折瀟 鄧艷春

基因檢測(cè)在腦血管病精準(zhǔn)醫(yī)療中的應(yīng)用

折瀟 鄧艷春

精準(zhǔn)醫(yī)療是以個(gè)體化醫(yī)療為基礎(chǔ)、隨著基因檢測(cè)技術(shù)快速進(jìn)步以及生物學(xué)信息和大數(shù)據(jù)科學(xué)交叉應(yīng)用而發(fā)展起來(lái)的新型醫(yī)學(xué)概念與醫(yī)療模式.基因檢測(cè)技術(shù)是精準(zhǔn)醫(yī)療的基礎(chǔ).腦血管病是遺傳因素和環(huán)境因素相互作用的多因素疾病,其中遺傳因素發(fā)揮重要作用.本文擬從單基因遺傳病、基因多態(tài)性、藥物遺傳學(xué)研究和精準(zhǔn)治療等方面闡述基因檢測(cè)在腦血管病精準(zhǔn)醫(yī)療中的應(yīng)用.

腦血管障礙; 基因; 綜述

精準(zhǔn)醫(yī)療(PM)是以個(gè)體化醫(yī)療為基礎(chǔ),隨著基因檢測(cè)技術(shù)迅速進(jìn)步以及生物學(xué)信息和大數(shù)據(jù)科學(xué)交叉應(yīng)用而發(fā)展起來(lái)的新型醫(yī)學(xué)概念與醫(yī)療模式.精準(zhǔn)醫(yī)療采用現(xiàn)代遺傳技術(shù)、分子影像學(xué)技術(shù)、生物學(xué)信息技術(shù),結(jié)合患者生活環(huán)境和臨床數(shù)據(jù),實(shí)現(xiàn)精準(zhǔn)疾病分類(lèi)與診斷,制定個(gè)體化預(yù)防、診斷與治療方案,包括精確預(yù)測(cè)風(fēng)險(xiǎn)、精確診斷與分類(lèi)、精確用藥、精確評(píng)價(jià)療效、精確預(yù)測(cè)預(yù)后等.美國(guó)"精準(zhǔn)醫(yī)療計(jì)劃"已經(jīng)明確首期任務(wù)是完成數(shù)百萬(wàn)個(gè)體的基因組測(cè)序.因此,基因檢測(cè)技術(shù)作為采集患者信息和精準(zhǔn)診斷與治療的依據(jù),是精準(zhǔn)醫(yī)療的支撐基礎(chǔ).

《全國(guó)第三次死因回顧抽樣調(diào)查報(bào)告》顯示,腦血管病已經(jīng)躍升至我國(guó)疾病死因的首位[1].急性腦血管病是單病種病殘率最高的疾病,其高發(fā)病率、高病殘率和高病死率給社會(huì)、家庭和患者帶來(lái)沉重負(fù)擔(dān)和巨大痛苦.腦血管病是遺傳因素和環(huán)境因素等相互作用的多因素疾病,遺傳因素起重要作用.本文擬從單基因遺傳病、基因多態(tài)性、藥物遺傳學(xué)研究、精準(zhǔn)治療等方面介紹基因檢測(cè)在腦血管病精準(zhǔn)醫(yī)療中的應(yīng)用.

表1 單基因遺傳性腦血管病[3?5]Table 1. Monogenic hereditary cerebrovascular disease[3?5]

一、腦血管病相關(guān)單基因遺傳病

相關(guān)研究顯示,有30%～40%青年缺血性卒中患者無(wú)明確危險(xiǎn)因素,其中一部分由單基因遺傳病所致[2].目前已發(fā)現(xiàn)多種單基因遺傳病可以導(dǎo)致腦血管病(表1)[3?5].對(duì)病因不明或某些特殊類(lèi)型腦血管病,應(yīng)行基因檢測(cè)以明確是否為單基因遺傳性腦血管病及其分型,從而制定個(gè)體化治療方案.

二、基因多態(tài)性與腦血管病

從遺傳因素角度看,絕大多數(shù)腦血管病為多基因遺傳病,與基因多態(tài)性密切相關(guān).如果將腦血管病遺傳因素視為內(nèi)因,高血壓、高脂血癥、糖尿病、高同型半胱氨酸血癥和血液成分異常等因素即為外因,外因通過(guò)內(nèi)因發(fā)揮作用而誘發(fā)腦血管病[6].因此,我們可以從遺傳因素角度篩選可能的腦血管病高危人群,通過(guò)基因多態(tài)性分析,提示何種基因型個(gè)體更易發(fā)生腦血管病.如果對(duì)這些高危人群進(jìn)行重點(diǎn)預(yù)防和早期抗高血壓、調(diào)脂、控制血糖等治療,可以有效降低腦血管病發(fā)病率.

1.腎素?血管緊張素基因多態(tài)性 (1)血管緊張素轉(zhuǎn)換酶(ACE)基因多態(tài)性:編碼血管緊張素轉(zhuǎn)換酶的基因根據(jù)其第16內(nèi)含子是否存在長(zhǎng)度287 bp的片段呈現(xiàn)插入(I)/缺失(D)多態(tài)性,即插入純合子型(II型)、缺失純合子型(DD型)和雜合子型(ID型)共3種基因型.D等位基因頻率與缺血性腦血管病發(fā)病率呈正相關(guān)[7],在亞洲人群中風(fēng)險(xiǎn)顯著增加,增加中國(guó)南方人群缺血性卒中易感性,但在白種人中的統(tǒng)計(jì)學(xué)結(jié)果不可靠[8].(2)血管緊張素原(AGT)基因多態(tài)性:AGT基因編碼區(qū)由5個(gè)外顯子和4個(gè)內(nèi)含子組成,當(dāng)位于第2外顯子第704位核苷酸胸腺嘧啶(T)被胞嘧啶(C)替代(c.704T>C),則導(dǎo)致第235位氨基酸由蛋氨酸突變?yōu)樘K氨酸(p.Met235Thr).根據(jù)等位基因的不同,AGT基因分為T(mén)T型、MT型、MM型.T等位基因可能增加中國(guó)北方漢族人群缺血性卒中風(fēng)險(xiǎn)[9].第174位氨基酸由蘇氨酸突變?yōu)榧琢虬彼?p.Thr174Met)增加亞洲人群缺血性卒中風(fēng)險(xiǎn)[10].

2.載脂蛋白基因多態(tài)性 (1)載脂蛋白E(ApoE)基因多態(tài)性:ApoE基因有6種常見(jiàn)基因型,即純合子型(E2/2型、E3/3型、E4/4型)和雜合子型(E2/3型、E2/4型、E3/4型),其中,E2和E4等位基因增加亞洲人群出血性腦血管病風(fēng)險(xiǎn)和中國(guó)北方漢族人群缺血性卒中風(fēng)險(xiǎn),且增加高血壓易感性[11?12];E4等位基因增加缺血性卒中風(fēng)險(xiǎn),故亞洲人群缺血性卒中發(fā)病率高于高加索人群[13?14].(2)對(duì)氧磷酶(PON)基因多態(tài)性:對(duì)氧磷酶是一種催化水解磷酸酯鍵的芳香酯酶,由355個(gè)氨基酸組成.在PON1 Gln192Arg多態(tài)性中,R等位基因增加缺血性卒中風(fēng)險(xiǎn)[15],尤其增加高加索人群缺血性卒中易感性[16].PON1 c.575A>G多態(tài)性和PON1 c.163T>A多態(tài)性可能與缺血性卒中風(fēng)險(xiǎn)增加有關(guān)[17].

3.β?纖維蛋白原基因多態(tài)性 纖維蛋白原(fibrinogen)是由α,β和γ共3對(duì)多肽鏈組成的糖蛋白,其中β鏈的合成是整個(gè)分子合成的限速步驟.研究顯示,β?fibrinogen基因突變是導(dǎo)致個(gè)體間血漿纖維蛋白原水平差異的重要遺傳因素,與腦血管病密切相關(guān).目前已發(fā)現(xiàn)β鏈基因簇存在10個(gè)多態(tài)性位點(diǎn).2014年的一項(xiàng)Meta分析顯示,β?fibrinogen c.455G>T多態(tài)性是缺血性卒中的易感因素[18].2015年的一項(xiàng)關(guān)于中國(guó)人缺血性卒中的Meta分析顯示,β?fibrinogen c.148C>T 和 c.?854G>A 多態(tài)性可能增加缺血性卒中易感性[19?20].

4.同型半胱氨酸相關(guān)基因多態(tài)性 N5,10?亞甲基四氫葉酸還原酶(MTHFR)主要作用是在葉酸代謝通路中將MTHFR轉(zhuǎn)化為具有生物學(xué)功能的5?甲基四氫葉酸.MTHFR基因包含12個(gè)外顯子,編碼656個(gè)氨基酸殘基組成的蛋白質(zhì).MTHFR c.1298A>C多態(tài)性增加缺血性卒中風(fēng)險(xiǎn),C等位基因是缺血性卒中重要危險(xiǎn)因素[21],增加亞洲成年人群腦血管病風(fēng)險(xiǎn)[22].MTHFR c.677C>T多態(tài)性增加缺血性卒中風(fēng)險(xiǎn)[23],亦增加兒童缺血性卒中易感性[24].T等位基因是中國(guó)人群缺血性卒中的另一危險(xiǎn)因素[25].胱硫醚β?合成酶(CBS)是同型半胱氨酸代謝關(guān)鍵酶,CBS c.833T>C多態(tài)性與腦卒中風(fēng)險(xiǎn)增加有關(guān)[26].

5.纖溶酶原激活物抑制物基因多態(tài)性 纖溶酶原激活物抑制物?1(PAI?1)是纖溶酶原系統(tǒng)主要調(diào)節(jié)因子,與纖溶酶原激活物結(jié)合后迅速失活而發(fā)揮抗纖溶作用.PAI?1是一種單糖蛋白,包含9個(gè)外顯子和8個(gè)內(nèi)含子,編碼379個(gè)氨基酸.2014年的一項(xiàng)Meta分析顯示,中國(guó)人群PAI?1 4G/4G基因型可能是缺血性卒中的危險(xiǎn)因素[27].亦有研究顯示,PAI?1基因多態(tài)性與腦血管病無(wú)關(guān)聯(lián)性[28].

6.凝血因子和血小板膜糖蛋白基因多態(tài)性 凝血因子Ⅴ(FⅤ)Leiden基因突變與靜脈血栓風(fēng)險(xiǎn)增加有關(guān),但并未增加青年人群缺血性卒中風(fēng)險(xiǎn)[29].FⅦ c.807C>T多態(tài)性可能增加心房顫動(dòng)患者腦卒中風(fēng)險(xiǎn)[30].既往研究顯示,F■基因多態(tài)性與腦血管病有關(guān)[31],但最新的Meta分析顯示二者無(wú)明顯關(guān)聯(lián)性,而增加白種人腦出血風(fēng)險(xiǎn)[32].血小板膜糖蛋白Ⅲa基因第33位氨基酸突變?yōu)楦彼崾切脑葱院痛笱茉葱匀毖宰渲械奈ｋU(xiǎn)因素[33].血小板膜糖蛋白Ⅰa c.807C>T多態(tài)性[34]和Ⅰb p.Met145Thr多態(tài)性和Koxak c.?5T>C多態(tài)性與缺血性腦血管病相關(guān)[32,35].

7.內(nèi)皮型一氧化氮合酶基因多態(tài)性 內(nèi)皮型一氧化氮合酶(eNOS)催化合成的一氧化氮可以通過(guò)對(duì)血小板聚集、白細(xì)胞黏附、平滑肌細(xì)胞增殖和遷移的抑制效應(yīng)發(fā)揮保護(hù)作用.eNOS基因包含26個(gè)外顯子和25個(gè)內(nèi)含子,編碼1203個(gè)氨基酸,基因型主要有:(1)第7外顯子c.894G>T突變,導(dǎo)致其編碼的第298位氨基酸由谷氨酸突變?yōu)樘於彼?(2)第4內(nèi)含子的27個(gè)堿基重復(fù)序列不一致,重復(fù)4次者為A等位基因,重復(fù)5次者為B等位基因.(3)啟動(dòng)子區(qū)c.?786T>C突變.2017年的一項(xiàng)Meta分析顯示,缺血性卒中與eNOS c.894G>T突變和4b/a基因多態(tài)性相關(guān),而與c.?786T>C突變無(wú)顯著關(guān)聯(lián)性[36].亦有研究顯示,c.?786T>C突變與亞洲人群缺血性卒中有關(guān)[37?38],而4b/a基因多態(tài)性與高加索人群缺血性卒中無(wú)關(guān)聯(lián)性[39].

8.炎癥反應(yīng)相關(guān)基因多態(tài)性 (1)白細(xì)胞介素(IL):2016年的一項(xiàng)Meta分析顯示,IL?6 c.174G>C和c.572G>C突變并未增加缺血性和出血性卒中易感性[40?41].IL?10 c.?1082A>G 突變?cè)黾觼喼奕巳喝毖宰渲幸赘行訹42],亦增加大血管病變和小血管病變易感性[22].腫瘤壞死因子?α(TNF?α)c.?238G>A突變與亞洲人群缺血性腦血管病風(fēng)險(xiǎn)增加有關(guān),而c.?308G>A突變與其無(wú)關(guān)聯(lián)性[43?44].亦有相關(guān)研究顯示,TNF?α c.?308G>A突變與青年缺血性卒中相關(guān)[45].E?選擇素(E?slection)是黏附分子選擇素家族成員之一,在炎癥反應(yīng)、動(dòng)脈粥樣硬化致血栓形成過(guò)程中發(fā)揮重要作用.E?slection基因包含14個(gè)外顯子和13個(gè)內(nèi)含子,AC基因型較AA基因型的缺血性卒中易感性更高[46],c.561A>C突變?cè)黾訚h族人群缺血性卒中易感性[47].(2)磷酸二酯酶4D(PDE4D):主要作用是降解cAMP,而cAMP水平降低可以引起血管平滑肌細(xì)胞增殖和遷移,局部炎癥反應(yīng)加劇,促進(jìn)動(dòng)脈粥樣硬化形成和斑塊不穩(wěn)定性增加,PDE4D c.83T>C多態(tài)性與中國(guó)人群缺血性卒中易感性相關(guān)[48].(3)轉(zhuǎn)化生長(zhǎng)因子β1(TGF?β1):系一種多效細(xì)胞因子,在缺血性腦血管病中具有抗炎癥反應(yīng)作用.TGF?β1?c.509C>T多態(tài)性與轉(zhuǎn)化生長(zhǎng)因子β1表達(dá)變化相關(guān),T等位基因增加轉(zhuǎn)化生長(zhǎng)因子β1總蛋白和活性蛋白水平;編碼區(qū)第10位氨基酸密碼子發(fā)生c.869T>C突變,使亮氨酸突變?yōu)楦彼?從而升高轉(zhuǎn)化生長(zhǎng)因子β1表達(dá)水平.然而Meta分析顯示,目前尚無(wú)法得出c.869T>C多態(tài)性和c.509C>T多態(tài)性與缺血性卒中易感性相關(guān)的結(jié)論[49?50].(4)脂聯(lián)素(APN):系脂肪細(xì)胞分泌的細(xì)胞因子,干預(yù)機(jī)體糖和脂肪代謝途徑,具有明確的抗炎癥反應(yīng)和抗動(dòng)脈粥樣硬化作用.包含3個(gè)外顯子和2個(gè)內(nèi)含子,c.45T>G多態(tài)性與北方漢族人群缺血性卒中易感性相關(guān),GG基因型是北方漢族女性人群缺血性卒中的危險(xiǎn)因素[51].

9.其他 研究顯示,淋巴毒素α(LTα)c.?252G>A突變?cè)黾痈呒铀魅巳喝毖宰渲幸赘行訹52],雌激素受體α(ERα)c.454?397T>C突變[53]、β2腎上腺素受體(β2AR)Gln27Glu多態(tài)性與缺血性卒中風(fēng)險(xiǎn)增加有關(guān)[54].

三、腦血管病藥物遺傳學(xué)研究

腦血管病預(yù)防藥物相關(guān)基因突變可能影響藥代動(dòng)力學(xué)和藥效學(xué),并增加不良事件風(fēng)險(xiǎn).藥物遺傳學(xué)是腦血管病的重要研究領(lǐng)域.

1.重組組織型纖溶酶原激活物靜脈溶栓治療

一項(xiàng)納入497例缺血性卒中患者的重組組織型纖溶酶原激活物(rt?PA)靜脈溶栓研究結(jié)果顯示,IL?1β和血管性血友病因子(vWF)基因突變均與早期血管再通有關(guān),vWF基因突變也與凝血因子Ⅷ(FⅧ)活性相關(guān)[55].α2巨球蛋白(α2M)c.669A>G多態(tài)性與rt?PA治療后出血性轉(zhuǎn)化有關(guān)[56].上述研究均表明遺傳學(xué)信息可能在未來(lái)用于預(yù)測(cè)缺血性卒中rt?PA治療反應(yīng),從而有助于rt?PA靜脈溶栓或替代療法如血管內(nèi)治療的決策.

2.華法林或達(dá)比加群抗凝治療 編碼細(xì)胞色素P?450酶的CYP2C9基因突變影響華法林代謝,編碼維生素K環(huán)氧化物還原酶的VKORC1基因突變影響華法林敏感性[57].對(duì)2944例長(zhǎng)期華法林抗凝治療的患者進(jìn)行全基因組相關(guān)性研究(GWAS)顯示,羧酸酯酶1(CES1)次要等位基因與較低活性的達(dá)比加群代謝物水平相關(guān),亦與達(dá)比加群治療后低出血風(fēng)險(xiǎn)相關(guān)[58].

3.抗血小板藥治療 抗血小板藥的臨床應(yīng)用存在顯著個(gè)體差異.有5%～40%的缺血性卒中患者對(duì)阿司匹林治療無(wú)反應(yīng),4%～30%患者氯吡格雷療效欠佳[59].存在阿司匹林抵抗的患者常合并氯吡格雷抵抗.因此,了解基因型并選擇適宜藥物,可以決定治療效果.參與阿司匹林作用機(jī)制的各種基因發(fā)生遺傳變異性,可以導(dǎo)致活性藥物濃度差異,影響藥物療效.研究顯示,環(huán)氧合酶?1(COX?1)?1676A>G 突變[60]和 COX?2 ?765G>C 突變[61]均與阿司匹林抵抗相關(guān).

4.他汀類(lèi)調(diào)脂藥治療 他汀類(lèi)調(diào)脂藥治療過(guò)程中,低密度脂蛋白膽固醇(LDL?D)每降低1 mmol/L,腦卒中相對(duì)風(fēng)險(xiǎn)降低約20%[62].肌肉病是他汀類(lèi)調(diào)脂藥罕見(jiàn)且嚴(yán)重的并發(fā)癥,劑量增加或與某些藥物同時(shí)應(yīng)用時(shí)風(fēng)險(xiǎn)增加.SLCO1B1基因突變使他汀類(lèi)調(diào)脂藥導(dǎo)致肌肉病的相對(duì)風(fēng)險(xiǎn)增加[63].

5.戒煙 某些基因型與吸煙起止時(shí)間、數(shù)量和治療反應(yīng)相關(guān).某些基因涉及多巴胺再攝取和代謝,與吸煙成癮性相關(guān)或與尼古丁代謝相關(guān)[64].

四、精準(zhǔn)醫(yī)療中應(yīng)注意的問(wèn)題

基因檢測(cè)有助于檢出更多的單基因遺傳性腦血管病,有助于發(fā)現(xiàn)腦血管病基因多態(tài)性易感位點(diǎn),有助于在腦血管病危險(xiǎn)因素出現(xiàn)前更早地預(yù)測(cè)腦血管病發(fā)生和發(fā)展機(jī)制,藥物代謝相關(guān)基因單核苷酸多態(tài)性(SNP)研究有助于檢測(cè)腦血管病藥物治療效果,從而提高腦血管病個(gè)體化預(yù)防、診斷與治療水平.然而,基因檢測(cè)僅是實(shí)現(xiàn)精準(zhǔn)醫(yī)療的一種技術(shù)支持,要全面實(shí)現(xiàn)精準(zhǔn)醫(yī)療還應(yīng)注意以下問(wèn)題:(1)基因檢測(cè)的臨床效度隨基因型的不同而異,這些不同基因型的改變可能對(duì)致疾病風(fēng)險(xiǎn)有不同的含義,其中一些變異可能有證據(jù)支持是明確的致病性突變,一些可能是無(wú)義突變,在人群數(shù)據(jù)庫(kù)中有超過(guò)5%的存在,另一些可能是臨床意義不明的突變.基因型與臨床表型關(guān)系的復(fù)雜性影響基因檢測(cè)的臨床效度.對(duì)于何種疾病患者應(yīng)行何種基因檢測(cè),最重要的考慮是對(duì)檢測(cè)結(jié)果呈陽(yáng)性的患者能否進(jìn)行有效干預(yù).(2)隨著高通量基因檢測(cè)設(shè)備的廣泛應(yīng)用,近年來(lái)檢測(cè)成本降低,基因數(shù)據(jù)量呈倍數(shù)增加.精準(zhǔn)醫(yī)療的發(fā)展需建立高效、便捷的數(shù)據(jù)處理和共享系統(tǒng),還應(yīng)建立標(biāo)準(zhǔn)化、可重復(fù)和可追蹤的數(shù)據(jù)流.(3)目前的高通量基因檢測(cè)技術(shù)可以數(shù)字或字母序列形式快捷、準(zhǔn)確地提供基因信息,但如何解讀基因檢測(cè)結(jié)果仍是絕大多數(shù)臨床醫(yī)師的難題.基因檢測(cè)從人工測(cè)序轉(zhuǎn)為數(shù)據(jù)分析,使很多醫(yī)師難以處理大規(guī)模數(shù)據(jù),不能準(zhǔn)確探尋基因與疾病、藥物選擇、患者之間關(guān)系.

因此,基因檢測(cè)只有與生物學(xué)信息和臨床表型相結(jié)合,才能被理解和正確使用.目前由于數(shù)據(jù)科學(xué)到生物學(xué)信息和醫(yī)學(xué)的脫節(jié),使得如何解讀基因檢測(cè)結(jié)果成為下一步工作的關(guān)鍵[65].

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Application of gene detection in precision medicine of cerebrovascular disease

ZHE Xiao1,DENG Yan?chun21Department of Neurology,the First Affiliated Hospital of Xi'an Medical University,Xi'an 710077,Shaanxi,China
2Department of Neurology,Xijing Hospital,the Fourth Military Medical University of Chinese PLA,Xi'an 710032,Shaanxi,China

DENG Yan?chun(Email:yanchund@fmmu.edu.cn)

Precision medicine(PM),a new type of medical concept and model which based on personalized medicine,is developed with the fast progress of genetic detection technology and the cross?application of biological information and large data science.Genetic detection technology is the basis of PM.Cerebrovascular disease is a multifactorial disease,in which genetic factors play an important role in the pathogenesis.This paper intends to discuss the application of gene detection technology in the PM of cerebrovasculardisease,includingsingle gene genetic disease,genetic polymorphism,drug genetics research and precision treatment.

Cerebrovascular disorders; Genes; Review

This study was supported by 2010 Science and Research Special Project of Shaanxi Provincial Education Department(No.2010JK811)and Science and Technology Project of Lianhu District,Shaanxi Province,China(No.K2011-024).

10.3969/j.issn.1672?6731.2017.07.005

陜西省教育廳2010年專(zhuān)項(xiàng)科學(xué)研究項(xiàng)目計(jì)劃(項(xiàng)目編號(hào):2010JK811);陜西省西安市蓮湖區(qū)科技計(jì)劃項(xiàng)目(項(xiàng)目編號(hào):K2011-024)

710077西安醫(yī)學(xué)院第一附屬醫(yī)院神經(jīng)內(nèi)科(折瀟);710032西安,第四軍醫(yī)大學(xué)西京醫(yī)院神經(jīng)內(nèi)科(鄧艷春)

鄧艷春(Email:yanchund@fmmu.edu.cn)

2017?06?24)