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Article(id=1198602005481619929, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198601997155922872, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2641.2024.0110, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1672243200000, receivedDateStr=2022-12-29, revisedDate=null, revisedDateStr=null, acceptedDate=1690992000000, acceptedDateStr=2023-08-03, onlineDate=1763698587054, onlineDateStr=2025-11-21, pubDate=1719504000000, pubDateStr=2024-06-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763698587054, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763698587054, creator=13701087609, updateTime=1763698587054, updator=13701087609, issue=Issue{id=1198601997155922872, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='6', pageStart='611', pageEnd='732', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763698585070, creator=13701087609, updateTime=1763698770557, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198602775211901122, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198601997155922872, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198602775211901123, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198601997155922872, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=636, endPage=642, ext={EN=ArticleExt(id=1198602005850718707, articleId=1198602005481619929, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Obstructive sleep apnea and hypertension: a bidirectional Mendelian randomization study, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the causal relationship between obstructive sleep apnea (OSA) and hypertension using bidirectional Mendelian randomization (MR). Methods Genetic data for OSA were obtained from the Genome-wide association study (GWAS) of FinnGen Biobank, including 16 761 cases and 201 194 controls, from which 5 single-nucleotide polymorphisms (SNPs) were screened as instrumental variables (IVs) for OSA. Genetic data for hypertension were obtained from GWAS of UK Biobank, including 124 227 cases and 337 653 controls from which 214 SNPs were selected as IVs for hypertension. Multiple MR methods, mainly Inverse variance weighted (IVW), were used for analysis. Sensitivity analysis of MR results was performed using MR-Egger regression et al, and IVs were evaluated using F values. Results OSA was associated with an increased risk of hypertension (OR=1.053, 95%CI 1.019-1.089, P<0.01), and hypertension was significantly associated with the risk of developing OSA (OR=1.812, 95%CI 1.354-2.425, P<0.001). Heterogeneity was observed in both two-way outcomes (OSA→ hypertension, P<0.001; hypertension→ OSA, P<0.001), but no evidence of horizontal pleiotropy was detected (OSA→ hypertension, P=0.666; hypertension→ OSA, P=0.556). The IVs selected in this study were strong instrumental variables for both OSA and hypertension (OSA-IVs F=14.695; hypertension-IVs F=39.624). Conclusions Our findings indicate a bidirectional causal relationship between OSA and hypertension, with a particularly significant effect of hypertension on the development of OSA.

, correspAuthors=Zhen-Qi Li, authorNote=null, correspAuthorsNote=
E-mail:
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目的 采用双向孟德尔随机化(MR)分析阻塞性睡眠呼吸暂停(OSA)与高血压的因果关系。方法 OSA的相关遗传数据来自全基因组关联研究(GWAS)中的芬兰基因数据库(n病例组=16 761，n对照组=201 194)，从中筛选出5个单核苷酸多态性(SNPs)作为OSA的工具变量(IVs)。高血压的相关遗传数据来源于GWAS中的英国基因数据库(n病例组=124 227，n对照组=337 653)，从中选取214个SNPs作为高血压的IVs。采用逆方差加权法(IVW)为主的多种MR方法进行分析。采用MR-Egger等方法对MR分析结果进行敏感性分析，并使用F值对IVs进行评估。结果 OSA与高血压的风险增高相关(OR=1.053，95%CI 1.019~1.089，P<0.01)，高血压与OSA的发病风险明显相关(OR=1.812，95%CI 1.354~2.425，P<0.001)。双向结果均存在异质性(OSA→高血压，P<0.001；高血压→OSA，P <0.001)，均无水平多效性(OSA→高血压，P=0.666；高血压→OSA，P=0.556)。所选的OSA及高血压的IVs均为强IVs(OSA-IVs F=14.695；高血压-IVs F=39.624)。结论 OSA与高血压具有双向因果关系，其中高血压对OSA发病的影响尤其明显。

, correspAuthors=李镇圻, authorNote=null, correspAuthorsNote=
李镇圻，E-mail：
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夏露，硕士研究生，主要从事耳鼻咽喉等方面的临床研究

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夏露，硕士研究生，主要从事耳鼻咽喉等方面的临床研究

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夏露，硕士研究生，主要从事耳鼻咽喉等方面的临床研究

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language=CN, orderNo=3, keyword=孟德尔随机化), Keyword(id=1198611599075410428, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=CN, orderNo=4, keyword=双向), Keyword(id=1198611599155102205, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=CN, orderNo=5, keyword=因果关系)], refs=[Reference(id=1198611600727966222, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, doi=null, pmid=null, pmcid=null, year=2014, volume=383, issue=9918, pageStart=736, pageEnd=747, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=Jordan AS, Mcsharry DG, Malhotra A, journalName=Lancet, refType=null, unstructuredReference=Jordan AS, Mcsharry DG, Malhotra A. 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Epidemiology, 2014, 25(6): 877-885., articleTitle=Instrumental variable analysis with a nonlinear exposure-outcome relationship, refAbstract=null)], funds=[Fund(id=1198611600472113676, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, awardId=2022Y863, language=EN, fundingSource=Scientific Research Foundation of Yunnan Provincial Department of Education(2022Y863), fundOrder=null, country=null), Fund(id=1198611600555999757, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, awardId=2022Y863, language=CN, fundingSource=云南省教育厅研究生项目(2022Y863), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198611596571410896, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, xref=1, ext=[AuthorCompanyExt(id=1198611596579799505, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, companyId=1198611596571410896, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Otorhinolaryngology, Chongqing Armed Police Corps Hospital, Chongqing 400061, China), AuthorCompanyExt(id=1198611596583993810, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, companyId=1198611596571410896, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1武警重庆总队医院耳鼻咽喉科，重庆 400061)]), AuthorCompany(id=1198611596655296979, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, xref=2, ext=[AuthorCompanyExt(id=1198611596663685588, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, companyId=1198611596655296979, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Otorhinolaryngology, the First Affiliated Hospital of Dali University, Dali, Yunnan 671000, China), AuthorCompanyExt(id=1198611596672074197, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, companyId=1198611596655296979, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2大理大学第一附属医院耳鼻咽喉科，云南大理 671000)]), AuthorCompany(id=1198611596734988759, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, xref=3, ext=[AuthorCompanyExt(id=1198611596743377368, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, companyId=1198611596734988759, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3Department of General Surgery, Chongqing Armed Police Corps Hospital, Chongqing 400061, China), AuthorCompanyExt(id=1198611596751765977, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, companyId=1198611596734988759, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3武警重庆总队医院普外科，重庆 400061)])], figs=[ArticleFig(id=1198611599318680062, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=EN, label=Fig.1, caption=Schematic diagram of bidirectional Mendelian randomization flow graph between OSA and hypertension, figureFileSmall=d50a/UZamlXrFUzB5RbvTQ==, figureFileBig=tWcZPY8Mm7sQqPFHf+mdfQ==, tableContent=null), ArticleFig(id=1198611599385788927, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=CN, label=图1, caption=OSA与高血压的双向孟德尔随机化流程

OSA. 阻塞性睡眠呼吸暂停；IVs. 工具变量；①相关性假设，IVs与暴露强相关(P<5×10-8)；②独立性假设，IVs与结局不相关；③排他性假设，IVs不通过暴露以外的途径影响结局

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MR. 孟德尔随机化；IVW. 逆方差加权；超过横轴坐标范围则显示为虚线

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MR. 孟德尔随机化；IVW. 逆方差加权；SE. 标准误；A. 正向MR留一法；B. 正向MR漏斗图

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MR. 孟德尔随机化

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MR. 孟德尔随机化；IVW. 逆方差加权；SE. 标准误；A. 反向MR留一法；B. 反向MR漏斗图

, figureFileSmall=3MyIFoW3Iy7/+aEVsSNtqg==, figureFileBig=KTM72Cdq0VrYt5sddYnlnw==, tableContent=null), ArticleFig(id=1198611600086237704, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=EN, label=Tab.1, caption=

Results of positive MR study

, figureFileSmall=null, figureFileBig=null, tableContent=
MR方法βSEOR(95%CI)P
IVW随机效应模型0.0520.0171.053(1.019~1.089)0.002
MR-Egger0.0070.0961.007(0.834~1.216)0.947
加权中位数0.0390.0101.039(1.019~1.061)<0.001
最大似然比0.0550.0071.056(1.042~1.071)<0.001
线性中位数加权0.0250.0121.025(1.001~1.050)0.041
IVW固定效应模型0.0520.0061.053(1.041~1.066)<0.001
), ArticleFig(id=1198611600157540873, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=CN, label=表1, caption=

正向MR研究结果

, figureFileSmall=null, figureFileBig=null, tableContent=
MR方法βSEOR(95%CI)P
IVW随机效应模型0.0520.0171.053(1.019~1.089)0.002
MR-Egger0.0070.0961.007(0.834~1.216)0.947
加权中位数0.0390.0101.039(1.019~1.061)<0.001
最大似然比0.0550.0071.056(1.042~1.071)<0.001
线性中位数加权0.0250.0121.025(1.001~1.050)0.041
IVW固定效应模型0.0520.0061.053(1.041~1.066)<0.001
), ArticleFig(id=1198611600241426954, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=EN, label=Tab.2, caption=

Results of reverse MR study

, figureFileSmall=null, figureFileBig=null, tableContent=
MR方法βSEOR(95%CI)P
IVW随机效应模型0.5940.1491.812(1.354~2.425)<0.001
MR-Egger0.3680.4111.445(0.646~3.233)0.371
加权中位数法0.3940.1991.482(1.004~2.187)0.047
最大似然比法0.6040.1211.829(1.443~2.318)<0.001
线性中位数加权法0.3980.1921.489(1.021~2.171)0.038
IVW固定效应模型0.5940.1191.812(1.435~2.289)<0.001
), ArticleFig(id=1198611600304341515, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198602005481619929, language=CN, label=表2, caption=

反向MR研究结果

, figureFileSmall=null, figureFileBig=null, tableContent=
MR方法βSEOR(95%CI)P
IVW随机效应模型0.5940.1491.812(1.354~2.425)<0.001
MR-Egger0.3680.4111.445(0.646~3.233)0.371
加权中位数法0.3940.1991.482(1.004~2.187)0.047
最大似然比法0.6040.1211.829(1.443~2.318)<0.001
线性中位数加权法0.3980.1921.489(1.021~2.171)0.038
IVW固定效应模型0.5940.1191.812(1.435~2.289)<0.001
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阻塞性睡眠呼吸暂停与高血压：一项双向孟德尔随机化研究
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夏露 1 , 谢治年 1 , 廖芯艺 1 , 张启星 2 , 李镇圻 3, *
解放军医学杂志 | 临床研究 2024,49(6): 636-642
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解放军医学杂志 | 临床研究 2024, 49(6): 636-642
阻塞性睡眠呼吸暂停与高血压：一项双向孟德尔随机化研究
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夏露1, 谢治年1, 廖芯艺1, 张启星2, 李镇圻3, *
作者信息
  • 1武警重庆总队医院耳鼻咽喉科，重庆 400061
  • 2大理大学第一附属医院耳鼻咽喉科，云南大理 671000
  • 3武警重庆总队医院普外科，重庆 400061

    • 夏露，硕士研究生，主要从事耳鼻咽喉等方面的临床研究

通讯作者:

李镇圻，E-mail：
Obstructive sleep apnea and hypertension: a bidirectional Mendelian randomization study
Lu Xia1, Zhi-Nian Xie1, Xin-Yi Liao1, Qi-Xing Zhang2, Zhen-Qi Li3, *
Affiliations
  • 1Department of Otorhinolaryngology, Chongqing Armed Police Corps Hospital, Chongqing 400061, China
  • 2Department of Otorhinolaryngology, the First Affiliated Hospital of Dali University, Dali, Yunnan 671000, China
  • 3Department of General Surgery, Chongqing Armed Police Corps Hospital, Chongqing 400061, China
出版时间: 2024-06-28 doi: 10.11855/j.issn.0577-7402.2641.2024.0110
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摘要
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目的 采用双向孟德尔随机化(MR)分析阻塞性睡眠呼吸暂停(OSA)与高血压的因果关系。方法 OSA的相关遗传数据来自全基因组关联研究(GWAS)中的芬兰基因数据库(n病例组=16 761，n对照组=201 194)，从中筛选出5个单核苷酸多态性(SNPs)作为OSA的工具变量(IVs)。高血压的相关遗传数据来源于GWAS中的英国基因数据库(n病例组=124 227，n对照组=337 653)，从中选取214个SNPs作为高血压的IVs。采用逆方差加权法(IVW)为主的多种MR方法进行分析。采用MR-Egger等方法对MR分析结果进行敏感性分析，并使用F值对IVs进行评估。结果 OSA与高血压的风险增高相关(OR=1.053，95%CI 1.019~1.089，P<0.01)，高血压与OSA的发病风险明显相关(OR=1.812，95%CI 1.354~2.425，P<0.001)。双向结果均存在异质性(OSA→高血压，P<0.001；高血压→OSA，P <0.001)，均无水平多效性(OSA→高血压，P=0.666；高血压→OSA，P=0.556)。所选的OSA及高血压的IVs均为强IVs(OSA-IVs F=14.695；高血压-IVs F=39.624)。结论 OSA与高血压具有双向因果关系，其中高血压对OSA发病的影响尤其明显。

阻塞性睡眠呼吸暂停  /  高血压  /  孟德尔随机化  /  双向  /  因果关系

Objective To investigate the causal relationship between obstructive sleep apnea (OSA) and hypertension using bidirectional Mendelian randomization (MR). Methods Genetic data for OSA were obtained from the Genome-wide association study (GWAS) of FinnGen Biobank, including 16 761 cases and 201 194 controls, from which 5 single-nucleotide polymorphisms (SNPs) were screened as instrumental variables (IVs) for OSA. Genetic data for hypertension were obtained from GWAS of UK Biobank, including 124 227 cases and 337 653 controls from which 214 SNPs were selected as IVs for hypertension. Multiple MR methods, mainly Inverse variance weighted (IVW), were used for analysis. Sensitivity analysis of MR results was performed using MR-Egger regression et al, and IVs were evaluated using F values. Results OSA was associated with an increased risk of hypertension (OR=1.053, 95%CI 1.019-1.089, P<0.01), and hypertension was significantly associated with the risk of developing OSA (OR=1.812, 95%CI 1.354-2.425, P<0.001). Heterogeneity was observed in both two-way outcomes (OSA→ hypertension, P<0.001; hypertension→ OSA, P<0.001), but no evidence of horizontal pleiotropy was detected (OSA→ hypertension, P=0.666; hypertension→ OSA, P=0.556). The IVs selected in this study were strong instrumental variables for both OSA and hypertension (OSA-IVs F=14.695; hypertension-IVs F=39.624). Conclusions Our findings indicate a bidirectional causal relationship between OSA and hypertension, with a particularly significant effect of hypertension on the development of OSA.

obstructive sleep apnea  /  hypertension  /  Mendelian randomization  /  bidirectional  /  causality
夏露, 谢治年, 廖芯艺, 张启星, 李镇圻. 阻塞性睡眠呼吸暂停与高血压：一项双向孟德尔随机化研究. 解放军医学杂志, 2024 , 49 (6) : 636 -642 . DOI: 10.11855/j.issn.0577-7402.2641.2024.0110
Lu Xia, Zhi-Nian Xie, Xin-Yi Liao, Qi-Xing Zhang, Zhen-Qi Li. Obstructive sleep apnea and hypertension: a bidirectional Mendelian randomization study[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (6) : 636 -642 . DOI: 10.11855/j.issn.0577-7402.2641.2024.0110
正文
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阻塞性睡眠呼吸暂停(obstructive sleep apnea，OSA)是指睡眠期间反复发生上呼吸道塌陷导致的氧饱和度下降和睡眠中断[1-2]。OSA影响着全球约30%的男性和15%的女性，且可能导致高血压、心肌梗死、充血性心力衰竭、卒中和糖尿病等全身性疾病[1,3-4]。其中高血压是指以体循环动脉血压[收缩压和(或)舒张压]增高为主要特征，可伴有心、脑、肾等器官的功能或器质性损害的临床综合征，是人群中常见的慢性病，影响全球约10亿人[5]。OSA也是临床常见疾病，许多研究发现，OSA经常与高血压共存，30%~70%的OSA患者合并高血压，而高血压患者中的OSA发生率为30%~50%[6-10]。OSA与高血压存在肥胖等共同危险因素的影响以及反向因果关系的干扰，因此两者的因果关系仍不明确。孟德尔随机化(Mendelian randomization，MR)是一种利用单核苷酸多态性(single nucleotide polymorphisms，SNPs)作为工具变量(instrumental variables，IVs)来推断暴露与结局之间因果关系的研究方法，被视为天然的随机对照试验，可在较大程度上避免混杂因素和反向因果关系的影响[11-12]。基于此，本研究设计了一项双向MR试验，旨在探究OSA与高血压之间的因果关系。
1 资料与方法
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1.1 研究设计
本研究设计为一项双向MR试验。MR基于3个重要假设：(1)相关性假设，IVs与暴露强相关(P<5×10-8)；(2)独立性假设，IVs与结局不相关；(3)排他性假设，IVs不通过暴露以外的途径影响结局[13]。OSA与高血压的双向MR流程如图1所示。
1.2 数据来源
OSA的汇总数据来源于近期一项大型全基因组关联研究(genome-wide association study，GWAS)荟萃分析，该研究包含来源于芬兰基因数据库(FinnGen Biobank)的16 761例OSA患者及201 194例欧洲血统对照者[14]。高血压的汇总数据来源于GWAS中的英国基因数据库(UK Biobank)，该研究包含124 227例高血压患者和337 653例欧洲血统对照者，为GWAS中样本量最大的高血压数据集。两个数据集为来源于同一人种的不同人群，满足双向MR的基本要求。
1.3 选择IVs
对于OSA作为暴露、高血压作为结局的MR正向分析，本研究进行了严格的SNPs筛选。首先，在OSA数据集中提取具有全基因组关联性的SNPs(P<5×10-8，连锁不平衡R2<0.001，遗传距离kb=10 000)。然后，从高血压数据集中提取与暴露相关的SNPs。最后，将暴露的SNPs与结局的SNPs进行汇总，并删除不相容等位基因和中等等位基因频率的回文等位基因。上述筛选步骤后留下的SNPs最终作为OSA的IVs用于MR正向分析。同时，本研究计算了OSA的IVs的统计量F值以评估IVs的强弱性，若F>10则为强IVs，反之即为弱IVs。统计量F值为IVs中单个SNP的F值总和，单个SNP的F值计算公式如下：
F=N-K-1K×R21-R2
N为IVs的有效样本量，K为IVs的个数，R2的计算公式如下：
R2=2×1-MAF×MAF×βSE×N
MAF为SNP的次要等位基因频率，β为SNP的等位基因效应值，SE为SNP的标准误(standard error，SE)。SE×N即为标准差SD(standard deviation，SD)。
对于将高血压作为暴露、OSA作为结局的反向MR分析，IVs的选择方法与正向MR分析的方法相同。
1.4 MR分析与敏感性分析
在双向MR分析中，逆方差加权法(inverse variance weighted，IVW)被用作主要分析方法。IVW法是使用多个SNP获得MR估计的最简单方法，包含随机效应模型和固定效应模型。当结果存在异质性时，以IVW随机效应模型作为金标准、IVW固定效应为补充方法；当结果无异质性时，则以IVW固定效应模型为金标准、IVW随机效应模型为补充方法[15]。此外，本研究还采用了MR-Egger、加权中位数、最大似然比和线性中位数加权等方法作为MR分析的补充方法。MR-Egger法要求所有IVs的方向一致，可放松排除性假设中不存在水平多效性的要求，当存在无效IVs时MR-Egger法可提高因果估计的稳健性。与IVW固定效应模型类似，最大似然比法假设暴露对每个SNP导致结果的影响相同，即假设不存在异质性或水平多效性，当SNP暴露效应中存在测量误差时，最大似然比法可提供更可靠的结果。在MR效应估计的权重不超过50%的情况下，线性中位数加权可得出相同的效应估计，其中权重由其与风险因子的关联程度决定。
采用MR Steiger对MR的方向进行验证，以排除反向因果关系的影响。采用Cochrane's Q检验对结果进行异质性检验，P<0.05为存在异质性，P>0.05为不存在异质性。采用MR-Egger截距法分析水平多效性。
采用留一法检验分析单个SNP对MR结果是否产生影响。通过观察漏斗图的对称性来检查可能存在的水平多效性，以衡量当前MR分析的可靠性。以Radial包分析离群值，用MR-PRESSO法检验离群值对结果的影响。采用MR Steiger检验验证暴露是否导致结果，以排除反向因果关系的干扰。
1.5 统计学处理
采用R 4.2.1中的“TwoSampleMR、MR-PRESSO”进行统计分析[16]。结果以比值比(odds ratio，OR)及相应的95%置信区间(confidence interval，CI)表示。P<0.05为差异有统计学意义。
2 结果
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2.1 正向MR结果
通过严格的IVs的筛选，5个与OSA独立相关的SNPs用作OSA的IVs进行正向MR分析，经检验为强IVs(F=14.695)。IVW随机效应模型结果显示，OSA与高血压的风险增高相关(OR=1.053，95%CI 1.019~1.089，P=2.402×10-3)。除MR-Egger结果无统计学意义以外，在加权中位数、最大似然比、线性中位数加权和IVW固定效应模型中均观察到了与IVW相似的因果估计。正向MR分析结果如表1所示。正向MR结果森林图如图2所示。
2.2 正向MR敏感性分析
Cochran's Q检验提示结果存在异质性(P<0.001)，故结果以IVW随机效应模型作为金标准。MR-Egger截距法提示结果无水平多效性(P=0.666)，提示IVs并不通过OSA以外的途径影响高血压。留一法提示结果稳定，没有单个SNP对MR结果造成明显影响。因5个IVs较少，漏斗图无法观察其对称性，且未进行离群值分析。正向MR的留一法和漏斗图如图3所示。正向MR Steiger检验结果为“TRUE”，提示OSA可导致高血压(P=0)。
2.3 反向MR分析结果
筛选出214个与高血压独立相关的SNPs作为高血压的IVs用于反向MR分析，根据公式进行计算，高血压的IVs的统计量F值为39.624，提示反向MR的IVs为强工具变量(F>10)。IVW随机效应模型结果显示，高血压与OSA的风险增高明显相关(OR=1.812，95%CI 1.354~2.425，P<0.001)。除MR-Egger结果无统计学意义以外，在加权中位数、最大似然比、线性中位数加权和IVW固定效应模型中均观察到与IVW随机效应模型相似的因果估计。反向MR结果如表2所示，反向MR结果森林图如图4所示。
2.4 反向MR敏感性分析
Cochran's Q检验提示结果存在异质性(P<0.001)，故结果以IVW作为金标准。MR-Egger截距法提示结果无水平多效性(P=0.556)，提示IVs并不通过高血压以外的途径影响OSA。留一法提示结果稳定，没有单个SNP对MR结果造成明显影响。漏斗图左右两侧对称，提示结果稳定。反向MR的留一法和漏斗图如图5所示。IVW radial法识别到离群值，但MRPRESSO法提示离群值对结果无明显影响，进一步显示研究结果稳定。MR Steiger检验结果为“TRUE”，提示高血压导致OSA，而非相反(P=0)。
3 讨论
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据研究报道，OSA患者中30%~70%患有高血压，而高血压患者中的OSA发生率为30%~50%，由于OSA与高血压的共患率较高，因此，学者们不断探究两者是否存在相互作用[6-8]。既往研究普遍认为OSA与高血压发病密切相关[17-29]。例如，一项横断面研究发现，OSA是收缩压和舒张压的重要预测指标，睡眠时每小时呼吸暂停事件每增加1次，高血压的概率就会增加约1%，而夜间血氧饱和度每降低10%，高血压的概率就会增加13%[30]。一项荟萃分析提示，OSA与难治性高血压之间存在明显关联(OR=2.842，95%CI 1.703~3.980，P<0.05)。与非OSA患者相比，轻度OSA患者患原发性高血压的风险为1.184倍(OR=1.184，95%CI 1.093~1.274，P<0.05)，中度OSA为1.316倍(OR=1.316，95%CI 1.197~1.433，P<0.05)，重度OSA为1.561倍(OR=1.561，95%CI 1.287~1.835，P<0.05)[31]。以上研究结果均提示OSA是高血压的危险因素，本研究的MR分析也显示OSA对高血压发病有促进作用，即基因预测的OSA患者患高血压的概率是基因预测非OSA患者的1.053倍，但并不如传统观察性研究中观察到的影响明显，提示既往研究中可能存在混杂因素或反向因果关系的干扰。OSA导致高血压发病可能存在多种机制。有学者提出，OSA期间低氧血症、高碳酸血症相关的交感神经激活与高血压的发生有关[32]。间歇性缺氧导致的肾素-血管紧张素-醛固酮系统激活、肠道菌群失调及血管内皮功能受损也可能是OSA患者高血压升高的原因[33-35]。这些机制有待进一步确认，且不同机制可能会相互影响，并干扰最终的作用效果。许多研究证实，持续气道正压通气治疗可使OSA患者的高血压明显改善，尤其是难治性高血压[37-39]。
也有学者认为，OSA与高血压之间存在双向因果关系，即高血压也是OSA的危险因素[40-43]。缺氧/高碳酸血症相关的交感神经激活可能是连接OSA与高血压的关键病理生理机制[6]。一项荟萃分析提示，针对高血压的降压治疗可降低OSA的严重程度[44]。总体而言，既往针对高血压对OSA发病影响的研究相对较少，研究者对于该方向的关注度远不如OSA影响高血压发病的研究，目前仍缺乏该方向的大样本临床研究。本研究双向MR分析显示OSA与高血压互为因果，同时发现高血压可明显影响OSA的发病，基因预测的高血压患者患OSA的概率是基因预测非高血压患者的1.812倍，这为两者的相关性分析提供了基因依据和新的研究方向。因此，在临床治疗中，对于高血压与OSA共患的患者，优先治疗高血压对于共病的有效性可能大于优先治疗OSA。
本研究具有以下优点：(1)MR在理论上消除了混杂偏倚，控制了反向因果关系对结果的干扰，较大程度地避免了混杂因素和反向因果关系的干扰，结果较为可靠[45]；(2)基于数十万人群的大型GWAS数据，避免了小样本造成的偏倚；(3)采用多种MR方法对IVW进行了补充，并对IVs进行了质量评估，增强了结果的可信度。
本研究也存在一定的局限性：(1)MR模型假设暴露与结局之间呈线性相关，但实际两者也存在非线性相关的可能性[46]；(2)OSA所选IVs的数量只有5个，未能识别离群值，可能会对结果造成一定影响；(3)本研究存在异质性，提示暴露与结局的关系可能受到不同年龄、性别等因素的影响，但目前因无法获取年龄、性别的相关数据，故并未进行分层分析，应在未来的研究中进一步深入探究；(4)本研究的对象为欧洲人群，结果不能简单地直接推广到其他人种。
综上所述，本研究双向MR分析显示OSA与高血压互为因果的关系，其中高血压对OSA发病的影响较为明显，为两者的因果关系提供了基因层面的证据。因此，对于高血压患者应常规进行打鼾情况的病史采集，并进行定期睡眠呼吸监测，以便尽早发现OSA并及时干预。同样，OSA患者也应规律监测血压、定期体检，以便早期发现高血压。
基金
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  • 云南省教育厅研究生项目(2022Y863)
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2024年第49卷第6期
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doi: 10.11855/j.issn.0577-7402.2641.2024.0110
  • 接收时间：2022-12-29
  • 首发时间：2025-11-21
  • 出版时间：2024-06-28
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  • 收稿日期：2022-12-29
  • 录用日期：2023-08-03
基金
Scientific Research Foundation of Yunnan Provincial Department of Education(2022Y863)
云南省教育厅研究生项目(2022Y863)
作者信息
    1武警重庆总队医院耳鼻咽喉科，重庆 400061
    2大理大学第一附属医院耳鼻咽喉科，云南大理 671000
    3武警重庆总队医院普外科，重庆 400061

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