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Article(id=1240950904866788135, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240950898113966774, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202311231, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1699804800000, receivedDateStr=2023-11-13, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773795351473, onlineDateStr=2026-03-18, pubDate=1712678400000, pubDateStr=2024-04-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773795351473, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773795351473, creator=13701087609, updateTime=1773795351473, updator=13701087609, issue=Issue{id=1240950898113966774, tenantId=1146029695717560320, journalId=1227665162245664772, year='2024', volume='51', issue='7', pageStart='1153', pageEnd='1344', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773795349862, creator=13701087609, updateTime=1773795519367, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240951609136567133, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240950898113966774, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240951609136567134, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240950898113966774, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1166, endPage=1174, ext={EN=ArticleExt(id=1240950905206526768, articleId=1240950904866788135, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=The causal relationship between intervenable risk factors and bronchial asthma by Mendelian randomized analysis, columnId=1240413921954295836, journalTitle=Modern Preventive Medicine, columnName=Epidemiology and Statistical Methods, runingTitle=null, highlight=null, articleAbstract=
Objective

To explore the causal relationship between lifestyle, diet, sleep, socioeconomic status and bronchial asthma by using two-sample Mendelian randomized method.

Methods

Two-sample Mendelian randomization analysis was performed based on inverse variance weighting method (IVW), and the stability and reliability of the results were verified by leaving-one-out method, heterogeneity test, and pleiotropy test.

Results

The results of IVW model showed that smoking (OR=1.17,95%CI: 1.08-1.28), drinking (OR=1.22, 95%CI: 1.05-1.41), sedentary behavior (OR=1.78, 95%CI: 1.38-2.31), sleep duration (OR=2.29, 95%CI: 1.38-2.31), and body mass index (OR=1.41, 95%CI: 1.29-1.53) were associated with the increased risk of bronchial asthma. Fresh fruit intake (OR=0.50, 95%CI: 0.34-0.73), dried fruit intake (OR=0.54, 95%CI: 0.34-0.73), cereal intake (OR=0.62, 95%CI: 0.41-0.94), education level (OR=0.57, 95%CI: 0.34-0.73), and social activity (OR=0.26, 95%CI:0.34-0.73) were associated with reduced risk of asthma. The results of MR-Egger intercept detection did not show pleiotropic effects, indicating that Mendelian randomization was an effective method for causal inference in this study. The heterogeneity test results of drinking (Q=139.92, P=0.001), sedentary behavior (Q=151.37, P=0.003), dried fruit intake (Q=40.00, P=0.007), cereal intake (Q=72.95, P=0.001), and body mass index (BMI) (Q=584.12, P < 0.001) were all statistically significant. Therefore, attention was paid to results of the random effect IVW model.

Conclusion

Smoking, drinking, sedentary behavior, sleep duration, and body mass index may be the risk factors of bronchial asthma. Fresh fruit intake, dried fruit intake, cereal intake, education level, and social activities may be the protective factors of bronchial asthma.

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目的

运用两样本孟德尔随机化（Mendelian randomization，MR）方法探究生活方式、饮食、睡眠及社会经济地位等因素与支气管哮喘的因果关系。

方法

研究主要使用逆方差加权法(IVW)进行两样本MR分析,同时采用留一法、异质性检验、水平基因多效性检验来验证结果的稳定性和可靠性。

结果

IVW模型结果显示吸烟（OR=1.17，95%CI：1.08～1.28）、饮酒（OR= 1.22，95%CI：1.05～1.41）、久坐（OR=1.78，95%CI：1.38～2.31）、睡眠时长（OR=2.29，95%CI：1.38～2.31）、体重指数（OR=1.41，95%CI：1.29～1.53）与支气管哮喘患病风险增加有关。新鲜水果摄入（OR=0.50，95%CI：0.34～0.73）、干果摄入（OR=0.54，95%CI：0.34～0.73）、谷类食物摄入（OR=0.62，95%CI：0.41～0.94）、教育程度（OR=0.57，95%CI：0.34～0.73）、社会活动（OR=0.26，95%CI：0.34～0.73）会降低支气管哮喘的发病风险。ME-Egger截距检测结果不存在多效性，故MR在本研究中为因果推断的有效方法。饮酒（Q=139.92，P=0.001）、久坐（Q=151.37，P=0.003）、干果摄入（Q=40.00，P=0.007）、谷类食物摄入（Q=72.95，P=0.001）、体重指数（Q=584.12，P<0.001）异质性检验结果P值均<0.05，故重点关注随机效应IVW模型。

结论

吸烟、饮酒、久坐、睡眠时长、体重指数可能是支气管哮喘的危险因素。新鲜水果摄入、干果摄入、谷类食物摄入、教育程度、社会活动可能是支气管哮喘的保护因素。

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宁康，E-mail:
, copyrightStatement=本刊刊出的所有文章不代表中华预防医学会和本刊编委会的观点，除非特别声明。, copyrightOwner=中华预防医学会和四川大学华西公共卫生学院, extLink=null, articleAbsUrl=null, sourceXml=Sf6TFPVCCPWuTUYmysSnwQ==, magXml=H/gPpUTRe+GnGPNFJdf+SQ==, pdfUrl=null, pdf=hMTKPZ9ymqQ+lzr9G1kPVA==, pdfFileSize=5346979, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=F9phEhtZxseA5AgU2CF7Ug==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=noQaBvcZnJnlF5D3zN2U7Q==, mapNumber=null, authorCompany=null, fund=null, authors=

常新伟（1999—），男，硕士在读，研究方向：呼吸系统疾病

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常新伟（1999—），男，硕士在读，研究方向：呼吸系统疾病

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常新伟（1999—），男，硕士在读，研究方向：呼吸系统疾病

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注：A～J分别为吸烟、饮酒、久坐、睡眠时长、体重指数、新鲜水果摄入、干果摄入、谷类食物摄入、教育程度、社会活动。

, figureFileSmall=EjSJ/RBilEkGkE3/MoguMA==, figureFileBig=43+TJnY6+h5KaCvnV/mPeg==, tableContent=null), ArticleFig(id=1240972175851713505, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240950904866788135, language=EN, label=Table 1, caption=

Summary of the GWAS included in this study

, figureFileSmall=null, figureFileBig=null, tableContent=
变量IEU GWAS样本量（例）人群性别年份（年）
吸烟idieu-b-142249 752欧洲男性和女性2019
饮酒ukb-b-5779462 346欧洲男性和女性2018
久坐ukb-b-5192437 887欧洲男性和女性2018
适量运动ukb-b-4710440 266欧洲男性和女性2018
新鲜水果摄入ukb-b-3881446 462欧洲男性和女性2018
干果摄入ukb-b-16576421 764欧洲男性和女性2018
咖啡摄入ukb-b-5237428 860欧洲男性和女性2018
茶摄入ukb-b-6066447 485欧洲男性和女性2018
谷类食物摄入ukb-b-15926441 640欧洲男性和女性2018
加工肉类摄入ukb-b-6324461 981欧洲男性和女性2018
失眠ukb-b-3957462 341欧洲男性和女性2018
白天午睡ukb-b-4616462 400欧洲男性和女性2018
打鼾ukb-b-17400430 438欧洲男性和女性2018
睡眠时长ebi-a-GCST003839127 573欧洲男性和女性2016
完成全日制教育时的年龄ukb-b-6134307 897欧洲男性和女性2018
涉及重体力劳动的工作ukb-a-503190 643欧洲男性和女性2017
招募时的汤森德剥夺指数ukb-a-44336 798欧洲男性和女性2017
社会活动ukb-b-4171461 369欧洲男性和女性2018
体重指数ukb-b-19953461 460欧洲男性和女性2018
支气管哮喘finn-b-J10_ASTHMA156 078欧洲男性和女性2021
), ArticleFig(id=1240972175935599590, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240950904866788135, language=CN, label=表1, caption=

MR研究中GWAS数据库的简要信息

, figureFileSmall=null, figureFileBig=null, tableContent=
变量IEU GWAS样本量（例）人群性别年份（年）
吸烟idieu-b-142249 752欧洲男性和女性2019
饮酒ukb-b-5779462 346欧洲男性和女性2018
久坐ukb-b-5192437 887欧洲男性和女性2018
适量运动ukb-b-4710440 266欧洲男性和女性2018
新鲜水果摄入ukb-b-3881446 462欧洲男性和女性2018
干果摄入ukb-b-16576421 764欧洲男性和女性2018
咖啡摄入ukb-b-5237428 860欧洲男性和女性2018
茶摄入ukb-b-6066447 485欧洲男性和女性2018
谷类食物摄入ukb-b-15926441 640欧洲男性和女性2018
加工肉类摄入ukb-b-6324461 981欧洲男性和女性2018
失眠ukb-b-3957462 341欧洲男性和女性2018
白天午睡ukb-b-4616462 400欧洲男性和女性2018
打鼾ukb-b-17400430 438欧洲男性和女性2018
睡眠时长ebi-a-GCST003839127 573欧洲男性和女性2016
完成全日制教育时的年龄ukb-b-6134307 897欧洲男性和女性2018
涉及重体力劳动的工作ukb-a-503190 643欧洲男性和女性2017
招募时的汤森德剥夺指数ukb-a-44336 798欧洲男性和女性2017
社会活动ukb-b-4171461 369欧洲男性和女性2018
体重指数ukb-b-19953461 460欧洲男性和女性2018
支气管哮喘finn-b-J10_ASTHMA156 078欧洲男性和女性2021
), ArticleFig(id=1240972176032068589, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240950904866788135, language=EN, label=Table 2, caption=

Cochran Q test results

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暴露因素Cochran Q值P值
吸烟31.6760.063
饮酒139.9170.001
久坐151.3650.003
新鲜水果摄入62.1590.158
干果摄入40.0000.007
谷类食物摄入72.9530.001
睡眠时长0.4390.803
教育程度52.6250.058
社会活动8.3490.870
体重指数584.121<0.001
), ArticleFig(id=1240972176128537590, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240950904866788135, language=CN, label=表2, caption=

Cochran Q检验结果

, figureFileSmall=null, figureFileBig=null, tableContent=
暴露因素Cochran Q值P值
吸烟31.6760.063
饮酒139.9170.001
久坐151.3650.003
新鲜水果摄入62.1590.158
干果摄入40.0000.007
谷类食物摄入72.9530.001
睡眠时长0.4390.803
教育程度52.6250.058
社会活动8.3490.870
体重指数584.121<0.001
), ArticleFig(id=1240972176229200891, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240950904866788135, language=EN, label=Table 3, caption=

Intercept item test of MR-Egger regression model

, figureFileSmall=null, figureFileBig=null, tableContent=
暴露因素截距P值
吸烟-0.0090.171
饮酒-0.0070.213
久坐-0.0060.374
新鲜水果摄入-0.0060.368
干果摄入0.0130.270
谷类食物摄入0.0090.495
睡眠时长0.0220.686
教育程度-0.0070.537
社会活动0.0070.672
体重指数<0.0010.995
), ArticleFig(id=1240972176367611904, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240950904866788135, language=CN, label=表3, caption=

MR-Egger回归模型截距项检验

, figureFileSmall=null, figureFileBig=null, tableContent=
暴露因素截距P值
吸烟-0.0090.171
饮酒-0.0070.213
久坐-0.0060.374
新鲜水果摄入-0.0060.368
干果摄入0.0130.270
谷类食物摄入0.0090.495
睡眠时长0.0220.686
教育程度-0.0070.537
社会活动0.0070.672
体重指数<0.0010.995
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基于孟德尔随机化方法探究可干预危险因素与支气管哮喘之间的因果关系
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常新伟 1 , 付延鑫 2 , 白亚虎 1 , 纪思禹 2 , 高胜寒 1 , 王冉 1 , 宁康 3
现代预防医学 | 流行病与统计方法 2024,51(7): 1166-1174
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现代预防医学 | 流行病与统计方法 2024, 51(7): 1166-1174
基于孟德尔随机化方法探究可干预危险因素与支气管哮喘之间的因果关系
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常新伟1, 付延鑫2, 白亚虎1, 纪思禹2, 高胜寒1, 王冉1, 宁康3
作者信息
  • 1.山东第一医科大学（山东省医学科学院）研究生部，山东 济南 250017
  • 2.潍坊医学院研究生部
  • 3.山东第一医科大学附属职业病医院呼吸内科，山东 济南 250062

    • 常新伟（1999—），男，硕士在读，研究方向：呼吸系统疾病

通讯作者:

宁康，E-mail:
The causal relationship between intervenable risk factors and bronchial asthma by Mendelian randomized analysis
Xin-wei CHANG1, Yan-xin FU2, Ya-hu BAI1, Si-yu JI2, Sheng-han GAO1, Ran WANG1, Kang NING3
Affiliations
  • Graduate Department of Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250017, China
出版时间: 2024-04-10 doi: 10.20043/j.cnki.MPM.202311231
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摘要
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目的

运用两样本孟德尔随机化（Mendelian randomization，MR）方法探究生活方式、饮食、睡眠及社会经济地位等因素与支气管哮喘的因果关系。

方法

研究主要使用逆方差加权法(IVW)进行两样本MR分析,同时采用留一法、异质性检验、水平基因多效性检验来验证结果的稳定性和可靠性。

结果

IVW模型结果显示吸烟（OR=1.17，95%CI：1.08～1.28）、饮酒（OR= 1.22，95%CI：1.05～1.41）、久坐（OR=1.78，95%CI：1.38～2.31）、睡眠时长（OR=2.29，95%CI：1.38～2.31）、体重指数（OR=1.41，95%CI：1.29～1.53）与支气管哮喘患病风险增加有关。新鲜水果摄入（OR=0.50，95%CI：0.34～0.73）、干果摄入（OR=0.54，95%CI：0.34～0.73）、谷类食物摄入（OR=0.62，95%CI：0.41～0.94）、教育程度（OR=0.57，95%CI：0.34～0.73）、社会活动（OR=0.26，95%CI：0.34～0.73）会降低支气管哮喘的发病风险。ME-Egger截距检测结果不存在多效性，故MR在本研究中为因果推断的有效方法。饮酒（Q=139.92，P=0.001）、久坐（Q=151.37，P=0.003）、干果摄入（Q=40.00，P=0.007）、谷类食物摄入（Q=72.95，P=0.001）、体重指数（Q=584.12，P<0.001）异质性检验结果P值均<0.05，故重点关注随机效应IVW模型。

结论

吸烟、饮酒、久坐、睡眠时长、体重指数可能是支气管哮喘的危险因素。新鲜水果摄入、干果摄入、谷类食物摄入、教育程度、社会活动可能是支气管哮喘的保护因素。

孟德尔随机化  /  支气管哮喘  /  可干预风险因素  /  因果关系
Objective

To explore the causal relationship between lifestyle, diet, sleep, socioeconomic status and bronchial asthma by using two-sample Mendelian randomized method.

Methods

Two-sample Mendelian randomization analysis was performed based on inverse variance weighting method (IVW), and the stability and reliability of the results were verified by leaving-one-out method, heterogeneity test, and pleiotropy test.

Results

The results of IVW model showed that smoking (OR=1.17,95%CI: 1.08-1.28), drinking (OR=1.22, 95%CI: 1.05-1.41), sedentary behavior (OR=1.78, 95%CI: 1.38-2.31), sleep duration (OR=2.29, 95%CI: 1.38-2.31), and body mass index (OR=1.41, 95%CI: 1.29-1.53) were associated with the increased risk of bronchial asthma. Fresh fruit intake (OR=0.50, 95%CI: 0.34-0.73), dried fruit intake (OR=0.54, 95%CI: 0.34-0.73), cereal intake (OR=0.62, 95%CI: 0.41-0.94), education level (OR=0.57, 95%CI: 0.34-0.73), and social activity (OR=0.26, 95%CI:0.34-0.73) were associated with reduced risk of asthma. The results of MR-Egger intercept detection did not show pleiotropic effects, indicating that Mendelian randomization was an effective method for causal inference in this study. The heterogeneity test results of drinking (Q=139.92, P=0.001), sedentary behavior (Q=151.37, P=0.003), dried fruit intake (Q=40.00, P=0.007), cereal intake (Q=72.95, P=0.001), and body mass index (BMI) (Q=584.12, P < 0.001) were all statistically significant. Therefore, attention was paid to results of the random effect IVW model.

Conclusion

Smoking, drinking, sedentary behavior, sleep duration, and body mass index may be the risk factors of bronchial asthma. Fresh fruit intake, dried fruit intake, cereal intake, education level, and social activities may be the protective factors of bronchial asthma.

Mendelian randomization  /  Bronchial asthma  /  Intervenable risk factors  /  Causality
常新伟, 付延鑫, 白亚虎, 纪思禹, 高胜寒, 王冉, 宁康. 基于孟德尔随机化方法探究可干预危险因素与支气管哮喘之间的因果关系. 现代预防医学, 2024 , 51 (7) : 1166 -1174 . DOI: 10.20043/j.cnki.MPM.202311231
Xin-wei CHANG, Yan-xin FU, Ya-hu BAI, Si-yu JI, Sheng-han GAO, Ran WANG, Kang NING. The causal relationship between intervenable risk factors and bronchial asthma by Mendelian randomized analysis[J]. Modern Preventive Medicine, 2024 , 51 (7) : 1166 -1174 . DOI: 10.20043/j.cnki.MPM.202311231
正文
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支气管哮喘是一种慢性、可逆性的气道炎症性疾病，哮喘患者常出现喘息、气短、胸闷、咳嗽以及不同程度的可变性呼气气流受限等呼吸道症状[1]。在过去的几十年里，支气管哮喘的发病率呈上升趋势[2-3]。目前对于支气管哮喘患者的治疗目标是将症状及不良后果的风险降至最低[4]，尽管通过当前的治疗措施已可以帮助大多数患者实现症状控制，但仍有部分患者面临着复发和急性加重的风险，甚至可能危及生命[5]。了解支气管哮喘的发病机制和病因学，探明支气管哮喘危险因素，对支气管哮喘进行针对性的危险因素预防，对减轻哮喘患者的经济负担、提高生活质量具有重大影响。
尽管支气管哮喘现已被广泛研究，但其病因仍不完全清楚。既往研究表明支气管哮喘的发生、发展是遗传、环境等多种因素共同作用的结果。支气管哮喘具有明显的家族聚集现象，多个基因已被发现与支气管哮喘的发病风险相关[6-8]；空气污染、过敏原暴露等环境因素也在支气管哮喘的发病过程中发挥着重要的作用[9-10]。最新研究发现，生活习惯、饮食、睡眠及社会经济地位等因素可能与支气管哮喘的发生、发展存在一定的关联，现有流行病学研究也对此进行了探索，但所得出的结论却不尽一致，因果关系也尚不清楚[10-11]。这也促使了本研究对此进行探究。
在传统临床实验的实施过程中，常常受到人力、物力以及伦理等方面的限制，暴露与结局的关系也容易受到相关混杂因素以及反向因果的影响[12]。随着基因遗传学的不断发展,促使了孟德尔随机化（Mendelian randomization，MR）在医学研究领域的应用。MR作为流行病学工具的一种，它是基于减数分裂过程中亲代等位基因随机分配给子代的遗传定律，通过利用遗传变异作为工具来评估变量之间的因果关系[13-14]。从理论上讲，由于遗传变异不受出生后环境等常见混杂因素的影响，并且遗传变异要早于暴露和结局的发生，MR可以有效的避免混杂因素、反向因果关系等方面的问题[15]。因此MR研究可作为因果推断的重要流行病学方法。
虽然早期已有MR研究对支气管哮喘可干预危险因素进行了初步探讨，但受到当时数据来源、研究方法等方面的限制，可能存在样本重叠偏倚、研究方法相对不完善、SNP纳入排除标准不一致、缺乏敏感性分析等问题，所得出的结论与既往观察性研究之间存在差异，且近年最新研究发现饮酒、久坐、睡眠等因素与支气管哮喘之间可能存在关联。因此本研究在既往相关研究的基础上，选取存在争议的可干预因素，并对近年较为关注的经济地位等方面进行补充；通过优化研究方法、提高纳入排除标准、排除离群值等方法进一步探究生活方式、饮食、睡眠及社会经济地位等因素与支气管哮喘之间的关系。
1　资料与方法
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1.1　数据来源
本研究暴露因素定义为生活习惯、饮食、睡眠及社会经济地位等因素，结局变量为是否患有支气管哮喘事件。本研究中所涉及的生活习惯相关暴露因素包括吸烟、饮酒、久坐、适量运动；饮食相关暴露因素包括新鲜水果摄入、干果摄入、咖啡摄入、茶摄入等；睡眠相关暴露因素包括失眠、白天午睡、打鼾、睡眠时长；社会经济地位包括以下特征：教育程度(定义为完成全日制教育时的年龄)、体力劳动(定义为涉及重体力劳动的工作)、家庭收入(定义为税前家庭平均总收入)、区域剥夺(定义为招募时的汤森德剥夺指数)和社会活动（定义为休闲/社交活动:酒吧或社交俱乐部）。暴露与结局因素均通过IEU OpenGWAS project (mrcieu.ac.uk)网站获取相关的GWAS数据。因为数据均来源于公开数据库，所以不需要额外的伦理批准。同时，所选择的人群均来源于欧洲血统人群，从而避免了因种族不同而造成的偏差。见表1。
1.2　工具变量的筛选
选择暴露因素与结局变量相互独立且高度相关的全基因组意义的SNPs作为工具变量。首先，从数据库中筛选出分别与暴露因素及结局强相关的SNPs(P<5×10-8)，并设置连锁不平衡参数（linkage disequilibrium, LD）R2<0.001，遗传距离为10 000 KB，以保证各SNP之间的相互独立性[13]。其次，为了保证所选择的SNPs与已知的混杂因素无关，使用在线网站PhenoSacnner(http://www.phenoscanner.medschl.cam.ac.uk)进行检索，排除与潜在混杂因素相关的SNP。同时利用F统计量评价遗传工具强度，计算SNP的F统计量，如F>10表明结果受弱工具变量影响的可能性较小。
1.3　MR分析
本研究使用R version 4.2.3及Two Sample MR version 0.5.6进行相关MR分析。主要采用逆方差加权法(inverse-variance weighted, IVW)来探究各暴露因素与支气管哮喘之间的潜在因果关系，并运用MR-Egger、加权中值法(weighted median)等方法对所得到的结果进一步验证[16]。如果IVW方法的结果是显著的（P<0.05），即使其他方法的结果不显著，只要其他方法的β值方向相同，也可以被视为阳性结果[17]。
1.4　敏感性分析
采用MR-Egger截距检测水平多效性，若MR-Egger截距分析中的截距项与0相比有统计学意义，则说明该研究存在水平多效性[18]；应用Cochran Q检验判断SNP的异质性，如Cochran Q统计量检验具有统计学意义，证明分析结果具有显著的异质性，则重点关注随机效应IVW法的结果[19]；采用留一法（leave-one-out）进行敏感性分析，即通过剔除单个SNP后，再次对剩余工具变量进行分析，从而探究单个SNP对因果关联的影响[20]。
2　结果
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2.1　工具变量
本研究通过共19个暴露因素探究生活习惯、饮食、睡眠及社会经济地位等方面与支气管哮喘的因果关系，本研究中使用的SNPs数量从3到414个，且所有工具变量的F值均大于10，表示存在弱工具变量偏倚可能性较小。
2.2　MR分析
通过MR结果分析，本研究发现共有10种暴露因素与支气管哮喘存在因果关系。其中吸烟（OR=1.17，95%CI：1.08～1.28）、饮酒（OR=1.22，95%CI：1.05～1.41）、久坐（OR=1.78，95%CI：1.38～2.31）、睡眠时长（OR=2.29，95%CI：1.38～2.31）、体重指数（OR=1.41，95%CI：1.29～1.53）与支气管哮喘患病风险增加有关。新鲜水果摄入（OR= 0.50，95%CI：0.34～0.73）、干果摄入（OR=0.54，95%CI：0.34～0.73）、谷类食物摄入（OR=0.62，95%CI：0.41～0.94）、教育程度（OR=0.57，95%CI：0.34～0.73）、社会活动（OR=0.26，95%CI：0.34～0.73）被视为保护因素。见图1、2。
2.3　敏感性分析
异质性检验主要采用Cochran Q检验，Cochran Q检验结果显示吸烟、新鲜水果摄入、睡眠时长、教育程度、社会活动未发现异质性；而饮酒、久坐、干果摄入、谷类食物摄入、体重指数Cochran Q检验结果P值<0.05，提示SNP间存在异质性，故重点关注随机效应IVW模型，见表2。采用MR-Egger截距检测水平多效性，结果显示吸烟、饮酒等10种暴露因素MR-Egger截距分析中的截距项与0相比均无统计学意义（P<0.05），见表3。表明本研究因果评估的结果受多效性影响可能性较小，结果可信程度较高。本研究主要采用留一法进行敏感性分析，经过逐个剔除SNP检验后，本研究并未存在单个SNP对结果的稳健性产生显著影响，表明本研究的MR分析结果相对稳健。
3　讨论
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本研究采用双样本MR的设计方法，利用GWAS数据从遗传学的角度探究生活习惯、饮食、睡眠及社会经济地位等暴露因素与支气管哮喘之间因果关联，结果显示吸烟、饮酒、久坐、睡眠时长、体重指数是支气管哮喘的危险因素，而新鲜水果摄入、干果摄入、谷类食物摄入、教育程度、社会活动是支气管哮喘的保护因素。
现有流行病学研究数据表明吸烟是支气管哮喘的危险因素，当前吸烟状态常常与哮喘较差的临床结局密切相关[21-22]。但是Shen等人[23]发现吸烟对哮喘风险有保护作用，这些研究表明吸烟与哮喘之间所存在的关联仍存在争议。本研究认为吸烟为支气管哮喘的危险因素，可促进支气管哮喘的发生与发展。这与Cerveri等人[24]所进行的基于人群的大规模国际队列研究的结果相一致。虽然就目前来看，吸烟所致哮喘患者的呼吸道炎症和组织重塑的致病机制尚不清楚，但这被认为是吸烟和哮喘相关的呼吸道炎症之间相互作用的结果。暴露在香烟烟雾中可诱导氧化应激，并通过激活的中性粒细胞、巨噬细胞和CD8+细胞毒性T细胞释放促炎介质[25-26]。酒精可对人体免疫系统产生影响，大量饮酒与较高的免疫球蛋白E (IgE)水平有关[27]。既往研究发现，饮酒与变应性鼻炎和特应性皮炎等变应性疾病的发生有关[28-29]。这些研究均表明，饮酒与支气管哮喘之间可能存在着潜在的因果关系，而本研究也进一步证实了这一观点。但这与既往MR研究所得出的结论存在差异。造成这种结果的原因可能如下：（1）数据来源不同。两项研究所选用的数据来源不同，样本人群的年龄、性别以及种族等特征可能存在差异。（2）MR研究受到混杂因素、弱工具变量、样本重叠等问题的影响，不同研究对上述问题的处理要求不同，可能也会导致结果存在差异。本研究除发现吸烟、饮酒为支气管哮喘的危险因素外，久坐也可能会促进支气管哮喘的发生、发展。世界卫生组织早已将久坐列为十大致死致病元凶之一，久坐的危害仅次于吸烟。早期研究已经表明，久坐会增加癌症死亡风险、抑郁症等[30-31]，最近也有研究学者发现久坐行为可能与支气管哮喘疾病高风险相关[32]，但久坐行为与支气管哮喘之间的发病机制仍需要进一步探究。
在饮食方面，本研究发现新鲜水果摄入、干果摄入、谷类食物摄入可降低支气管哮喘的发病风险。既往大量研究已经表明水果摄入量与支气管哮喘症状的发生呈负相关[33-35]，但并非所有的研究都呈相同的看法[9]，这也促使了本研究对饮食因素的探讨。本研究运用两样本MR研究发现新鲜水果摄入、干果摄入、谷类食物摄入为支气管哮喘的保护因素。气道容易受到氧化损伤，氧化剂可以通过诱导释放包括细胞因子和趋化因子在内的促炎介质来诱发哮喘症状的发生[36]，而水果中则含有多种抗氧化剂。除此之外，饮食因素可能是通过肠道菌群来发挥作用。不同食物的摄入会影响肠道内细菌的组成，从而影响营养物质的代谢[37]。在小鼠模型中发现肠道菌群的变化和气道高反应性改善之间存在一定的联系[38]。有趣的是，既往一项前瞻性队列研究发现，咖啡和茶摄入可能对支气管哮喘保护作用[39]，但本研究及既往MR研究均未发现两者之间存在因果关系，这为进一步深入了解咖啡及茶摄入量与哮喘之间的关系提供了强有力的新证据。
以往的研究表明，失眠、打鼾、睡眠时长等睡眠情况均与特定的炎症反应有关[40-43]。由于支气管哮喘也是一种慢性炎症性疾病，睡眠情况是否与支气管哮喘的发生风险存在联系，是否代表了支气管哮喘早期进展的信号，目前尚不清楚。一些具体的研究揭示了初步的证据。一项临床队列研究表明，睡眠时间过长与支气管哮喘之间存在关联[44]。既往MR研究也表明，睡眠质量差与支气管哮喘之间存在因果关系[45]。这些研究证据表明，睡眠情况可能在一定程度上影响支气管哮喘的发病风险，需进一步进行综合评估。本研究发现睡眠时长可能会促进支气管哮喘的发病风险，这与既往临床研究得出了一致的结果。值得注意的是，在本研究中，并未发现失眠与支气管哮喘之间存在潜在的因果关系，这与既往观察性研究所得出的结果存在差异[46]，存在差异的原因可能如下：第一，观察性研究可能受到潜在混杂因素的影响。第二，失眠与哮喘之间确实存在因果关系，但MR研究作为新兴的研究方法，受限于人群分层、发育代偿等问题，并没有发现这一点。因此，未来需要更多的观察性研究、设计更为巧妙的MR研究以及更为完善的校正及估计方法来进一步揭示两者之间的关系。
据报道，经济地位也是支气管哮喘的危险因素[47]。在一项在世界贸易中心健康登记研究中，Brite等人[47]发现社会经济地位较低的支气管哮喘患者的预后更差。但Hanco等人[48]所报道的一项前瞻性队列研究具有不同的看法，他们发现社会经济地位对支气管哮喘的患病率没有显著影响。因此，社会经济地位与哮喘之间的因果关系尚不清楚，需要对此进一步探究，既往已有MR研究发现受教育程度与支气管哮喘的发病风险相关[49]，但社会经济地位包括教育程度、体力劳动、家庭收入、区域剥夺和社会活动五个特征，因此本研究在既往研究的基础上进一步深入研究，从上述五个方面综合探究社会经济地位与支气管哮喘之间的关系，最终发现教育程度、社会活动（定义为休闲/社交活动：酒吧或社交俱乐部）可降低支气管哮喘的发病风险，虽然受教育程度对于降低支气管哮喘的原因尚不明确，但可能与更易接触健康知识和信息、更倾向于健康的生活方式、更容易获得更好的医疗保健、更易获得更好的医疗保健等方面有关。除教育程度外，本研究还发现社会活动同样与支气管哮喘的发病风险相关，但目前尚无相关实验对此进行探究，这为探究支气管哮喘危险因素提供了新的思路与方向。
本研究具有一定的优势。本研究基于大样本公开GWAS数据，在基因的层次来探究生活方式、饮食、睡眠及社会经济地位等因素与支气管哮喘之间存在的因果关系。具有样本量大，研究省时省力，同时避免了伦理方面的限制等方面的优势。但本研究也存在一定的局限性。一是本研究所应用的GWAS数据均来源于欧洲人群，所得出的结果是否适用于其他人群还有待进一步研究。二是在探究饮酒、饮食等方面的暴露因素时，本研究中是将所涉及的暴露因素作为一个整体纳入，没有针对具体的进食方式、进食的频次等方面进行分类分析，这也需要我们在未来设计更为巧妙的MR研究。
综上，本研究采用两样本MR的方法探究生活方式、饮食、睡眠及社会经济地位等因素与支气管哮喘之间的因果关系，结果显示吸烟、饮酒、久坐、睡眠时长、体重指数是支气管哮喘的危险因素，而新鲜水果摄入、干果摄入、谷类食物摄入、教育程度、社会活动是支气管哮喘的保护因素。该结果对未来支气管哮喘的防治及相关研究具有一定的参考价值，而且将为公共卫生政策制定者和临床预防支气管哮喘提供新的视角。
基金
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  • 山东省自然科学基金(ZR2021MH200)
文献
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参考文献 引证文献
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2024年第51卷第7期
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doi: 10.20043/j.cnki.MPM.202311231
  • 接收时间：2023-11-13
  • 首发时间：2026-03-18
  • 出版时间：2024-04-10
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  • 收稿日期：2023-11-13
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山东省自然科学基金(ZR2021MH200)
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    1.山东第一医科大学（山东省医学科学院）研究生部，山东 济南 250017
    2.潍坊医学院研究生部
    3.山东第一医科大学附属职业病医院呼吸内科，山东 济南 250062

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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