劉蘭 王為珍 王喬樹

腦卒中是嚴重威脅人類健康的疾病之一，居全球病死原因第2位，亦是成人主要病殘原因［1］。腦卒中是遺傳因素和環(huán)境因素共同作用的結果，其中遺傳因素在發(fā)病機制中起重要作用。近年來，缺血性卒中候選基因研究已成為腦卒中遺傳學機制的研究重點。根據TOAST分型，缺血性卒中可以分為5種類型，即大動脈粥樣硬化型（LAA型）、心源性栓塞型（CE型）、小動脈閉塞型（SAO型）、其他明確病因型（SOD型）和不明病因型（SUD型），其中，LAA型缺血性卒中系腦血管造影證實與缺血性卒中神經功能缺損相對應的顱內或顱外大動脈狹窄率＞50%或閉塞，且符合動脈粥樣硬化改變。動脈粥樣硬化是以脂質代謝障礙、血管內皮細胞功能障礙、炎性細胞浸潤致炎癥反應、動脈粥樣硬化斑塊破裂、最終形成血栓為特點的復雜慢性病理生理學過程［2］?；谏鲜霭l(fā)病機制探尋LAA型缺血性卒中基因治療靶點，近年國內外學者已經進行大量研究揭示LAA型缺血性卒中的遺傳易感性，并結合其他危險因素（如高血壓、糖尿病、高脂血癥和心臟病等）進行評價，對指導臨床醫(yī)師建立更佳、更新的診斷與治療方法具有積極意義。本文擬對目前研究較多的LAA型缺血性卒中易感基因研究進展進行簡要綜述。

一、ApoE基因

載脂蛋白E（ApoE）是包含299個氨基酸的磷脂糖蛋白，主要存在于血液乳糜顆粒（CM）、極低密度脂蛋白（VLDL）、中密度脂蛋白（IDL）和部分高密度脂蛋白（HDL）中，對脂質代謝和心血管相關疾病有決定性作用。ApoE基因定位于染色體19q13.2，由3597個核苷酸組成，含4個外顯子和3個內含子。ApoE是多態(tài)性蛋白質，包含3個常見異構體即E2、E3和E4，分別編碼3種亞型即ApoE2、ApoE3和ApoE4。ApoE各亞型與不同脂蛋白受體相互作用，通過乳糜顆粒和極低密度脂蛋白與肝臟不同酶類結合，調節(jié)吸收和分解代謝過程以改變血清膽固醇水平。ApoE基因型與高密度脂蛋白和膽固醇水平密切相關，可以影響動脈進展和動脈疾病進程。研究顯示，E2等位基因是低回聲和潰瘍型頸動脈斑塊的獨立危險因素［3］；與其他基因型相比，E3/E3基因型是腦卒中保護因素，特別是女性患者，E3等位基因可能具有潛在的神經保護作用［4］。根據LAA型缺血性卒中與ApoE基因之間的相關性評價其對頸動脈內?中膜厚度（IMT）的作用，共納入22項臨床試驗計30 879例存在血管病或血管危險因素的患者進行Meta分析，其結果顯示，ApoE2基因型患者頸動脈內?中膜厚度最低，ApoE3基因型患者適中，ApoE4基因型患者最高，提示頸動脈內?中膜厚度增加與ApoE基因特異性表達有關，尤其與ApoE4基因型有關，并與環(huán)境因素（如高血壓、吸煙等）相互作用，增加腦卒中發(fā)病風險［5］。馬飛煜等［6］在 LAA 型缺血性卒中患者中發(fā)現(xiàn)，含E4等位基因的患者血清低密度脂蛋白（LDL）水平顯著高于含E3等位基因的患者；LAA型缺血性卒中患者E4等位基因和E3/E4基因型頻率高于對照組，E3等位基因和E3/E3基因型頻率低于對照組；E4等位基因可以升高血清低密度脂蛋白水平，與LAA型缺血性卒中相關，而與其他類型缺血性卒中無明顯關聯(lián)性。

二、MMP?12基因

基質金屬蛋白酶（MMPs）是一組依賴金屬離子作為輔助因子催化降解細胞外基質（ECM）的酶群?；|金屬蛋白酶?12（MMP?12）是基質金屬蛋白酶家族成員，可降解細胞外基質蛋白，并在動脈粥樣硬化中有關鍵作用。研究顯示，MMP?12 mRNA高表達可以促進巨噬細胞侵襲［7］和血管新生［8］，并在斑塊中活性增強［9］。MMP?12基因多態(tài)性對腦卒中的作用可能通過脂質代謝、遺傳因素、環(huán)境因素或炎癥反應機制介導。MMP?12基因除降解細胞外基質外，還可通過激活腫瘤壞死因子?α（TNF?α）或調節(jié)促炎性因子如單核細胞趨化蛋白?1（MCP?1），促使巨噬細胞募集至血管壁［10］。Traylor等［11］進行全基因組相關性研究（GWAS）發(fā)現(xiàn)，MMP?12基因在頸動脈斑塊中呈明顯過表達，MMP?12基因rs660599多態(tài)性與LAA型缺血性卒中有關，這種易感基因增加早發(fā)性缺血性卒中發(fā)病風險［12］?；谵D基因兔模型的動物實驗證實，MMP?12基因可以促進動脈粥樣硬化的發(fā)生，刺激脂肪條紋形成至纖維斑塊的進展［13］。Johnson 等［14］予 ApoE 基因敲除小鼠模型選擇性MMP?12抑制劑RXP470.1，結果顯示，RXP470.1可以延緩動脈粥樣硬化進展，究其原因，RXP470.1通過增加平滑肌細胞/巨噬細胞比例，減少巨噬細胞凋亡，增加纖維帽厚度，減少壞死核心，降低鈣化，從而增加斑塊穩(wěn)定性。MMP?12基因表達變化與頸動脈斑塊進展、破裂［15］和晚期發(fā)育有關［16］，其轉錄水平影響頸動脈斑塊穩(wěn)定性?；谥袊鴿h族人群的研究顯示，MMP?12基因可能并非頸動脈斑塊的危險因素［17］。

三、HDAC9基因

組蛋白去乙?；?（HDAC9）是對染色體結構修飾和基因表達調控發(fā)揮重要作用的蛋白質。HDAC9基因定位于染色體7p21.1，表達于動脈內膜和平滑肌細胞、顱內血管、頸動脈和冠狀動脈等。研究顯示，HDAC9基因可以導致血管內皮細胞損傷，是將腦損傷與表觀遺傳修飾相關聯(lián)的信號轉導通路的關鍵組成部分之一［18］。HDAC9蛋白可以抑制肌細胞生成，參與心臟發(fā)育，通過改變腦組織缺血性反應增加腦卒中發(fā)病風險，并對神經元存活有影響。HDAC9基因敲除可以導致脂質平衡基因增加、炎癥基因減少，巨噬細胞在ATP結合盒轉運子A1（ABCA1）、ATP結合盒轉運子G1（ABCG1）和過氧化物酶增殖物激活受體γ（PPARγ）基因啟動子處通過H3和H3K9乙?；M蛋白聚集，促進巨噬細胞向M2型轉化。HDAC9基因表達上調可抑制膽固醇外排和活化巨噬細胞產生，促進動脈粥樣硬化［19］。2012年，英國和德國等歐洲國家進行的一項全基因組相關性研究確定HDAC9基因與LAA型缺血性卒中的關系，此后多項國際多中心全基因組相關性研究均證實HDAC9基因多態(tài)性與LAA型缺血性卒中相 關［20?22］。 Markus 等［23］發(fā) 現(xiàn) ，HDAC9 基 因rs11984041和rs2107595多態(tài)性與無癥狀性頸動脈斑塊和頸動脈內?中膜厚度增加相關，HDAC9 mRNA在頸動脈斑塊中表達上調，這與加速動脈粥樣硬化進展機制相一致，而少見于其他動脈，可能是通過加快斑塊進展、促進斑塊不穩(wěn)定，增加缺血性卒中發(fā)病風險。研究業(yè)已證實HDAC9基因是心肌梗死、冠心病的主要風險基因［24?25］。故推測 HDAC9 基因靶向抑制劑有可能預防動脈粥樣硬化，成為LAA型缺血性卒中的有效 治療藥 物［19，24］。HDAC9 基因rs2107595多態(tài)性與歐洲人群LAA型缺血性卒中相關，但中國南方漢族人群腦卒中與rs2107595多態(tài)性無關聯(lián)性，而與血清總膽固醇和甘油三酯（TG）相關，可能是由于rs2107595位點的等位基因頻率不同造成歐洲和中國人群腦卒中風險差異［26］。第二軍醫(yī)大學附屬長海醫(yī)院共納入279例腦卒中患者和984例正常對照者，基因檢測顯示，LAA型缺血性卒中與HDAC9基因rs11984041多態(tài)性無關聯(lián)性，而與rs2389995 和rs2240419 多態(tài)性相關［27］。

四、NINJ2基因

神經損傷誘導蛋白2（NINJ2）系由142個氨基酸組成、NINJ2基因編碼的黏附分子，在神經系統(tǒng)發(fā)育、分化、再生過程中調節(jié)細胞之間或細胞與基質之間的相互作用。NINJ2基因是腦損傷修復相關基因，是腦卒中相關單核苷酸多態(tài)性（SNP）基因，其產物是神經損傷誘導蛋白，于神經損傷后呈高表達，參與神經修復和再生，表達于成熟感覺神經元，促進神經軸突增生，使受損神經遠端施萬細胞數(shù)目增加［28］。NINJ2基因表達變化影響腦組織對缺氧缺血的耐受［29］。NINJ2基因啟動子（rs3809263 G＞A）單核苷酸多態(tài)性是功能性的，是LAA型缺血性卒中的生物學標志物［30］。Ikram等［29］的全基因組相關性研究顯示，臨近NINJ2基因染色體12p13區(qū)的rs11833579和rs12425791多態(tài)性與白種人腦卒中相關，特別是增加LAA型缺血性卒中的發(fā)病風險。王鋒等［31］對128例LAA型缺血性卒中患者和112例正常對照者進行基因檢測，結果顯示，NINJ2基因rs11833579位點隱性模型（AA/AG基因型）與LAA型缺血性卒中密切相關，且在后循環(huán)動脈粥樣硬化中的頻率顯著高于其他基因型，提示NINJ2基因多態(tài)性可能與動脈粥樣硬化的責任血管有關，而且不同血管發(fā)生動脈粥樣硬化的概率可能與遺傳因素密切相關。基于中國人群的研究顯示，NINJ2基因染色體12p13區(qū)rs11833579和rs12425791多態(tài)性與LAA 型缺血性卒中密切相關［31?33］，且 rs12425791 位點 A 等位基因增加腦卒中發(fā)病風險［34?35］；亦有少數(shù)研究結果顯示，rs11833579多態(tài)性與腦卒中無關聯(lián)性［28，36］；在非洲裔美國人群和巴基斯坦人群中，NINJ2基因染色體12p13區(qū)rs11833579和rs12425791多態(tài)性與缺血性卒中無關聯(lián)性［37］。

五、CXCL16基因

CXC型趨化因子配體16（CXCL16）基因定位于染色體17p13區(qū)，包含5個外顯子。CXCL16蛋白是集趨化因子、黏附分子、清道夫受體為一體的免疫因子，與其受體共同表達于血管平滑肌細胞，在誘導大動脈平滑肌細胞增殖、細胞間粘附、脂質累積和基質降解中發(fā)揮重要作用［38］。研究顯示，CXCL16基因通過促動脈粥樣硬化因子、干擾素?γ（IFN?γ）以及炎癥反應等促進斑塊形成［39］和斑塊不穩(wěn)定［40］。CXCL16 mRNA表達于培養(yǎng)的動脈內皮細胞［41］，不僅可以活化血小板，而且可以促進CXCL16蛋白成為有效的新型血小板黏附配體，誘導血小板粘附至血管壁［42］。Wang等［43］對 244 例 LAA 型缺血性卒中患者、153例存在動脈粥樣硬化危險因素但未發(fā)生腦卒中的患者和167例正常對照者進行聚合酶鏈反應?限制性片段長度多態(tài)性（PCR?RFLP），結果顯示，LAA型缺血性卒中患者CXCL16蛋白水平明顯升高，而3組患者CXCL16 p.Ala181Val基因型分布以及等位基因頻率差異無統(tǒng)計學意義。劉丹等［44］的研究顯示，LAA型缺血性卒中患者CXCL16 p.Ala181Val的AA基因型分布和A等位基因頻率明顯高于正常對照者，多因素Logistic回歸分析顯示，AA基因型是缺血性卒中的獨立危險因素，表明CXCL16 p.Ala181Val多態(tài)性與LAA型缺血性卒中遺傳易感性相關，A等位基因是LAA型缺血性卒中的遺傳易感基因之一。亦有研究顯示，血清CXCL16蛋白水平與LAA型缺血性卒中和頸動脈粥樣硬化相關［43，45］，測定 CXCL16 蛋白水平不僅有助于識別LAA型缺血性卒中高?；颊?，且與急性缺血性卒中不良預后相關［38，40］。CXCL16 基因參與和促進動脈粥樣硬化形成和進展，與動脈粥樣硬化性疾病如冠心病、頸動脈粥樣硬化、腦卒中等的發(fā)病密切相關。

六、其他

染色體9p21.3區(qū)與LAA型缺血性卒中相關的主要單核苷酸多態(tài)性長度約100×103bp，該片段與INK4位點反義非編碼RNA（ANRIL）的外顯子18～24部分重疊［46］。ANRIL基因表達于人類動脈粥樣硬化血管和頸動脈內膜，亦表達于血管內皮細胞、單核細胞起源的巨噬細胞以及冠狀動脈平滑肌細胞［46］，在動脈粥樣硬化中發(fā)揮一定作用。染色體9p21.3區(qū)的遺傳片段不僅與甲硫腺苷磷酸（MTAP）基因剪接變體外顯子5進一步重疊，而且臨近細胞周期蛋白依賴性激酶抑制基因2A/B（CDKN2A/B，分別表達p16INK4A和p15INK4B基因），上述基因在細胞增殖、衰老和凋亡中發(fā)揮重要作用。相關研究顯示，ANRIL、p16INK4A、p15INK4B、染色體9p21.3區(qū)共同協(xié)調轉錄［49］。2012年，METASTROKE協(xié)作組對多個全基因組相關性研究進行Meta分析，證實染色體9p21.3區(qū)與LAA型缺血性卒中相關（r=1.150，P＜0.001）［21］；近年的多項研究均證實二者具有相關性［49?50］。染色體 9p21 區(qū) rs2383206 和 rs4977574 多態(tài)性與中國漢族人群頸動脈斑塊潛在相關［51］，rs10757278多態(tài)性與女性頸動脈斑塊呈正相關（r=2.420，P=0.013）［52］，rs1333035 多態(tài)性可能與斑塊破裂和血栓形成相關［53］。Musunuru 等［54］發(fā)現(xiàn)，染色體9p21.3區(qū)與血小板聚集明顯相關（P＜0.001），推測染色體9p21.3區(qū)可能通過調節(jié)血小板活性而增加斑塊破裂和血栓形成風險，從而導致本身已存在動脈粥樣硬化的人群發(fā)生LAA型缺血性卒中。未來尚待進一步確定LAA型缺血性卒中與染色體9p21.3區(qū)之間的聯(lián)系是否通過上述基因或其他可能途徑進行遠距離調節(jié)［46］。盡管目前業(yè)已證實染色體9p21.3區(qū)是冠狀動脈疾病和心肌梗死的主要風險基因，但該基因和腦卒中的關系不依賴冠狀動脈疾病、心肌梗死或者其他血管危險因素而獨立發(fā)揮作用［25］。

綜上所述，腦卒中是多基因、多因素互相作用疾病。目前與其發(fā)病相關的基因研究大部分針對單基因，且國內外報道多不盡一致，究其原因，主要有以下幾方面：（1）種族和人群差異。（2）大部分臨床研究樣本量較小，統(tǒng)計學說服力參差不齊。（3）對多基因遺傳性疾病，單一基因作用較小，易受其他基因和環(huán)境的影響。（4）不同的入組標準存在選擇偏倚。因此，為準確篩選LAA型缺血性卒中候選基因，尚待更大樣本量，同時開展遺傳流行病學和分子流行病學調查，以及綜合考慮多種因素。通過腦卒中易感基因研究，使臨床醫(yī)師可以從遺傳學角度篩查腦卒中高危人群，早期預防疾病發(fā)生；也可以從遺傳學角度對腦卒中進行病因分型，針對不同患者的個體化治療將是未來腦卒中基因研究的重點。

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