重癥新型冠狀病毒肺炎患者遺傳易感性研究進(jìn)展

劉文兵，劉丹，閆進(jìn)，劉欣，王前飛

重癥新型冠狀病毒肺炎患者遺傳易感性研究進(jìn)展

劉文兵1,2，劉丹1，閆進(jìn)1，劉欣1,2，王前飛1,2

1. 中國(guó)科學(xué)院北京基因組研究所(國(guó)家生物信息中心)，中國(guó)科學(xué)院精準(zhǔn)基因組醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，北京 100101 2. 中國(guó)科學(xué)院大學(xué)，北京 100049

新型冠狀病毒肺炎是由新型冠狀病毒感染引起的全球大流行疾病?；颊叱尸F(xiàn)出無(wú)癥狀感染、輕癥到(危)重癥不同嚴(yán)重程度的臨床表現(xiàn)。部分重癥患者因發(fā)生細(xì)胞因子風(fēng)暴而出現(xiàn)多器官功能衰竭并最終導(dǎo)致死亡。除性別、年齡、基礎(chǔ)疾病(如高血壓、糖尿病)等增加重型感染風(fēng)險(xiǎn)外，宿主先天遺傳缺陷也被認(rèn)為與疾病嚴(yán)重程度(包括細(xì)胞因子風(fēng)暴的發(fā)生)密切相關(guān)。在重癥患者中，相繼發(fā)現(xiàn)與病毒識(shí)別、殺傷等相關(guān)的關(guān)鍵基因(如、等)先天遺傳變異。本文主要總結(jié)了宿主抗病毒免疫應(yīng)答機(jī)制及與新型冠狀病毒感染嚴(yán)重程度相關(guān)的先天變異基因，以期為新型冠狀病毒肺炎的早期干預(yù)和分層治療提供遺傳學(xué)依據(jù)。

重癥新型冠狀病毒肺炎患者；先天遺傳變異；免疫缺陷

新型冠狀病毒(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)是具有外套膜包裹的正鏈單鏈RNA病毒，序列長(zhǎng)度約30 kb，與SARS病毒基因組序列相似度為80%[1]。SARS-CoV-2的結(jié)構(gòu)蛋白包括刺突蛋白、包膜蛋白、膜蛋白和核衣殼蛋白[2]。刺突蛋白包含S1和S2兩個(gè)亞基，S1包含受體結(jié)合區(qū)負(fù)責(zé)識(shí)別宿主細(xì)胞膜受體，S2負(fù)責(zé)病毒與細(xì)胞膜融合[3]。SARS-CoV-2通過(guò)刺突蛋白感染宿主，引發(fā)呼吸系統(tǒng)疾病新型冠狀病毒肺炎(coronavirus disease 2019, COVID-19)[4]。截止到2022年4月23日，世界衛(wèi)生組織報(bào)道全球共有505,817,953人被感染，確認(rèn)死亡人數(shù)高達(dá)6,213,876人。COVID-19患者臨床表現(xiàn)具有明顯的異質(zhì)性。輕癥患者表現(xiàn)出發(fā)燒、咳嗽、乏力等癥狀，多數(shù)患者預(yù)后良好。重癥患者可出現(xiàn)呼吸困難及低血氧等臨床表現(xiàn)。少數(shù)患者可進(jìn)展為危重癥，出現(xiàn)細(xì)胞因子風(fēng)暴導(dǎo)致的急性呼吸窘迫綜合征及多器官功能衰竭，其中重癥監(jiān)護(hù)室治療的危重癥患者死亡率高達(dá)50%[5]。在臨床上需要加強(qiáng)對(duì)SARS-CoV-2感染人群的監(jiān)測(cè)，提供重癥相關(guān)的預(yù)警指標(biāo)，預(yù)防患者(危)重癥化。與重癥相關(guān)的風(fēng)險(xiǎn)因素除年齡、吸煙、高血壓、糖尿病等之外，還有病毒感染者的先天遺傳因素。以往嚴(yán)重的流感病毒(如甲型流感病毒)感染者中，發(fā)現(xiàn)其存在細(xì)胞毒殺傷通路相關(guān)基因先天突變，提示先天遺傳因素在呼吸道病毒感染中發(fā)揮重要作用[6]。COVID-9患者的遺傳易感性包括：基礎(chǔ)疾病相關(guān)基因變異、病毒感染(入侵、復(fù)制、釋放、傳播)及宿主抗病毒免疫應(yīng)答(固有免疫、適應(yīng)性免疫)相關(guān)基因變異等方面。本文將重點(diǎn)關(guān)注病毒感染、宿主抗病毒免疫應(yīng)答過(guò)程中的先天遺傳因素，包括病毒入侵相關(guān)的受體基因、抗原抗體系統(tǒng)相關(guān)的ABO血型、人類白細(xì)胞抗原(human leukocyte antigen, HLA)、I型干擾素信號(hào)通路相關(guān)基因和細(xì)胞因子風(fēng)暴產(chǎn)生相關(guān)基因的關(guān)鍵多態(tài)性位點(diǎn)和先天罕見(jiàn)變異位點(diǎn)，討論了病毒入侵和宿主抗病毒免疫應(yīng)答過(guò)程相關(guān)的遺傳學(xué)研究，梳理了重癥患者可能存在的潛在先天遺傳因素。加強(qiáng)對(duì)SARS-CoV-2感染人群的遺傳學(xué)研究，發(fā)現(xiàn)宿主先天遺傳因素在該疾病發(fā)生、發(fā)展中作用，將有助于闡明重癥化的分子遺傳機(jī)制，進(jìn)而尋找潛在的遺傳標(biāo)志物，為實(shí)現(xiàn)對(duì)重癥高風(fēng)險(xiǎn)人群及早鑒別干預(yù)提供遺傳學(xué)依據(jù)。

1 病毒入侵和宿主抗病毒免疫應(yīng)答過(guò)程

SARS-CoV-2的刺突蛋白與宿主細(xì)胞的血管緊張素轉(zhuǎn)換酶2 (angiotensin-converting enzyme 2, ACE2)受體結(jié)合[7]，位于宿主細(xì)胞膜表面的跨膜絲氨酸蛋白酶2 (transmembrane serine protease 2, TMPRSS2)會(huì)對(duì)其進(jìn)行水解活化[8]。然后病毒通過(guò)膜融合進(jìn)入細(xì)胞質(zhì)，脫殼后釋放RNA，完成感染。在細(xì)胞質(zhì)中，病毒利用宿主細(xì)胞的核糖體進(jìn)行翻譯。SARS-CoV-2感染細(xì)胞后，宿主的固有免疫系統(tǒng)迅速反應(yīng)，參與抗病毒免疫應(yīng)答。主要為中性粒細(xì)胞通過(guò)誘導(dǎo)多種死亡模式殺傷病毒；自然殺傷細(xì)胞(natural killer cell, NK)通過(guò)釋放顆粒酶與穿孔素對(duì)病毒感染細(xì)胞進(jìn)行殺傷；巨噬細(xì)胞對(duì)病毒及其感染細(xì)胞進(jìn)行吞噬[9]。位于細(xì)胞膜表面Toll樣受體(toll-like receptors, TLRs)或者細(xì)胞質(zhì)RIG-I樣受體(retinoic acid-inducible gene I-like receptors, RLRs)等模式識(shí)別受體與SARS- CoV-2的RNA結(jié)合，通過(guò)相應(yīng)的配體β干擾素TIR結(jié)構(gòu)域銜接蛋白(TIR-domain-containing adaptor indu-cing interferon-β, TRIF)、髓樣分化因子88 (myeloid differentiation primary response protein 88, MyD88)和線粒體抗病毒信號(hào)蛋白(mitochondrial antiviral- signaling protein, MAVS)激活下游信號(hào)通路，啟動(dòng)NF-kB信號(hào)通路調(diào)控炎癥因子應(yīng)答，以及活化干擾素調(diào)節(jié)因子3/7 (interferon regulatory factor 3/7, IRF3/7)促進(jìn)I型干擾素表達(dá)[10]。I型干擾素抑制病毒復(fù)制，且能夠結(jié)合相鄰細(xì)胞表面的干擾素α/β受體1/2 (interferon alpha/beta receptor 1/2, IFNAR1/2)，激活下游JAK-STAT信號(hào)通路，促進(jìn)干擾素刺激基因表達(dá)[11]。干擾素刺激基因可抑制病毒復(fù)制。

宿主的適應(yīng)性免疫應(yīng)答在抗病毒感染中起重要作用。B細(xì)胞攝取病毒感染細(xì)胞的抗原后，可分化為能夠合成和分泌抗體殺傷病毒感染的漿細(xì)胞，也可以將抗原呈遞給T細(xì)胞。T細(xì)胞識(shí)別抗原呈遞細(xì)胞加工處理的抗原之后，進(jìn)行增殖和分化，可分化為細(xì)胞毒性T細(xì)胞(cytotoxic T lymphocyte, CTL)。CTL釋放顆粒酶和穿孔素殺傷病毒感染的細(xì)胞，以此清除病毒感染細(xì)胞[12]。在宿主抗病毒免疫應(yīng)答過(guò)程中，如果SARS-CoV-2無(wú)法及時(shí)被清除，會(huì)持續(xù)刺激免疫細(xì)胞(巨噬細(xì)胞、NK細(xì)胞、T細(xì)胞等)釋放大量炎性細(xì)胞因子(白介素、干擾素、趨化因子等)，進(jìn)而吸引更多的免疫細(xì)胞形成反饋循環(huán)，產(chǎn)生細(xì)胞因子風(fēng)暴[13]。大量炎性細(xì)胞因子聚集于肺泡，并且破壞血管使得體液和血細(xì)胞進(jìn)入肺泡，導(dǎo)致水腫和急性呼吸窘迫綜合征，加重患者病情[14]。細(xì)胞因子風(fēng)暴常發(fā)生在危重癥患者中，例如中國(guó)武漢一項(xiàng)COVID-19患者臨床特征研究發(fā)現(xiàn)危重癥患者血漿中存在高表達(dá)水平的多種炎性細(xì)胞因子[15]。圖1匯總了上述病毒的入侵和宿主的抗病毒免疫應(yīng)答過(guò)程，以及涉及到的重要基因。

研究表明COVID-19的易感性和嚴(yán)重程度會(huì)受到宿主先天遺傳因素的影響。解析重癥COVID-19患者的遺傳基礎(chǔ)可對(duì)其發(fā)病遺傳機(jī)制和精準(zhǔn)治療提供新思路。篩選潛在的重癥感染遺傳標(biāo)志物，這將有助于疾病的及早發(fā)現(xiàn)和進(jìn)行風(fēng)險(xiǎn)分層。研究者發(fā)現(xiàn)COVID-19與多個(gè)基因上的突變/多態(tài)性位點(diǎn)相關(guān)聯(lián)，例如病毒入侵相關(guān)的基因、ABO血型、HLA、I型干擾素信號(hào)通路和細(xì)胞因子風(fēng)暴產(chǎn)生相關(guān)基因(表1)。

2 病毒入侵相關(guān)基因ACE2和TMPRSS2的遺傳變異研究

SARS-CoV-2感染宿主需要經(jīng)過(guò)兩個(gè)步驟，首先病毒的刺突蛋白受體結(jié)合區(qū)與ACE2氨基末端催化結(jié)構(gòu)域結(jié)合，隨后TMPRSS2水解活化病毒刺突蛋白誘導(dǎo)其與宿主細(xì)胞膜融合[8]。ACE2是細(xì)胞表面的功能性受體，在心臟、腎臟和肺等組織中高表達(dá)，這些靶器官都可能成為病毒感染和疾病進(jìn)展的場(chǎng)所[16]。已有研究表明基因的多態(tài)性和高血壓的發(fā)生相關(guān)，重癥COVID-19患者常伴有高血壓等基礎(chǔ)疾病，人群中基因多態(tài)性可能與COVID-19易感性和嚴(yán)重程度有一定的關(guān)聯(lián)性[17]。Horowitz等[18]通過(guò)整合4個(gè)歐美人群的基因組數(shù)據(jù)，利用2,630個(gè)COVID-19患者和704,016健康人數(shù)據(jù)進(jìn)行全基因組關(guān)聯(lián)分析，發(fā)現(xiàn)COVID-19人群攜帶基因的rs190509934多態(tài)性位點(diǎn)比例較低(=4.5×10?13)。在COVID-19患者中，攜帶rs190509934的患者重癥風(fēng)險(xiǎn)較低(風(fēng)險(xiǎn)比為0.69)[18]。對(duì)2035例樣本的肝組織轉(zhuǎn)錄組數(shù)據(jù)分析發(fā)現(xiàn)基因的rs190509934多態(tài)性位點(diǎn)顯著降低的表達(dá)，可提供對(duì)SARS- CoV-2感染的保護(hù)，并且與疾病嚴(yán)重程度相關(guān)[18]。Benetti等[19]整合5個(gè)中心的6,930名對(duì)照意大利人的外顯子測(cè)序數(shù)據(jù)，發(fā)現(xiàn)基因的rs41303171多態(tài)性位點(diǎn)出現(xiàn)在歐洲人群(頻率為0.011)，幾乎不出現(xiàn)在東亞人群。通過(guò)模擬分析預(yù)測(cè)rs41303171多態(tài)性位點(diǎn)影響ACE2蛋白的結(jié)構(gòu)和穩(wěn)定性，造成TMPRSS2無(wú)法水解活化病毒刺突蛋白和ACE2結(jié)合體，影響病毒進(jìn)入細(xì)胞的過(guò)程[19]。上述基因的多態(tài)性位點(diǎn)影響表達(dá)或蛋白結(jié)構(gòu)，可能影響病毒入侵過(guò)程，對(duì)病毒感染風(fēng)險(xiǎn)和疾病的嚴(yán)重程度有一定貢獻(xiàn)?；蛲蛔?cè)贑OVID-19的發(fā)生過(guò)程中同樣起到重要作用。Andolfo等[20]對(duì)歐洲6,406個(gè)COVID-19患者和902,088健康人數(shù)據(jù)進(jìn)行全基因組關(guān)聯(lián)分析，發(fā)現(xiàn)COVID-19人群攜帶基因的rs12329760多態(tài)性位點(diǎn)比例較低(=3.13×10?6)?；虻膔s12329760多態(tài)性位點(diǎn)位于編碼區(qū)。該位點(diǎn)可能降低TMPRSS2蛋白質(zhì)穩(wěn)定性，影響與ACE2的結(jié)合，進(jìn)而抑制病毒的入侵，是保護(hù)性位點(diǎn)[20]。Wang等[21]對(duì)332例無(wú)癥狀和重癥COVID- 19患者進(jìn)行全外顯子測(cè)序，發(fā)現(xiàn)基因的rs12329760多態(tài)性位點(diǎn)在重癥患者中頻率較低，提示該位點(diǎn)可能影響COVID-19患者疾病的嚴(yán)重程度?；虻膔s12329760多態(tài)性位點(diǎn)在東亞人(頻率為0.384)和歐洲人(頻率為0.232)頻率的差異，可能與意大利患者發(fā)病率和死亡率較高相關(guān)[22]。由此可見(jiàn)，和基因的多態(tài)性位點(diǎn)在不同種族發(fā)生頻率具有差異，這提示不同種族人群感染SARS-CoV-2的遺傳多態(tài)性位點(diǎn)存在區(qū)別。

圖1 宿主抗新型冠狀病毒免疫應(yīng)答機(jī)制

SARS-CoV-2通過(guò)刺突蛋白與宿主的ACE2受體結(jié)合，經(jīng)宿主的TMPRSS2水解活化后，進(jìn)入宿主細(xì)胞釋放RNA。宿主通過(guò)模式識(shí)別受體識(shí)別病毒RNA，通過(guò)相應(yīng)的配體激活下游信號(hào)通路，促進(jìn)炎癥因子和干擾素的表達(dá)，觸發(fā)抗病毒免疫應(yīng)答。I型干擾素可作用于具有相應(yīng)受體的相鄰細(xì)胞，并且激活下游的JAK-STAT信號(hào)通路，促進(jìn)干擾素刺激基因表達(dá)。干擾素刺激基因可抑制病毒復(fù)制、組裝等過(guò)程。在宿主抗病毒免疫過(guò)程中，NK或T細(xì)胞可通過(guò)細(xì)胞毒殺傷過(guò)程消滅病毒感染的細(xì)胞。如果上述過(guò)程出現(xiàn)缺陷，病毒無(wú)法及時(shí)被清除，會(huì)持續(xù)刺激免疫細(xì)胞。聚集的免疫細(xì)胞釋放大量炎性細(xì)胞因子，產(chǎn)生細(xì)胞因子風(fēng)暴破壞肺組織。根據(jù)參考文獻(xiàn)[49]修改繪制。

表1 重癥COVID-19相關(guān)基因匯總

3 ABO血型相關(guān)的遺傳變異研究

A、B、O、AB四種遺傳表型是根據(jù)紅細(xì)胞表面抗原的低聚糖結(jié)構(gòu)決定，A型血的寡糖序列末端殘基是N-乙酰半乳糖胺，B型血是半乳糖，O型血缺少這兩種殘基，AB型血兩種殘基都存在[23]。在血液中天然存在ABO抗原的對(duì)應(yīng)抗體：A血型血清中存在抗B抗體；B血型血清中存在抗A抗體；O血型血清中存在抗A和抗B抗體；AB血型不存在相應(yīng)的抗體。血型天然抗體主要是IgM (Immunog-lobulin M)，IgM也是抗病毒免疫應(yīng)答中最早出現(xiàn)的抗體，當(dāng)前研究顯示感染性疾病與血型之間存在關(guān)聯(lián)[24]。COVID-19發(fā)生也可能與ABO血型有一定的關(guān)聯(lián)性[25]。Zhao等[26]統(tǒng)計(jì)中國(guó)武漢市3694健康對(duì)照和1775名COVID-19患者的ABO血型人群占比，發(fā)現(xiàn)COVID-19患者中A型血占比顯著高于正常人，O型血占比顯著低于對(duì)照人群，可能與血型天然抗體有關(guān)，提示不同ABO血型人群感染SARS-CoV-2的風(fēng)險(xiǎn)存在差異。一項(xiàng)研究對(duì)意大利和西班牙1980例重癥COVID-19患者和2381名對(duì)照個(gè)人進(jìn)行全基因組關(guān)聯(lián)分析，發(fā)現(xiàn)9q34.2位點(diǎn)rs657152與重癥感染顯著相關(guān)(<5×10?8)[27]?；蜃?q34.2處共有38個(gè)顯著相關(guān)的變異位點(diǎn)，與ABO血型相關(guān)的位點(diǎn)重合。矯正性別和年齡發(fā)現(xiàn)A型血的人群重癥風(fēng)險(xiǎn)高(風(fēng)險(xiǎn)比為1.45)，O型血的人群重癥風(fēng)險(xiǎn)低(風(fēng)險(xiǎn)比為0.65)[27]。抗A抗體可以干擾病毒與宿主細(xì)胞的粘附，從而阻止病毒刺突蛋白與細(xì)胞表面ACE2之間的相互作用，提示A血型人群可能更易感染病毒[28]。A抗原可引起更多的P-選擇素和粘附分子附著于內(nèi)皮細(xì)胞增加心血管疾病的風(fēng)險(xiǎn)[29]。上述研究表明A型血人群SARS-CoV-2感染及重癥風(fēng)險(xiǎn)較高，O型血相對(duì)風(fēng)險(xiǎn)較低，ABO血型可能作為COVID-19患者易感性和嚴(yán)重程度的標(biāo)志物。

4 白細(xì)胞抗原HLA相關(guān)的遺傳變異研究

HLA在抗病毒免疫的過(guò)程中起著重要的作用，主要分為內(nèi)源性抗原的遞呈分子HLA-I (HLA-A、HLA-B和HLA-C)和外源性抗原的遞呈分子HLA-II (HLA-DP、HLA-DQ和HLA-DR)[30]。HLA相關(guān)基因的多態(tài)性與SARS-CoV-2感染和嚴(yán)重程度之間的關(guān)聯(lián)在多項(xiàng)研究中被報(bào)道。Wang等[21]對(duì)比了69例重癥和215例輕癥COVID-19中國(guó)患者的HLA等位基因頻率，發(fā)現(xiàn)I類分子HLA-A*11:01(=0.008512)、HLA-B*51:01 (=0.007017)和HLA-C*14:02 (= 0.003028)顯著富集于重癥患者，也發(fā)現(xiàn)II類分子HLA-DRB1*14:04 (=0.01027)和HLA-DQA1*01:01 (=0.03947)顯著富集于重癥患者，提示這些位點(diǎn)是重癥COVID-19患者的風(fēng)險(xiǎn)位點(diǎn)。其中HLA-B*51:01與自身免疫性疾病的發(fā)生相關(guān)，這提示該位點(diǎn)相關(guān)的宿主免疫應(yīng)答異?？赡苁菍?dǎo)致患者不良臨床結(jié)局的原因[21]。Weiner等[31]整合了4個(gè)歐美國(guó)家的435個(gè)患者的基因組數(shù)據(jù)進(jìn)行薈萃分析，發(fā)現(xiàn)HLA-C*04:01 (=0.0074)為重癥COVID-19患者的風(fēng)險(xiǎn)位點(diǎn)，并且進(jìn)行了獨(dú)立驗(yàn)證。攜帶HLA-C*04:01的患者HLA結(jié)合親和力較低，導(dǎo)致患者對(duì)病毒免疫應(yīng)答能力下降，這可能是攜帶HLA-C*04:01的患者嚴(yán)重臨床結(jié)局的潛在生物學(xué)解釋[31]。Novelli等[32]通過(guò)對(duì)比99例意大利患者和1017健康人群HLA的多態(tài)性發(fā)現(xiàn)HLA-DRB1*15:01 (=0.0015)、HLA-DQB1*06:02 (=0.0001)和HLA-B*27:07 (=0.00001)顯著性富集于COVID-19患者中，提示HLA的多態(tài)性位點(diǎn)和SARS-CoV-2感染相關(guān)。HLA等位基因的頻率可能是COVID-19嚴(yán)重程度的潛在標(biāo)志物。值得注意的是，不同人群觀察到HLA等位基因頻率不同，仍需要大規(guī)模的人群驗(yàn)證才能針對(duì)不同的人群進(jìn)行精準(zhǔn)治療，相應(yīng)的人群設(shè)計(jì)相應(yīng)的SARS-CoV-2疫苗，有利于增強(qiáng)人群抵抗力。

5 I型干擾素抗病毒應(yīng)答相關(guān)基因遺傳變異研究

I型干擾素通路在宿主抗SARS-CoV-2免疫應(yīng)答中起重要作用。SARS-CoV-2感染后，宿主免疫細(xì)胞通過(guò)模式識(shí)別受體識(shí)別SARS-CoV-2響應(yīng)病毒感染，促進(jìn)I型干擾素的表達(dá)，進(jìn)而啟動(dòng)JAK-STAT信號(hào)通路誘導(dǎo)干擾素刺激基因的表達(dá)，實(shí)現(xiàn)抗病毒的功能[33]。參與病毒識(shí)別功能的基因包括、、等，調(diào)節(jié)干擾素生成相關(guān)基因包括和等，參與抗病毒功能的基因包括、和JAK-STAT信號(hào)通路相關(guān)基因，這些基因的先天突變可能影響重癥COVID-19患者抗病毒免疫應(yīng)答。一項(xiàng)COVID-19患者家系研究發(fā)現(xiàn)兩個(gè)重癥COVID-19年輕男性患者中分別攜帶基因的先天移碼突變(c.2129_2132del;p.[Gln710Argfs*18])和錯(cuò)義突變(c.2383G>T;p.[Val795Phe])[34]。攜帶上述基因突變的重癥患者，其外周血單核細(xì)胞中基因表達(dá)低。對(duì)突變的重癥患者和非SARS-CoV-2感染者的外周血單核細(xì)胞進(jìn)行對(duì)比分析，發(fā)現(xiàn)在TLR7激活劑處理下，重癥患者的I型干擾素相關(guān)基因、未發(fā)生顯著上調(diào)[34]。這提示發(fā)生失活突變后，未能啟動(dòng)I型干擾素反應(yīng)。失活突變與干擾素應(yīng)答功能受損相關(guān)，這為理解重癥新冠病毒患者的致病機(jī)制提供新視角。Zhang等[35]通過(guò)對(duì)比659例重癥COVID-19患者和534名輕癥或無(wú)癥狀患者基因組先天突變，發(fā)現(xiàn)3.5%重癥COVID-19患者存在I型干擾素途徑相關(guān)基因(等)先天突變，同時(shí)在等I型干擾素途徑相關(guān)基因突變的細(xì)胞系中發(fā)現(xiàn)等基因表達(dá)較低，且產(chǎn)生干擾素水平較低，更容易感染病毒。與輕癥或無(wú)癥狀患者相比，重癥COVID-19患者存在多種I型干擾素途徑相關(guān)基因缺陷，這提示I型干擾素異常與重癥疾病發(fā)生相關(guān)。當(dāng)前基于SARS-CoV-2重癥感染家系研究以及疾病–對(duì)照研究中發(fā)現(xiàn)I型干擾素抗病毒應(yīng)答的罕見(jiàn)突變，這些基因先天突變與疾病的嚴(yán)重程度具有密切關(guān)系，將為臨床風(fēng)險(xiǎn)分層提供遺傳學(xué)依據(jù)。

6 炎癥因子風(fēng)暴相關(guān)基因遺傳變異研究

重癥COVID-19患者促炎性細(xì)胞因子IL-6、TNF-α等顯著升高，呈現(xiàn)出細(xì)胞因子風(fēng)暴的特征[36]。目前細(xì)胞因子風(fēng)暴被認(rèn)為是急性呼吸窘迫綜合征和多器官衰竭的主要原因之一[37]，有效抑制細(xì)胞因子風(fēng)暴是防止COVID-19患者病情惡化和挽救患者生命的重要途徑。COVID-19患者和噬血細(xì)胞綜合征(hemophagocytic lymphohistiocytosis, HLH)患者的臨床特征、免疫學(xué)和組織病理學(xué)數(shù)據(jù)有相似之處，存在共同的炎癥分子機(jī)制[38]。已有研究表明EB病毒感染是HLH發(fā)生的關(guān)鍵因素，原發(fā)性免疫相關(guān)基因缺陷可能會(huì)引發(fā)EB病毒相關(guān)的噬血細(xì)胞綜合征[39]。攜帶HLH易感基因缺陷的患者在SARS-CoV-2感染下也有可能觸發(fā)炎癥因子風(fēng)暴，包括、、、、、等基因的先天突變[40]。Luo等[41]通過(guò)對(duì)233例不同臨床表現(xiàn)的COVID-19患者進(jìn)行全外顯子測(cè)序，發(fā)現(xiàn)高細(xì)胞因子水平患者顯著富集HLH相關(guān)基因和上的先天突變。攜帶和基因突變的患者重癥率和死亡率較高[41]。上述突變均位于基因的保守結(jié)構(gòu)域，被預(yù)測(cè)可能損害蛋白的結(jié)構(gòu)，進(jìn)而影響基因功能。這兩個(gè)基因功能異常導(dǎo)致患者細(xì)胞毒殺傷功能缺陷，無(wú)法有效清除病毒，引起宿主免疫系統(tǒng)過(guò)度激活。諸如HLH相關(guān)基因類似的免疫缺陷基因的先天突變，可能是重癥COVID-19患者產(chǎn)生炎癥因子風(fēng)暴的關(guān)鍵遺傳因素。這提示盡早檢測(cè)感染者是否存在免疫缺陷對(duì)重癥COVID-19早期診斷和有效治療具有重要的指導(dǎo)意義。

7 結(jié)語(yǔ)與展望

先天遺傳因素在疾病發(fā)生發(fā)展中的作用值得被關(guān)注。原發(fā)性免疫缺陷人群對(duì)病毒抵抗力差并更易引發(fā)嚴(yán)重的病毒感染相關(guān)疾病。在重癥COVID-19人群中同樣發(fā)現(xiàn)干擾素信號(hào)通路、NK/T細(xì)胞毒殺傷功能相關(guān)基因發(fā)生先天變異，并且細(xì)胞毒殺傷功能基因異常顯著出現(xiàn)于細(xì)胞因子表達(dá)水平高的重癥感染者中。上述研究均提示抗病毒免疫功能先天缺陷/失調(diào)增加個(gè)體成為重癥/危重癥感染者的風(fēng)險(xiǎn)。關(guān)注重癥感染者先天遺傳基礎(chǔ)的研究日益增加，這將對(duì)未來(lái)防治危重癥新冠感染提供遺傳學(xué)依據(jù)。目前，已篩選出的候選基因/位點(diǎn)尚未開展深入的分子機(jī)制探索和功能性驗(yàn)證；如對(duì)候選基因的精細(xì)作用機(jī)理進(jìn)一步探索，將有助于理解免疫系統(tǒng)在抗冠狀病毒感染的關(guān)鍵節(jié)點(diǎn)并提供潛在的分子治療靶點(diǎn)。同時(shí)，仍需要基于獨(dú)立人群的大樣本驗(yàn)證已知的候選基因，進(jìn)一步明確關(guān)鍵的候選變異基因/位點(diǎn)[42]。各項(xiàng)研究所鑒定的與疾病關(guān)聯(lián)性關(guān)鍵基因涉及到SARS-CoV-2入侵相關(guān)基因和、ABO血型、白細(xì)胞抗原HLA、干擾素應(yīng)答相關(guān)基因TLRs、細(xì)胞毒殺傷通路基因等。如何整合上述突變基因信息、并結(jié)合已有其他SARS-CoV-2感染人群?jiǎn)渭?xì)胞圖譜[43]，逐步構(gòu)建系統(tǒng)性和綜合性的SARS-CoV-2感染相關(guān)基因知識(shí)庫(kù)，仍是值得研究者思考的科學(xué)問(wèn)題。綜合利用上述信息，將有助于應(yīng)對(duì)SARS-CoV-2及日后可能出現(xiàn)的其他冠狀病毒流行性疾病。

基于現(xiàn)有研究，病毒入侵相關(guān)基因多態(tài)性位點(diǎn)發(fā)生頻率呈現(xiàn)出種族差異性[22]。這提示遺傳學(xué)研究以及鑒定關(guān)鍵候選基因，需考慮人種差異。出現(xiàn)SARS-CoV-2無(wú)癥狀感染的免疫機(jī)理、無(wú)癥狀感染人群是否存在特異性的免疫基因先天變異同樣是值得進(jìn)一步探討和研究的方向。

SARS-CoV-2的變異毒株Delta和Omicron相繼出現(xiàn)，病毒的傳播效率越來(lái)越高，這種演化路徑在流感病毒中很常見(jiàn)；在日后，SARS-CoV-2有可能成為一種類似于流感病毒的地方性流行病毒[44,45]。與Delta相比，Omicron變異毒株感染后，無(wú)癥狀或輕癥感染者比例增高[46,47]，但是仍有21%的Omicron變異毒株感染導(dǎo)致的住院患者存在嚴(yán)重的臨床結(jié)局[48]。這提示早發(fā)現(xiàn)SARS-CoV-2重癥感染者仍是公共衛(wèi)生領(lǐng)域值得重視的問(wèn)題之一。探索與COVID-19嚴(yán)重程度相關(guān)的先天遺傳因素十分重要，鑒別高風(fēng)險(xiǎn)人群有助于降低住院率和重癥死亡率，為國(guó)家醫(yī)療事業(yè)減輕負(fù)擔(dān)。

綜上所述，遺傳學(xué)是SARS-CoV-2以及其他冠狀病毒感染中不容忽視的研究方向。個(gè)體免疫系統(tǒng)先天遺傳差異將影響病毒感染及疾病發(fā)展程度。綜合現(xiàn)有臨床指標(biāo)并結(jié)合遺傳學(xué)指征，將為未來(lái)實(shí)現(xiàn)早期甄別高危感染人群、及早干預(yù)、精準(zhǔn)分層治療提供新的思路。

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Genetic predisposition in patients with severe COVID-19

Wenbing Liu1,2, Dan Liu1, Jin Yan1, Xin Liu1,2, Qianfei Wang1,2

The coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. COVID-19 has a variety of clinical manifestations, ranging from asymptomatic infection or mild symptoms to severe symptoms. Severe COVID-19 patients experience cytokine storm, resulting in multi-organ failure and even death. Male gender, old age, and pre-existing comorbidities (such as hypertension and diabetes ) are risk factors for COVID-19 severity. Recently, a series of studies suggested that genetic defects might also be related to disease severity and the cytokine storm occurence. Genetic variants in key viral immune genes, such asandhave been identified in severe COVID-19 patients from previous reports. In this review, we summarize the mechanisms underlying immune responses against SARS-CoV-2 and genetic variants that associated with the severity of COVID-19. The study of genetic basis of COVID-19 will be of great benefit for early disease detection and intervention.

severe COVID-19 patients; germline variants; immunodeficiency

2022-03-06;

2022-05-25;

2022-06-10

北京市自然科學(xué)基金資助項(xiàng)目(編號(hào)：M21022)[Supported by Beijing Natural Science Foundation (No. M21022)]

劉文兵，在讀博士研究生，研究方向：遺傳學(xué)。E-mail: liuwenbing@big.ac.cn

王前飛，博士，研究員，研究方向：白血病基因組學(xué)。E-mail: wangqf@big.ac.cn

10.16288/j.yczz.22-058

(責(zé)任編委: 岑山)