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Article(id=1240977226901017379, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240977214964036360, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202412174, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1733846400000, receivedDateStr=2024-12-11, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773801627135, onlineDateStr=2026-03-18, pubDate=1748102400000, pubDateStr=2025-05-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773801627135, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773801627135, creator=13701087609, updateTime=1773801627135, updator=13701087609, issue=Issue{id=1240977214964036360, tenantId=1146029695717560320, journalId=1227665162245664772, year='2025', volume='52', issue='10', pageStart='1729', pageEnd='1920', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773801624289, creator=13701087609, updateTime=1773825591019, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241077738770068227, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240977214964036360, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241077738770068228, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240977214964036360, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1909, endPage=1914, ext={EN=ArticleExt(id=1240977227374973754, articleId=1240977226901017379, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Mendelian randomization study of the association between nuclear magnetic resonance determined lipoprotein profiles and osteoarthritis, columnId=1228016569138213037, journalTitle=Modern Preventive Medicine, columnName=Clinical Medicine and Prevention, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the association between lipoproteins determined by nuclear magnetic resonance (NMR) and osteoarthritis (OA) using Mendelian randomization (MR).

Methods

Using the genome-wide association study (GWAS) of 116 NMR-based lipoproteins and total OA, knee OA, and hip OA, univariate MR analyses were conducted to assess the association between lipoproteins and osteoarthritis.

Results

Univariate MR results showed that 73 lipoproteins were significantly associated with total OA, LDL diameter (OR=1.07, 95% CI: 1.03-1.11) and small HDL phospholipids (OR=1.05, 95% CI: 1.01-1.08) presented risk effects on total OA,while the remaining lipoproteins were protective and were distributed in apolipoprotein B, cholesterols, intermediate density lipoprotein, and very-low-density lipoprotein subclasses. 57 lipoproteins were significantly associated with knee OA, all of which were found in total OA, with LDL diameter (OR=1.11, 95% CI: 1.05-1.18) presenting a risk effect on knee OA, while the remaining lipoproteins were protective. 90 lipoproteins were significantly associated with hip OA, with 7 of which presenting risk effects, distributed among HDL cholesterol (OR=1.07, 95% CI: 1.01-1.18)and most of its medium- and large-sized subclasses, while the remaining lipoproteins were protective.

Conclusion

NMR-based lipoproteins were causally associated with OA, as their different sizes and lipid compositions play different roles for OA at different sites.

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目的

采用孟德尔随机化（Mendelianrandomization,MR）探索核磁共振测定的脂蛋白谱与骨关节炎（osteoarthritis，OA）之间的因果关联。

方法

利用核磁共振测定的116个脂蛋白和总体OA及膝OA、髋OA的全基因组关联研究汇总数据，采用单变量MR分析评估脂蛋白与OA的因果关联。

结果

单变量MR结果显示，共有73个脂蛋白与总体OA显著相关，其中LDL直径（OR=1.07，95% CI：1.03~1.11）和小HDL磷脂（OR=1.05，95% CI：1.01~1.08）对总体OA起危险作用，其余脂蛋白均起保护作用，分布在载脂蛋白B、胆固醇类、中间密度脂蛋白类及极低密度脂蛋白类中。57个脂蛋白与膝OA显著相关，均可在总体OA中发现，其中LDL直径（OR=1.11，95% CI ：1.05~1.18）对膝OA起危险作用，其他脂蛋白均起保护作用。90个脂蛋白与髋OA显著相关，其中7个脂蛋白呈现危险作用，分布在HDL胆固醇（OR=1.07，95% CI：1.01~1.13）及其大部分中大型亚类中，其他脂蛋白均起保护作用。

结论

核磁共振测定的脂蛋白谱与OA存在因果关联，其不同尺寸、不同脂质成分对不同部位的OA效应不同。

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蒲小兵，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=8laLcVXetKH9ASMqorIRhA==, magXml=CvTTP0oP/TMiKWJGl9maDQ==, pdfUrl=null, pdf=FAOu4TENDP72olFJI060lQ==, pdfFileSize=835344, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=NIcfRY3rq/SH701VsxlBAw==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=9uFLbEip7zIHoigAcLk2Zg==, mapNumber=null, authorCompany=null, fund=null, authors=

谭芷馨（2001—），女，硕士在读，研究方向：流行病与卫生统计学

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谭芷馨（2001—），女，硕士在读，研究方向：流行病与卫生统计学

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谭芷馨（2001—），女，硕士在读，研究方向：流行病与卫生统计学

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Trends in Endocrinology and Metabolism: TEM, 2012, 23(11): 576-581., articleTitle=Estrogen and the skeleton, refAbstract=null)], funds=[Fund(id=1240996915299545792, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, awardId=2022YFC3600604, language=CN, fundingSource=国家重点研发计划(2022YFC3600604), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1240996908018233676, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, xref=1., ext=[AuthorCompanyExt(id=1240996908026622284, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, companyId=1240996908018233676, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=West China School of Public Health/West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China), AuthorCompanyExt(id=1240996908035010894, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, companyId=1240996908018233676, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.四川大学华西公共卫生学院/华西第四医院，四川 成都 610041)]), AuthorCompany(id=1240996908144062802, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, xref=2., ext=[AuthorCompanyExt(id=1240996908152451411, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, companyId=1240996908144062802, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.海南医科大学附属海南总医院)]), AuthorCompany(id=1240996908244726104, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, xref=3., ext=[AuthorCompanyExt(id=1240996908253114713, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, companyId=1240996908244726104, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.四川大学华西公共卫生学院/华西第四医院骨科)])], figs=[ArticleFig(id=1240996913051398768, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, language=EN, label=Fig.1, caption=Framework for the two - sample Mendelian randomization study design, figureFileSmall=baqklSDnb4xAO2vzYP/g0g==, figureFileBig=aYtHbb385xc4u6MuuHWEiQ==, tableContent=null), ArticleFig(id=1240996913156256377, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, language=CN, label=图1, caption=两样本MR设计框架, figureFileSmall=baqklSDnb4xAO2vzYP/g0g==, figureFileBig=aYtHbb385xc4u6MuuHWEiQ==, tableContent=null), ArticleFig(id=1240996913303057035, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, language=EN, label=Fig.2, caption=A The OR and 95%CIfor the causal associations between lipoprotein profiles and total osteoarthritis; B The OR and 95%CI for the causal associations between lipoprotein profiles and knee osteoarthritis; C The OR and 95%CI for the causal associations between lipoprotein profiles and hip osteoarthritis, figureFileSmall=riqZaErONkDeu3mBHpzCNw==, figureFileBig=Qrlm+Yqzx1/5Z10Fg+wfqw==, tableContent=null), ArticleFig(id=1240996913395331738, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, language=CN, label=图2, caption=A脂蛋白谱与总体骨关节炎因果关联的OR值与95%CI；B脂蛋白谱与膝骨关节炎因果关联的OR值与95%CI；C 脂蛋白谱与髋骨关节炎因果关联的OR值与95%CI, figureFileSmall=riqZaErONkDeu3mBHpzCNw==, figureFileBig=Qrlm+Yqzx1/5Z10Fg+wfqw==, tableContent=null), ArticleFig(id=1240996913508577957, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, language=EN, label=Table 1, caption=

GWAS summary data of lipoprotein profiles and osteoarthritis

, figureFileSmall=null, figureFileBig=null, tableContent=
表型SNP数量样本量
（病例/对照）		人群性别发表年份PMID
暴露
核磁共振测定的脂蛋白谱20~65136 016混合人群（欧洲和亚洲，主要为欧洲）男女混合202438 448 586
结局
总体骨关节炎-826 690（177 517/649 173）欧洲男女混合202134 450 027
膝骨关节炎-396 054（62 497/333 557）欧洲男女混合202134 450 027
髋骨关节炎-353 398（36 445/316 943）欧洲男女混合202134 450 027
), ArticleFig(id=1240996915018527404, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240977226901017379, language=CN, label=表1, caption=

脂蛋白谱与骨关节炎GWAS汇总数据简要信息

, figureFileSmall=null, figureFileBig=null, tableContent=
表型SNP数量样本量
（病例/对照）		人群性别发表年份PMID
暴露
核磁共振测定的脂蛋白谱20~65136 016混合人群（欧洲和亚洲，主要为欧洲）男女混合202438 448 586
结局
总体骨关节炎-826 690（177 517/649 173）欧洲男女混合202134 450 027
膝骨关节炎-396 054（62 497/333 557）欧洲男女混合202134 450 027
髋骨关节炎-353 398（36 445/316 943）欧洲男女混合202134 450 027
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核磁共振测定的脂蛋白谱与骨关节炎关联的孟德尔随机化研究
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谭芷馨 1 , 武璇 1 , 邱伶俐 1 , 姜侠 1 , 李佳圆 1 , 张本 1, 2 , 蒲小兵 3
现代预防医学 | 临床与预防 2025,52(10): 1909-1914
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现代预防医学 | 临床与预防 2025, 52(10): 1909-1914
核磁共振测定的脂蛋白谱与骨关节炎关联的孟德尔随机化研究
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谭芷馨1, 武璇1, 邱伶俐1, 姜侠1, 李佳圆1, 张本1, 2, 蒲小兵3
作者信息
  • 1.四川大学华西公共卫生学院/华西第四医院，四川 成都 610041
  • 2.海南医科大学附属海南总医院
  • 3.四川大学华西公共卫生学院/华西第四医院骨科

    • 谭芷馨（2001—），女，硕士在读，研究方向：流行病与卫生统计学

通讯作者:

蒲小兵，E-mail：
Mendelian randomization study of the association between nuclear magnetic resonance determined lipoprotein profiles and osteoarthritis
Zhi-xin TAN1, Xuan WU1, Ling-li QIU1, Xia JIANG1, Jia-yuan LI1, Ben ZHANG1, 2, Xiao-bing PU3
Affiliations
  • West China School of Public Health/West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China
出版时间: 2025-05-25 doi: 10.20043/j.cnki.MPM.202412174
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摘要
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目的

采用孟德尔随机化（Mendelianrandomization,MR）探索核磁共振测定的脂蛋白谱与骨关节炎（osteoarthritis，OA）之间的因果关联。

方法

利用核磁共振测定的116个脂蛋白和总体OA及膝OA、髋OA的全基因组关联研究汇总数据，采用单变量MR分析评估脂蛋白与OA的因果关联。

结果

单变量MR结果显示，共有73个脂蛋白与总体OA显著相关，其中LDL直径（OR=1.07，95% CI：1.03~1.11）和小HDL磷脂（OR=1.05，95% CI：1.01~1.08）对总体OA起危险作用，其余脂蛋白均起保护作用，分布在载脂蛋白B、胆固醇类、中间密度脂蛋白类及极低密度脂蛋白类中。57个脂蛋白与膝OA显著相关，均可在总体OA中发现，其中LDL直径（OR=1.11，95% CI ：1.05~1.18）对膝OA起危险作用，其他脂蛋白均起保护作用。90个脂蛋白与髋OA显著相关，其中7个脂蛋白呈现危险作用，分布在HDL胆固醇（OR=1.07，95% CI：1.01~1.13）及其大部分中大型亚类中，其他脂蛋白均起保护作用。

结论

核磁共振测定的脂蛋白谱与OA存在因果关联，其不同尺寸、不同脂质成分对不同部位的OA效应不同。

孟德尔随机化  /  脂蛋白  /  核磁共振  /  骨关节炎
Objective

To investigate the association between lipoproteins determined by nuclear magnetic resonance (NMR) and osteoarthritis (OA) using Mendelian randomization (MR).

Methods

Using the genome-wide association study (GWAS) of 116 NMR-based lipoproteins and total OA, knee OA, and hip OA, univariate MR analyses were conducted to assess the association between lipoproteins and osteoarthritis.

Results

Univariate MR results showed that 73 lipoproteins were significantly associated with total OA, LDL diameter (OR=1.07, 95% CI: 1.03-1.11) and small HDL phospholipids (OR=1.05, 95% CI: 1.01-1.08) presented risk effects on total OA,while the remaining lipoproteins were protective and were distributed in apolipoprotein B, cholesterols, intermediate density lipoprotein, and very-low-density lipoprotein subclasses. 57 lipoproteins were significantly associated with knee OA, all of which were found in total OA, with LDL diameter (OR=1.11, 95% CI: 1.05-1.18) presenting a risk effect on knee OA, while the remaining lipoproteins were protective. 90 lipoproteins were significantly associated with hip OA, with 7 of which presenting risk effects, distributed among HDL cholesterol (OR=1.07, 95% CI: 1.01-1.18)and most of its medium- and large-sized subclasses, while the remaining lipoproteins were protective.

Conclusion

NMR-based lipoproteins were causally associated with OA, as their different sizes and lipid compositions play different roles for OA at different sites.

Mendelian randomization  /  Lipoproteins  /  Nuclear magnetic resonance  /  Osteoarthritis
谭芷馨, 武璇, 邱伶俐, 姜侠, 李佳圆, 张本, 蒲小兵. 核磁共振测定的脂蛋白谱与骨关节炎关联的孟德尔随机化研究. 现代预防医学, 2025 , 52 (10) : 1909 -1914 . DOI: 10.20043/j.cnki.MPM.202412174
Zhi-xin TAN, Xuan WU, Ling-li QIU, Xia JIANG, Jia-yuan LI, Ben ZHANG, Xiao-bing PU. Mendelian randomization study of the association between nuclear magnetic resonance determined lipoprotein profiles and osteoarthritis[J]. Modern Preventive Medicine, 2025 , 52 (10) : 1909 -1914 . DOI: 10.20043/j.cnki.MPM.202412174
正文
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骨关节炎（osteoarthritis，OA）是一种以关节疼痛、活动受限为主要临床表现的慢性退行性关节疾病[1]，常见于膝、髋等关节[2]。随着人口老龄化程度的加深，OA的患病率和发病率居高不下；据报道，我国OA的总患病率约为15%，并且随年龄增长而增加，60岁以上达50%，而70岁以上则可高达80%[3]，给个人和社会带来了巨大的经济负担。
OA的危险因素包括年龄、性别、肥胖和遗传等[4-5]，近年来有研究发现代谢稳态失衡也与其发病机制有关[6]。一些观察性研究发现了可能与OA发生发展密切相关的脂质指标，包括甘油三酯(Total triglycerides，TG)、总胆固醇(Total cholesterol，TC)、高密度脂蛋白(High-density lipoprotein，HDL)和低密度脂蛋白(Low-density lipoprotein，LDL)。研究普遍认为TG和TC对OA起到危险作用[7-8]，然而HDL和LDL对OA的作用在不同研究中并不统一，Charles-Lozoya等人的一项横断面研究报道了HDL对OA的保护作用（OR=0.97，95% CI：0.95~0.99）[9]，但在另一项前瞻性队列研究中发现HDL对OA起到危险作用（OR=1.05，95% CI：1.02~1.07）[8]，类似的争议还发生在LDL中[7，10]。由于观察性研究容易受到反向因果和环境混杂因素的影响，可能会导致研究结果相互矛盾。
孟德尔随机化（Mendelianrandomization,MR）通过遗传变异作为工具变量（instrumentalvariable，IV）来评估暴露-结果的因果关联[11]，可以克服传统流行病学研究的局限。迄今为止，已有6篇关于脂质指标与OA的MR研究，在LDL、TG和TC中都没有得到一致的结论[12-17]，且没有一篇研究发现HDL与OA存在因果关联。目前所有的研究都仅限于四种众所周知的“临床血脂”，而脂蛋白可通过基于核磁共振的代谢组学技术来进行更精确的测量，根据颗粒尺寸和脂质成分精细绘制脂蛋白图谱[18-19]，不同的组合可以发挥不同的生理功能作用[20]。该技术已被用于多种代谢相关疾病，以阐明亚类脂蛋白的不同病因作用[21-24]，但其在OA中尚未有所应用。
因此，在本研究中，我们利用当前最大的核磁共振测定的脂蛋白谱和OA（总体及膝关节、髋关节）全基因组关联研究（genome-wide association study, GWAS）汇总数据，利用鉴定发现的工具变量，通过单变量MR分析，探讨脂蛋白谱与OA之间的因果关联，为OA防治提供潜在治疗靶点与策略。
1　方法
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1.1　数据来源
本研究使用的GWAS均为可公开获得的汇总数据结果，基本信息见表1。基于核磁共振技术测定的脂蛋白谱GWAS来源于目前最新且规模最大的一项全基因组关联研究汇总数据[25]，该研究涉及136 016名不同血统的成年个体（4 435名东亚人、11 340名南亚人、120 241名欧洲人）。该研究将脂蛋白颗粒尺寸、颗粒浓度和脂质成分结合起来，测量并注释了116个脂质性状。在传统的脂蛋白分类（HDL、LDL、中间密度脂蛋白（Intermediate-density lipoprotein，IDL）和极低密度脂蛋白（Very-low-density lipoprotein，VLDL））基础上，根据核磁共振确定的脂蛋白颗粒尺寸进一步细分为不同亚类，分别注释为非常小（very small，XS）、小（small，S）、中（middle，M）、大（large，L）、非常大（very large，XL）和极大（extremely large，XXL）。同时，量化了这些亚类的总体颗粒特征，即颗粒浓度（particle concentration，P）和直径（diameter，D）。此外，还评估了这些亚类的脂质成分，包括总胆固醇（total cholesterol，C）、胆固醇酯（cholesteryl esters，CE）、游离胆固醇（free cholesterol，FC）、总脂质（total lipids，L）、磷脂（phospholipids，PL）和甘油三酯（triglycerides，TG）。比如：VLDL-D表示VLDL的直径，S-HDL-P表示小HDL的整体浓度，S-VLDL-TG表示小VLDL的甘油三酯。
OA的汇总数据来源于骨关节炎遗传学（Genetics of Osteoarthritis，GO）联盟[26]，是迄今为止最大规模的OA全基因组关联研究荟萃分析，这项广泛的研究整合了13个国际OA队列的数据，多达826 690名参与者，参与者为欧洲血统并提供了知情同意。OA的定义如下：自我报告的骨关节炎、临床诊断、第十版国际疾病分类（International Classification of Diseases, Tenth Revision，ICD-10）代码或放射学，具体取决于队列中可用的数据。对照组为无骨关节炎患者或基于人群，有或没有ICD代码排除。从身体的不同部位选择了骨关节炎表型，我们将任何部位的OA（总体OA）作为主要研究结果（177 517例病例/649 173例对照），并将不同部位的OA（两个负重关节，即膝关节OA（KOA）（62 497例病例/333 557例对照）和髋关节OA（HOA）（36 445例病例/316 943例对照））作为次要研究结果。
1.2　工具变量的选择
对于116个脂蛋白，我们都逐一从其原始GWAS中提取了具有显著意义的独立单核苷酸多态性位点（Single Nucleotide Polymorphism，SNP）作为工具变量（P< 5×10-8，距离<1 000 kb，连锁不平衡参数r2<0.001）。为避免弱工具变量偏倚，我们使用F统计量公式计算工具变量强度，F> 10说明不存在弱工具变量偏倚，计算公式为：
N指的是暴露表型的GWAS样本含量，K指的是所选择的工具变量个数，R2（遗传工具变量解释的表型变异）从原始GWAS中提取，或使用β（SNP与暴露的估计遗传关联）和MAF通过公式计算得出：
116个脂蛋白的工具变量个数从20个到65个不等，R2从2.8%到12.9%不等，F统计量从15.4到38.5不等，表明不存在弱工具变量偏倚。
1.3　统计分析
本研究使用单变量MR方法探究116个脂蛋白和OA之间的因果关联，分析原理见图1。采用随机效应逆方差加权法（inverse-variance weighted，IVW）作为主要分析方法来估计因果效应。IVW是一种将结果效应系数与暴露效应系数进行回归的方法，不设置截距项，针对每个作为工具变量的SNPs计算Wald Ratio，然后运用固定效应模型或随机效应模型进行多个SNPs位点Wald Ratio的合并，得到最终的效应值[27]。此外还采用MR-Egger回归和加权中位数法（weighted medianestimator, WME）作为敏感性分析进一步验证主要分析结果，确保分析结果的稳健性和一致性。MR-Egger法允许作为工具变量的所有SNPs存在水平多效性，可以对暴露和结局的因果关联性提供准确估计[28-29]。MR-Egger法与IVW法的主要区别在于MR-Egger法要考虑截距项，并且通过截距进行定向水平多效性的检测[28]，截距项等于零或者不存在显著的统计学意义时（P>0.05），表示不存在水平多效性，因果关联的估计值则用其斜率表示。WME法允许少于50%的SNPs具有水平多效性，将作为工具变量的所有遗传易感位点按照权重进行排序后，选取中位数作为统计分析的研究结果，该方法可以在50%无效工具变量的情况下仍提供一致的效应估计值[30]。FDR（false discovery rate）法用于校正多重比较，如果IVW方法能通过FDR校正（PFDR<0.05），且MR-Egger回归和WME方法的结果方向与IVW方法一致，则认为该脂蛋白与OA的关联具有统计学意义。
根据MR-Egger回归截距判断是否存在水平多效性，当P<0.05时，提示水平多效性存在，并采用Cochran Q检验判断SNPs异质性，若检验P<0.05，则表示SNPs之间存在异质性。
所有分析均使用“Two Sample MR（0.5.7）”、“Mendelian Randomization（0.7.0）”在R Version 4.3.1软件中进行。
2　结果
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2.1　脂蛋白谱对总体OA的因果关联
异质性检验结果显示，存在部分统计量的P < 0.05，提示SNP间存在异质性，故使用随机效应IVW模型。结果如图2所示，在116个遗传预测的脂蛋白中，有73个与总体OA显著相关（PFDR<0.05），MR-Egger回归法和WME法结果与IVW法一致，提示结果的稳健性。
在LDL类中，除LDL-D增加总体OA的发病风险外（OR=1.07，95% CI：1.03~1.11），其他LDL，包括LDL-C（OR=0.95，95% CI：0.92~0.98）、LDL-TG（OR=0.95，95% CI：0.91~0.98）及其亚类（LDL亚类：OR=0.93~0.95）均降低总体OA的发病风险（PFDR< 0.05）。在HDL类中，尽管未发现HDL-C对总体OA的作用，但发现其亚型HDL3-C降低总体OA的发病风险（OR=0.94，95% CI：0.90~0.99），其大部分亚类结果也与此一致（OR=0.937~0.943，PFDR<0.05），仅有S-HDL-PL（OR=1.05，95% CI：1.01~1.08）增加总体OA的发病风险。
此外，其余的脂蛋白均降低总体OA发病风险，分别是载脂蛋白B（ApoB：OR=0.94，95%CI：0.91~0.96），胆固醇类（OR=0.94~0.95，PFDR<0.05），所有的IDL（OR=0.95~0.96，PFDR<0.05）以及大部分VLDL（包括VLDL-C及其亚类）（OR=0.93~0.96，PFDR< 0.05）。
2.2　脂蛋白谱对不同部位OA的因果关联
在不同部位OA中，KOA的结果与总体OA大致相同，共有57个脂蛋白与KOA显著相关（PFDR< 0.05），均可在总体OA中发现。与总体OA结果一致，除LDL-D增加KOA发病风险外（OR=1.11，95% CI：1.05~1.18），其余脂蛋白都降低KOA的发病风险。
在HOA中，共有90个脂蛋白与HOA显著相关（PFDR<0.05）。与总体OA相比，新增了血清TG（Serum-TG：OR=0.92，95%CI：0.87~0.98）降低HOA的发病风险。在VLDL类中，新增了VLDL-TG（OR=0.92，95% CI：0.87~0.98），并进一步覆盖了所有的VLDL亚类（OR=0.88~0.94，PFDR<0.05），均降低HOA的发病风险。此外，尽管在总体OA中起危险作用的2个脂蛋白（LDL-D、S-HDL-PL）并没有在HOA中得到验证，但新增了7个脂蛋白增加HOA的发病风险，分布在HDL-C（OR=1.07，95% CI：1.01~1.13）及其大部分中大型尺寸亚类中（OR=1.06~1.11，PFDR<0.05）。同为中型尺寸的HDL，M-HDL-CE增加HOA的发病风险（OR=1.11，95% CI：1.01~1.21），而M-HDL-TG则降低HOA的发病风险（OR=0.93，95% CI：0.87~0.99）。其他脂蛋白都降低HOA的发病风险，与总体OA保持一致。
MR-Egger回归法截距显示不存在水平多效性(P>0.05)，以上结果说明结果均不受水平多效性或其他潜在偏移影响，具有稳健性和可靠性。
3　讨论
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本研究利用GWAS汇总数据，运用单变量MR方法分析了核磁共振测定的脂蛋白谱与总体OA、KOA、HOA之间的因果关联。结果证实脂蛋白谱与OA之间存在因果关联，且不同尺寸，不同脂质成分组合的脂蛋白对不同部位的OA效应不一。本研究的发现为理解OA的复杂病理机制提供了新的视角，提示了潜在的生物标志物，可能作为不同OA患病人群疾病风险筛查和预后评估的指标，有助于开发新的预防、诊断和治疗策略。
既往观察性研究发现LDL会增加OA的发病风险，例如，Liu等人研究发现高LDL-C水平与KOA的发生有关（OR=1.79，95% CI：1.14~2.82）[7]。由于肥胖和高脂血症都是代谢综合征的表现，而肥胖是OA的危险因素，在观察性研究中LDL升高与OA有关可能是由于肥胖的干扰，尽管LDL胆固醇通常被视为“坏胆固醇”，我们的MR结果提供了另一种假设，即遗传预测的LDL水平与OA风险降低相关，这与此前George、D. Gill、Wang等的MR研究均发现LDL是OA的保护因素的结果一致[12-13,17]。可能的机制是LDL可以降低人原代软骨细胞和成纤维样滑膜细胞中ApoA1水平及血清淀粉样蛋白A诱导的关节炎性炎症[31]。未来还需要进一步研究来解释肥胖、脂质代谢及OA之间的复杂机制。此外，LDL-D在总体OA和KOA中都发挥危险作用，这与其他LDL类的作用相矛盾，提示我们需要进一步研究来明确LDL粒径在OA进展中的作用。作为LDL的载脂蛋白和LDL受体的配体，ApoB对OA的保护作用可能是通过LDL介导的[32]。ApoB和LDL同时升高是否发挥保护作用尚不清楚，需要进一步研究。
HDL胆固醇通常被认为是一种“好胆固醇”，尤其是在心血管代谢疾病方面，但最近也有研究发现其亚类具有截然相反的作用。Li等人进行了一项前瞻性队列研究，涉及来自UKBB的65 275名2型糖尿病患者，发现了不同尺寸HDL颗粒对心血管疾病风险的影响相反（S-HDL-P：HR=0.78，95%CI：0.69~0.87；L-HDL-P：HR=1.28，95%CI：1.12~1.45）[33]。这些结果与我们的MR结果相似，我们不仅观察到了亚类HDL在HOA中的颗粒尺寸的异质性，还发现了其脂质成分的异质性。例如，S-HDL-CE与HOA负相关，而M-HDL-CE与HOA正相关，同为中型尺寸的M-HDL-TG却与HOA负相关。这一证据提示我们精细分型的脂蛋白谱相较于传统的粗略测量方法能提供更多的信息，强调了不同脂蛋白颗粒尺寸和脂质成分的亚类HDL可能发挥不同的病因作用。具体的机制尚不清楚，还需要更多实验室证据来支持这一结论。
VLDL是一组主要由甘油三酯组成的脂蛋白，可转运几乎所有的内源性甘油三酯[34]。VLDL释放甘油三酯降解后形成IDL，并可进一步降解为LDL。相较于TG和LDL，VLDL和IDL在临床上的运用较少，但它们也有其优越性，VLDL相较于TG可以更全面反映脂质代谢，而IDL水平的变化可能对早期异常脂质代谢更为敏感[35]。目前越来越多的研究开始挖掘IDLs和VLDL及其亚类的潜在临床意义，本研究提示了VLDL及其亚类及IDLs对OA的潜在价值，未来的OA研究还可多关注VLDLs和IDLs，以综合评估疾病的发病情况并制定治疗策略。
本研究利用当前发表的最大最新的GWAS数据进行分析，样本量充足，具有较高的统计效能，是第一个探讨精细分型的脂蛋白谱与OA之间关联的MR研究，可为OA患者提供更精确的风险评估和药物开发提供更有意义的参考。但本研究仍有很多不足与有待发展的地方，首先，由于数据受限，我们使用了混合了欧洲人群和部分亚洲人群的脂蛋白谱数据库，而其他GWAS数据库均来自欧洲人群，因此脂蛋白谱与OA之间的关联可能存在一定程度的不准确性。但欧洲人在该数据库中占比大于88％，因此，可以认为这种不准确性的影响是有限的。其次，本研究的人群主要由欧洲血统的个体组成，这可能导致种族偏倚，在将本研究的结果推广到其他种族背景的人群时，需要保持谨慎，未来需要更多在不同种族的GWAS研究，以验证该结果的普适性。此外，考虑到雌激素在骨代谢中的重要作用，对性别和绝经状态进行分层分析可能提供更多信息[36]，但由于缺乏相关的GWAS数据，无法进行深入分析。关于肥胖、脂代谢和OA的复杂作用机制，还需要进一步研究进行多维度地探索。
综上所述，本研究应用MR方法探究核磁共振测定的脂蛋白谱与OA之间的因果关联，发现ApoB、胆固醇类、LDL、IDL、大部分VLDL类对OA（总体及膝关节、髋关节）发挥保护作用，LDL-D对总体OA和KOA发挥危险作用，而部分中大型HDL亚类对HOA发挥危险作用。该研究结论为进一步了解骨关节炎的潜在机制并寻找新的策略进行早期干预和延缓进展提供依据。
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  • 国家重点研发计划(2022YFC3600604)
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doi: 10.20043/j.cnki.MPM.202412174
  • 接收时间：2024-12-11
  • 首发时间：2026-03-18
  • 出版时间：2025-05-25
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  • 收稿日期：2024-12-11
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    1.四川大学华西公共卫生学院/华西第四医院，四川 成都 610041
    2.海南医科大学附属海南总医院
    3.四川大学华西公共卫生学院/华西第四医院骨科

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