慢性阻塞性肺疾病全基因组关联研究进展

钱国清

综 述

慢性阻塞性肺疾病全基因组关联研究进展

钱国清1,2,3

1. 宁波大学附属宁波市第一医院内科，宁波 315010 2. 浙江大学宁波医院呼吸科，宁波 315010 3. 英国诺丁汉大学医学院，诺丁汉 NG7 2RD

慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是一种以不完全可逆的气流受限为主要特征的慢性气道炎症，是一种由遗传因素和环境因素共同作用的复杂疾病，也是世界主要致死疾病之一。近年来，随着全基因组关联研究(genome-wide association study, GWAS)的不断深入，研究者们发现了大量与肺功能或COPD相关的遗传变异或基因位点、药物靶点等。本文综述了2007年以来世界范围内针对肺功能或COPD的GWAS方面的研究工作及其进展综述，分析了可能存在的药物靶点，并探讨了COPD在全基因组关联研究中面临的挑战和困难，为深入研究COPD发病机制提供新思路。

慢性阻塞性肺疾病；肺功能；全基因组关联研究；遗传变异；基因座；易感基因；致病基因

慢性阻塞性肺疾病(chronic obstructive pulmo­nary disease, COPD)是一种以气流受限为主要特征的慢性气道炎症。肺功能检查可评估COPD气流受限程度，当吸入支气管扩张剂后，第一秒用力呼气容积(forced expiratory volume in one second, FEV1)和用力肺活量(forced vital capacity, FVC)之间比值<0.7表明存在持续气流受限，排除其他疾病后，可确诊COPD。因此，肺功能是诊断COPD的金标准[1]。据报道我国40岁以上人群COPD患病率高达13.7%，总人数近1亿[2]。2015年，全球预计有320万人死于COPD，其中中国有100多万[3]；根据世界卫生组织预测，至2020年COPD将成为全球第3大致死疾病[4]。吸烟、空气污染、职业暴露等多种因素均可导致COPD，其中吸烟患者仅有10%~20%发展成为COPD[5]，然而25%的COPD患者终生不吸烟[6]，因此表明，COPD是遗传因素与环境因素共同作用的结果。近年，随着全基因组关联研究(genome-wide association study, GWAS)在肺功能和COPD中的应用，发现了大量易感基因(susceptibility gene)或基因座(locus)，为进一步阐述COPD的发病机制提供了全新的思路。

GWAS研究是在一定人群中选择病例组和对照组，基于单核苷酸多态性(single nucleotide polymor­phism, SNP)作为分子遗传标记，比较全基因组范围内所有SNP位点的等位基因或基因型频率在病例组和对照组间的差异；然后，利用连锁不平衡关系推测可能的疾病或性状的易感基因或区域，从而寻找与疾病发生相关的致病位点。随着人类基因组计划和基于SNP的国际人类单体型图谱(HapMap)构建完成，GWAS得以实现并被广泛应运于糖尿病、精神分裂症和哮喘等疾病[7,8]。经典的GWAS通过建立全基因组高频遗传变异与表型的关联，进行多阶段设计的病例对照研究，并将多个研究结果合并验证。GWAS中<5.0´10–8的SNP位点才被认为具有全基因组水平阳性。从2005年首次发表年龄相关性视网膜黄斑变性的GWAS以来，至今已经发表数千项常见复杂性疾病或性状的研究。2007年来，肺功能和COPD相关GWAS研究层出不穷，特别是COPD遗传流行病学(COPD genetic epidemiology, COPDGene)和英国生物标本库(UK Biobank)等大样本研究，极大地推动了COPD发病机制和寻找有效药物靶点的研究。利用GWAS手段探讨呼吸系统疾病，特别是鉴定COPD的潜在致病基因非常重要：(1)可以更加全面地了解疾病发展和呼吸道正常病理生理功能；(2)有利于根据确定的药物靶标研发新的治疗策略；(3)通过确定一系列风险性和安全性遗传变异，可改善风险评估预防疾病，或者做出更早、更准确的诊断；(4)利用遗传信息将疾病分为不同表型或亚型；(5)利用遗传信息数据，使患者药物治疗获益更多、副作用更少，推动药物遗传学发展[9]。截至2019年11月21日，通过查询NHGS-GWAS catalog (https://www.ebi.ac.uk/gwas/)网站发现，共有4200余篇文章涉及COPD，有近40项肺功能或COPD的GWAS队列研究，发现大量SNPs与肺功能或COPD相关(图1，图2)。本文将从GWAS与肺功能、GWAS与COPD及COPD亚型的关系进行阐述，并介绍基于GWAS的COPD药物研发，以期为COPD基因和基因组学研究提供参考。

1 GWAS与肺功能

肺功能检测是诊断COPD的必备条件。据报道，COPD与FEV1和FVC的遗传相关性分别为−0.76和−0.9[10]；在欧洲和美国的双胞胎研究中发现，FEV1的遗传力估计达0.77[11]。随着研究的深入，发现肺功能和COPD两者均具有相关性的易感基因位点。Hall等[12]通过文献复习发现28个易感基因位点同时与肺功能和COPD相关(表1)。Wain等[13]分析发现在97个与肺功能相关的致病基因中，95个与COPD有关。这些重叠的遗传变异/致病基因进一步确认了基因座与疾病的相关性，并预计其可能发挥重要的病理生理功能。因此，基于肺功能的GWAS可发现更多致病基因，对于揭示COPD发病机制具有很好的科学意义。

Wilk等[14]于2007年在美国雷明汉心脏研究中心开展了第1项肺功能GWAS研究，该研究涉及10项肺功能测量(表2)和70,987个常染色体SNP，提示和是与肺功能相关的基因。2009年，他和同事又在7691名参与者中研究表型FEV1/FVC，发现在4q31区域上有4个SNP与FEV1/FVC相关，其中SNP rs13147758还与家系的FEV1/FVC显著相关；这些SNPs均与基因靠近[15]。由此，他们认为4号染色体区域具有影响肺功能的遗传效应，值得进一步研究。

图1 与肺功能(Pulmonary function measurement)相关SNPs分布图

以关键词“pulmonary function measurement”使用NHGS-GWAS catalog (https://www.ebi.ac.uk/gwas/)查询获得相关研究109项、相关SNPs 6306个。其中rs6828540(位于Chr.4:144542079，定位基因AC098588.1、AC098588.2)的值最显著。数据查询截至2020年6月4日。

图2 与COPD相关的SNPs点状分布图

以关键词“chronic obstructive pulmonary disease”使用NHGS-GWAS catalog (https://www.ebi.ac.uk/gwas/)查询，共获得相关研究51项、相关SNPs 1076个。其中rs13140176(位于Chr.4:144567946，风险等位基因A，定位基因AC098588.1、AC098588.2)的值最显著。数据查询截至2020年6月4日。

随着meta分析的应用，更多与肺功能相关变异位点被确定。2010年，Hancock等[16]对4个组群(Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Rotterdam Study (RS)) (Cohorts for Heart and Aging Research in Genomic Epidemiology consortium study, CHARGE研究)的20,890名欧洲后裔meta分析，明确8个与FEV1/FVC相关的基因变异位点(、、、、、、和)及1个与FEV1相关的基因位点()。同年，Repapi等[17]对SpiroMeta、CHARGE等研究涉及的74,564名欧洲后裔进行meta分析，明确了5个新的肺功能(FEV1、FEV1/FVC)相关常见变异(com­mon variant)，分别为2q35()、4q24()、5q33 ()、6p21()和15q23()；并在人类肺组织中验证、、、和的mRNA表达。2012年，Hancock等[18]通过meta分析，确定了2个(和)与FEV1/FVC相关、1个()与FEV1相关的新基因座，另外位于、、和、的SNPs与FEV1/FVC或FEV1相关。2014年，Loth等[19]发现6个与肺功能FVC相关的SNPs，并定位于、、、、和；同时，在基于多民族动脉粥样硬化研究(multi-ethnic study of atherosclerosis，MESA)的563名中国裔中未发现有与中国裔肺功能相关的SNPs。

表1 肺功能与COPD重叠致病基因

表2 首项肺功能全基因组关联研究采用的测量指标

上述指标是2007年由Wilk等[14]首次采用，用于评估肺功能测量指标与相关变异位点的相关性。

随着世界最大队列样本库(UK Biobank)的应用，肺功能GWAS研究获得了更多的成果。2017年，Wain等[13]基于UK BiLEVEL的48,943名参与者和第二阶段基于95,375名来自UK Biobank、SpiroMeta和英国家庭纵向研究(UK household longitudinal study, UKHLS)的参与者，发现与肺功能(FEV1、FVC或FEV1/FVC)相关的遗传变异位点从54个增加至97个，其中新发现43个；经富集分析发现该97个遗传变异位点均与发育、弹性纤维和表观遗传学调节通路相关。因此，随着GWAS研究的深入和生物信息学的应用，将会进一步揭示致病基因的生物学功能。

2019年，Shrine等[20]发表了迄今为止样本量最大、相关位点最多的研究，他们发现有257个位点与肺功能(FEV1、FVC、FEV1/FVC和PEF)相关，其中新发现位点139个，共确认107个参与基因表达、蛋白表达和功能注释的致病基因(causal gene) (表3)，8个同时与有害变异(deleterious variant)和表达数量性状基因座(expression quantitative trait locus, eQTL)有关，1个同时与eQTL和蛋白质数量性状基因座(protein quantitative trait locus, pQTL)有关，1个同时与有害变异和pQTL有关，13个仅与有害变异有关，81个与eQTL及3个与pQTL关联。该研究首次利用GWAS发现与最大呼气流量(peak expi­ratory flow，PEF)关联的致病基因，其中有133个位点与PEF相关(<10E-5)，如已经明确与囊性纤维化相关，同时在UK Biobank中发现与PEF高度相关。将致病基因富集分析，发现有部分致病基因参与纤毛生成(ciliogenesis，包括KIAA0753、CDK2和CEP72)过程，提示纤毛功能的损伤与COPD的发生发展密切相关。因此，肺功能的GWAS研究，不仅局限于肺功能的表型研究，同时可揭示COPD的发病机制和病理生理过程，为后续单基因或多基因的基础提供理论基础。

2 GWAS与COPD

虽然肺功能作为检测COPD气流受限的必备手段，但肺功能相关的遗传变异/致病基因与疾病(COPD)是否相关，仍受到人们的质疑。因此，需要对遗传变异与COPD相关性展开GWAS研究。

2009年，Pillai等[32]首次开展COPD的GWAS研究：通过823名COPD患者和810名吸烟者的队列研究，选取前100个SNPs在NETT和NAS研究中验证，发现2个SNPs(rs8034191和rs1051730)位于位点；同时虽未达到基因组关联统计学意义，但也与FEV1/FVC相关；因此，提示和均存在COPD的重要风险位点。2010年，Cho等[33]通过2940名COPD和1380名对照组(两组均为既往或正在吸烟者)，确认rs7671167和rs1903003位于1个新的致病基因(4q22.1)位点。此后陆续有较多COPD的GWAS研究报道，如Van Durme等[34]基于著名的鹿特丹研究，发现了与COPD风险相关；Brehm等[35]研究表明2个SNPs位于，SNP的不同可能与表达有关，肺组织中表达升高与肺功能恶化有关；Castaldi等[23]研究发现32个SNPs位于/靠近17个致病基因，其中11个为既往4项GWAS研究(NETT/NAS、挪威病例对照研究、ECLIPSE、COPDGene)已报道。2012年，Cho等[36]基于4项研究(ECLIPSE、NAS和NETT、GenKOLS、COPDGene)发现了一个位于19q13的新基因座，rs7937和rs2604894与严重COPD相关。2012~2017年间，Wilk等[28]、Hanse等l[37]、Cho等[24]、Dijkstra等[26]、Hardin等[38]及其他研究者[31,39~43]又先后发表了多篇GWAS在COPD中的研究，先后发现、、、和等易感基因与COPD相关。2017年，Hobbs等[10]发现22个与COPD相关的基因座，其中新发现13个基因座(同时包含9个与肺功能相关)，但未发现与哮喘存在基因座重叠。最新研究表明在6p21-22区域、、、和存在COPD与哮喘的共享片段，除外，其余基因座作用方向一致[21]。因此，随着GWAS研究的深入和样本量的增多，COPD相关的致病基因或基因座研究不断取得新进展

表3 107个参与基因表达、蛋白表达和功能注释的致病基因

随后，科学家们又发现了更多的致病基因。Wain等[13]发现的97个致病基因中，51个与COPD定义相关，30个与COPD易感性相关(<5.26´10–4)，但未发现有遗传变异或遗传危险系数与COPD急性发作相关。他们还研究了来自中国慢性病前瞻研究项目协作组(China Kadoorie Biobank cohort, CKB)的7116例COPD (20,919例对照)和5292例急性加重病例(1824 对照组)的71个遗传变异，发现有39个致病基因在欧洲人和中国人样本中作用方向一致，其中7个达到统计学意义(<0.05) (表4)，说明在欧洲人群与中国人群中，某些遗传因素对COPD具有共同的效应，但仍需进一步的实验证明。

2019年，Sakornsakolpat等[21]汇总25项GWAS的35,735例COPD和222,076例对照组，发现82个与肺功能或COPD相关的基因座，其中原有47个、新发现35个；发现156个致病基因位于该82个基因座中，为阐述COPD疾病易感性和临床异质性提供新的视角。35个新基因座中，有9个与Shine等[20]报道相同。包括该82个基因座在内，使用10%的COPD患病率解释了7.0%表型变异(phenotypic variant)，与最近的22个基因座所解释的4.7%相比[10]，所解释的COPD表型变异增加了48%，可能存在一定的效应高估。通过富集分析发现165个基因集的FDR<5%，其中44%与发育过程相关，如肺发育、肺泡发育和肺形态发生等；还有细胞外基质相关途径，及Wnt、SMAD、MAPK等信号通路[21]。因此，进一步支持早期生活事件在COPD患病风险中的关键作用，COPD患病风险的很大一部分可能在生命的早期即已决定，遗传变异可能会决定初始的肺功能和肺生长模式。

目前已进入后GWAS时代，如何实现GWAS成果转化是当前的研究热点。Zhou等[44]使用shRNA干扰表达，发现参与细胞外基质和细胞增殖等过程。COPD易感基因在人类气道和肺脏中均有表达，通过使用基因敲除(Fam13a)小鼠和在人类肺组织中验证，其可通过抑制β-catenin信号通路促进肺气肿形成[45]；另外还在香烟诱导小鼠模型中发现可促进脂肪酸- β氧化(fatty acid β-oxidation, FAO)过程[46]。本课题组也先后进一步阐明了[47~49]、[50]和[51]等易感基因的表达和病理生理功能。通过单个基因或多个基因的细胞模型和/或动物模型试验，为揭示COPD潜在发病机制提供了全新的思路。

3 GWAS与COPD亚型

虽然肺功能是诊断COPD的金标准，然而依赖肺功能检测指标诊断COPD存在明显缺陷，因为COPD的发病机制存在不同的遗传和环境因素，包含不同的病理生理学机制，因此只有研究基于不同遗传背景、环境因素的病理生理相关的亚型才更具有意义。

表4 欧洲人群与中国人群7个作用方向一致的变异位点

*<0.05。

COPD精准治疗需要兼顾亚型和表型，根据分子标志物实现不同亚型的鉴别，实现分层医学(stra­tified medicine)，真正实现个体化和个性化治疗。

4 基于GWAS的COPD药物研发

实现GWAS成果转化可能需要几年甚至十几年的时间，但是基于GWAS靶标设计药物可事半功倍，加速药物研发。目前，共114种临床试验或批准的药物涉及COPD，160个靶标正在开展研究(截至2019年12月15日，https://www.targetvalidation.org/)。比如，由编码的毒蕈碱型乙酰胆碱受体M3是明确的药物靶标，针对该药物靶标已有许多批准的药物，包括用于治疗哮喘和慢性阻塞性肺疾病的药物[13]。编码5-羟色胺受体的在早期的肺功能GWAS中就已被发现。与FVC(和FEV1)相关，编码肌醇多磷酸5磷酸酶E，另一成分磷酸肌醇3激酶(PI3K)δ是正在开发中的COPD和哮喘的药物靶标[13]。

肺组织中的表达减少和COPD风险降低有关，因此，抑制表达可能具有保护性作用。Hedgedog信号通路在肺脏早期发育中发挥重要的作用，其中、和作为该信号通路分子，它们是肺功能相关联的潜在致病基因[61]。另外，据报道新发现有7个与COPD和肺功能相关的可治疗靶标，包括、、、、、和[21]；目前许多靶标仅依赖于细胞模型的初步探索，但其在细胞内或体内的相互作用和效果仍需进一步通过开展临床试验评估。随着后GWAS时代转化研究的深入，必将发现更多的药物靶标及开发新型高效药物提供基础。

5 结语与展望

尽管在COPD中成功地开展了全基因组关联研究，但仍存在如下挑战：(1) GWAS通过病例对照寻找差异SNPs，但大部分SNPs位于非编码区，仅有一部分基因变异与疾病表型相关。(2)通过GWAS识别的遗传变异仅占遗传力的一小部分，已知肺功能信号分别占FEV1、FVC和FEV1 / FVC的遗传力的9.6%、6.4%和14.3%[13]。因此，GWAS仅识别常见变异，而忽略了罕见变异、基因拷贝数量变异等其他类型变异。(3)当前商业化的SNPs芯片多基于高加索人群设计，亟需设计基于亚洲人群遗传多态性的芯片。(4)基于肺功能诊断的COPD，受多种因素的影响，如对样本量、资料收集的完整性、研究对象的选择及诊断方法等。(5)在COPD研究中，大多数研究均聚焦于肺通气功能测量，而非COPD本身，使得在疾病中的应用和转化面临困难。(6)无法完全匹配病例组与对照组参与者，而且COPD患者可能存在多种并发症，如心血管疾病、2型糖尿病等其他疾病。

在欧美等国家，开展了大规模的COPD基因和基因组学研究，但目前国内COPD基因组学研究严重落后，尚无一项特定的针对COPD开展大规模GWAS研究[62]。因此，应该抓住机遇，加强国际合作，建立以中国汉族人群为基础的慢性阻塞性肺疾病全基因组关联研究，利用先进的分子生物学技术，阐明中国人COPD的发病机制、寻找有效治疗靶点、发现新型生物标志物和改善COPD和亚型的预测。推进个性化预防和治疗COPD，降低我国COPD患病率和死亡率，全面提高全民健康水平。

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Advances in genome-wide association study of chronic obstructive pulmonary disease

Guoqing Qian1,2,3

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and chronic airway inflammation, caused by a combination of environmental and genetic factors. It is the third leading cause of death worldwide. In recent years, researchers have applied the genome-wide association study (GWAS) and identified a large number of genetic variants associated with lung functions and potential drug targets for treating COPD. In this review, we summarize the results of GWAS studies and perform a review of the literature since 2007 to highlight the progress of GWAS on COPD. We discuss the challenges, the underlying mechanisms, and the possible drug targets, thereby providing insights on the pathogenesis and potential treatment strategies for COPD.

chronic obstructive pulmonary disease; lung function; genome-wide association study; genetic variant; locus; susceptibility gene; causal gene

2020-02-25;

2020-05-29

浙江省自然科学基金项目(编号：Q17H010001)和宁波市自然科学基金项目(编号：2017A610246)资助[Supported by the Natural Science Foundation of Zhejiang Province (No. Q17H010001), and the Natural Science Foundation of Ningbo City (No. 2017A610246)]

钱国清，博士，副主任医师，研究方向：呼吸病学。E-mail: guoqing.qian@foxmail.com

10.16288/j.yczz.19-381

2020/6/29 11:04:48

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20200628.1028.001.html

(责任编委: 周钢桥)