(guān)，D等位基因?yàn)轱L(fēng)險(xiǎn)因素[13, 30]。

本研究的不足之處和局限性：納入文獻(xiàn)的數(shù)量和樣本量均不大，且文獻(xiàn)偏倚風(fēng)險(xiǎn)較高，亟待更多的研究證實(shí)RAS基因多態(tài)性與兒童青少年高血壓關(guān)聯(lián)。

結(jié)論：ANG基因M235T、AT1R基因A1166C與兒童青少年高血壓發(fā)病風(fēng)險(xiǎn)無關(guān)聯(lián)，ACE基因I/D多態(tài)性可能與肥胖兒童青少年高血壓的發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)。

[1] The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics, 2004,114(2 Suppl 4th Report):555-576

[2] Kavey RE, Daniels SR, Flynn JT. Management of high blood pressure in children and adolescents. Cardiol Clin, 2010,28(4):597-607

[3] Redwine KM, Acosta AA, Poffenbarger T, et al. Development of hypertension in adolescents with pre-hypertension. J Pediatr, 2012,160(1):98-103

[4] Sorof JM, Lai D, Turner J, et al. Overweight, ethnicity, and the prevalence of hypertension in school-aged children. Pediatrics, 2004,113(3 Pt 1):475-482

[5] Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation, 2008,117(25):3171-3180

[6] Munroe PB, Caulfield MJ. Genetics of hypertension. Curr Opin Genet Dev, 2000,10(3):325-329

[7] Thiel B, Weder AB. Genes for Essential Hypertension: Hype, Help, or Hope? J Clin Hypertens (Greenwich), 2000,2(3):187-193

[8] Bonnardeaux A, Davies E, Jeunemaitre X, et al. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension, 1994,24(1):63-69

[9] Lifton RP. Molecular genetics of human blood pressure variation. Science, 1996, 272(5262):676-680

[10] 王衛(wèi)平,主編. 兒科學(xué). 第8版. 北京：人民衛(wèi)生出版社, 2013.3-4

[11] Chanock SJ, Manolio T, Boehnke M, et al. Replicating genotype-phenotype associations. Nature, 2007,447(7145):655-660

[12] Alavi-Shahri J, Behravan J, Hassany M, et al. Association between angiotensin II type 1 receptor gene polymorphism and metabolic syndrome in a young female Iranian population. Arch Med Res, 2010,41(5):343-349

[13] Lemes VA, Neves AL, Guazzelli IC, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with increased adiposity and blood pressure in obese children and adolescents. Gene, 2013,532(2):197-202

[14] Pall D, Settakis G, Katona E, et al. Angiotensin-converting enzyme gene polymorphism, carotid intima-media thickness, and left ventricular mass index in adolescent hypertension. J Clin Ultrasound, 2004,32(3):129-135

[15] Papp F, Friedman AL, Bereczki C, et al. Renin-angiotensin gene polymorphism in children with uremia and essential hypertension. Pediatr Nephrol, 2003;18(2):150-154

[16] Siklar Z, Berberoglu M, Savas Erdeve S, et al. Contribution of clinical, metabolic, and genetic factors on hypertension in obese children and adolescents. J Pediatr Endocrinol Metab,2011,24(1-2):21-24

[17] Suh I, Nam CM, Kim S, et al. Association analysis of the essential hypertension susceptibility genes in adolescents: Kangwha study. J Prev Med Public Health, 2006,39(2):177-183

[18] Wu F(吳凡), Li GL, Song XH, et al.Relationship between angiotensin converting enzyme gene polymorphism and essential hypertension in children. Chin J Contemp Pediatr(中國(guó)當(dāng)代兒科雜志),2011,13(11):883-885

[19] Porto PI, Garcia SI, Dieuzeide G, et al. Renin-angiotensin-aldosterone system loci and multilocus interactions in young-onset essential hypertension. Clin Exp Hypertens, 2003,25(2):117-130

[20] Bloem LJ, Manatunga AK, Tewksbury DA, et al. The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest, 1995,95(3):948-953

[21] Erdos EG, Skidgel RA. The angiotensin I-converting enzyme. Lab Invest,1987,56(4):345-348

[22] Giner V, Poch E, Bragulat E, et al. Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension. Hypertension, 2000,35(1 Pt 2):512-517

[23] Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet, 1992, 51(1):197-205

[24] Ajala AR, Almeida SS, Rangel M, et al. Association of ACE gene insertion/deletion polymorphism with birth weight, blood pressure levels, and ACE activity in healthy children. Am J Hypertens, 2012,25(7):827-832

[25] Min J, Kim YJ, Lee H, et al. Is the association between ACE genes and blood pressure mediated by postnatal growth during the first 3 years? Early Hum Dev, 2012,88(6):425-429

[26] Dyson PA, Anthony D, Fenton B, et al. High rates of child hypertension associated with obesity: a community survey in China, India and Mexico. Paediatr Int Child Health, 2014,34(1):43-49

[27] Hosseini M, Ataei N, Aghamohammadi A, et al. The relation of body mass index and blood pressure in Iranian children and adolescents aged 7-18 years old. Iran J Public Health. 2010;39(4):126-134

[28] Lu X, Shi P, Luo CY, et al. Prevalence of hypertension in overweight and obese children from a large school-based population in Shanghai, China. BMC Public Health, 2013;13:24

[29] Monyeki KD, Kemper HC, Makgae PJ. The association of fat patterning with blood pressure in rural South African children: the Ellisras Longitudinal Growth and Health Study. Int J Epidemiol, 2006,35(1):114-120

[30] Eisenmann JC, Sarzynski MA, Glenn K, et al. ACE I/D genotype, adiposity, and blood pressure in children. Cardiovasc Diabetol, 2009,8:14

(本文編輯：丁俊杰)

The association between renin-angiotensin gene polymorphisms and risk of childhood hypertension: a systematic review and meta-analysis

YEBing-bing,SUDan-yan,LIUDong-li,QINSu-yuan,LAOJin-quan,PANGYu-sheng

(DepartmentofPediatrics,TheFirstAffiliatedHospitalofGuangxiMedicalUniversity,Nanning530021,GuangxiAutonomousRegion,China)

PANG Yu-sheng，E-mail:pangyush@163.com

ObjectiveTo explore the association between the genetic markers angiotensin converting enzyme (ACE) (I/D), angiotensinogen (ANG) (M235T) and angiotensin Ⅱ receptor-1AT1R(A1166C) and risk of hypertension in pediatric subjects.MethodsEMBASE, PubMed, Hartford User Group Exchange (HUGE), CNKI, VIP, Wanfang data and CBM database were searched for the case-control studies on the association of three gene polymorphisms with hypertension in pediatric patients from the establishment to November 27th2015. Data extraction, quality assessment and pooled analysis were conducted. Meta-analysis on the association of three gene polymorphisms with hypertension between hypertension group and control group under recessiveness, dominance, co-dominance, addition and allele gene models were performed. Statistical analysis was performed by Stata 12.0 software.ResultsA total of 824 patients and 1 731 controls from 7 case-control studies with moderate bias risk were included. An association between hypertension andACE(I/D) D variant was identified in 6 included studies in the meta-analysis under recessive model (OR=1.405, 95%CI =1.073-1.840,P=0.013). Neither ANG (M235T) polymorphism in 3 enrolled studies norAT1R(A1166C) polymorphism in 2 enrolled studies was associated with hypertension in pediatric population under recessiveness, dominance, co-dominance, addition or allele gene models. Subgroup analysis revealed thatACE(I/D) D variant was associated with an increased risk of hypertension in obese pediatric population under recessive model(OR=1.564 , 95%CI:1.054-2.321,P=0.026), additive model (OR=2.017, 95%CI:1.137-3.576,P=0.016) and allele model (OR=1.406, 95%CI: 1.076-1.838,P=0.013). There were no significant differences in the frequencies distribution ofACE(I/D) between two groups in general population by considering ethnicity and classification of hypertension. ConclusionNo significant association was found between ANG M235T,AT1RA1166C polymorphisms and hypertension in pediatric population. TheACE(I/D) polymorphism might be associated with susceptibility to hypertension in the obese pediatric population.

Gene polymorphism; Renin-angiotensin; Hypertension; Pediatrics and children； Meta-analysis; Systematic review

廣西醫(yī)科大學(xué)第一附屬醫(yī)院兒科 南寧，530021

龐玉生，E-mail:pangyush@163.com

10.3969/j.issn.1673-5501.2015.06.009

2015-07-10

2015-11-15)