摘要
背景:动脉型肺动脉高压是一种破坏性心肺疾病,尚无法根治。有研究表明血浆蛋白与动脉型肺动脉高压之间存在关联,但其中的因果关系未得到具体阐明。目的:运用两样本孟德尔随机化方法,阐明血浆蛋白质组与动脉型肺动脉高压之间的因果关系,寻找动脉型肺动脉高压的潜在治疗靶点。方法:从冰岛数据库中获取35559名冰岛人的4907个适配体测量的血浆蛋白全基因组关联分析统计数据;从R9版Finn Gen数据库中获取动脉型肺动脉高压的全基因组关联分析统计数据,包括234例病例和265626例对照。利用孟德尔随机化和贝叶斯共定位分析方法进行分析,使用敏感性分析对研究结果进行检验,并构建蛋白-蛋白互作网络图,探索血浆蛋白与动脉型肺动脉高压的因果关系。结果与结论:①逆方差加权法、最大似然法和Wald比率法结果显示有19种蛋白与动脉型肺动脉高压存在因果关系(P<0.05),其中MFNG(OR=0.12,95%CI 0.02-0.61,P=0.01)、IFNAR1(OR=0.45,95%CI 0.24-0.84,P=0.012)等10种蛋白可能与动脉型肺动脉高压风险降低相关;GXYLT1(OR=3.48,95%CI 1.51-8.00,P=0.003)、PLG(OR=42.78,95%CI 2.49-734.31,P=0.01)等9种蛋白与动脉型肺动脉高压风险升高相关。运用错误发现率校正后,19种蛋白仍与动脉型肺动脉高压显著相关。②MR-Egger截距检验法、留一法等多项敏感性分析显示研究结果不存在水平多效性和异质性,说明研究结果的稳定性。③贝叶斯共定位分析结果显示,有PLG6(PPH4=1.0)、GXYLT1(PPH4=0.94)等6种血浆蛋白的PPH4>0.8,说明血浆蛋白和动脉型肺动脉高压全基因组关联研究在遗传关联方面具有相似的因果方差。④通过构建蛋白-蛋白互作网络图,发现PLG、Annexin A1、FGG、MMP7为核心蛋白。⑤文章采用孟德尔随机化的分析方法揭示了4907种血浆蛋白与动脉型肺动脉高压之间潜在的因果关联,提示血浆蛋白可能是动脉型肺动脉高压的潜在治疗靶点,研究中发现的核心蛋白也为进一步深入研究动脉型肺动脉高压的病理生理机制提供了理论依据;其次使用冰岛和FinnGen大规模的国际数据库进行分析,为动脉型肺动脉高压在特定人群和环境中提供了新的研究方向与治疗思路,同时也为中国防治动脉型肺动脉高压提供了可借鉴的思路与方法。
BACKGROUND:Pulmonary arterial hypertension is a destructive cardiopulmonary disease for which there is no cure.An association between plasma proteins and pulmonary arterial hypertension has been suggested,but the causal relationship has not been specifically elucidated.OBJECTIVE:To elucidate the causal relationship between plasma proteome and pulmonary arterial hypertension using a two-sample Mendelian randomization method,thereby searching for potential therapeutic targets for pulmonary arterial hypertension.METHODS:Plasma Protein Gene-Wide Association Analysis Statistics for 4907 Aptamer Measurements in 35559 Icelanders from the Icelandic Database;Genome-wide association analysis statistics for pulmonary arterial hypertension were obtained from the Finn Gen database,version R9,including 234 cases and 265626 controls.Analyses were performed using Mendelian randomization and Bayesian co-localization analysis,the findings were examined using sensitivity analyses,and protein-protein interaction network maps were constructed to explore the causal relationship between plasma proteins and pulmonary arterial hypertension.RESULTS AND CONCLUSION:(1)The results of inverse variance weighting,maximum likelihood and Wald ratio methods showed 19 proteins causally associated with pulmonary arterial hypertension(P<0.05).Among them,10 plasma proteins,including Beta-1,3-N-acetylglucosaminyltransferase manic fringe(odds ratio[OR]=0.12,95%confidence interval[CI]0.02-0.61,P=0.01)and interferon alpha/beta receptor 1(OR=0.45,95%CI 0.24-0.84,P=0.012),might be associated with a reduced risk of pulmonary arterial hypertension.In contrast,nine plasma proteins,such as glucoside xylosyltransferase 1(OR=3.48,95%CI 1.51-8.00,P=0.003)and plasminogen(OR=42.78,95%CI 2.49-734.31,P=0.01),might be associated with an increased risk of pulmonary arterial hypertension.After the false discovery rate was corrected,19 proteins remained significantly associated with pulmonary arterial hypertension.(2)Multiple sensitivity analyses such as the MR-Egger intercept test and leave-one-out method showed no horizontal multiplicity or heterogeneity in the results of the study,indicating the stability of the study’s results.(3)Bayesian co-localization analysis showed that six plasma proteins,including plasminogen(PPH4=1.0)and glucoside xylosyltransferase 1(PPH4=0.94),had PPH4>0.8,suggesting that plasma proteins and the genome-wide association study of pulmonary arterial hypertension had similar causal variance in terms of genetic association.(4)By constructing a protein-protein interaction network map,plasminogen,Annexin A1,fibrinogen gamma chain and matrix metalloproteinase 7 were found to be core proteins.(5)The article used Mendelian randomization analysis to reveal a potential causal association between 4907 plasma proteins and pulmonary arterial hypertension,suggesting that plasma proteins may be potential therapeutic targets for pulmonary arterial hypertension.The core proteins identified in the study also provide a theoretical basis for further in-depth study of the pathophysiological mechanisms of pulmonary arterial hypertension.Secondly,analyses using the large-scale international databases of Iceland and FinnGen provide new research directions and treatment ideas for pulmonary arterial hypertension in specific populations and environments,as well as ideas and methods that can be used to prevent and treat pulmonary arterial hypertension in China.
作者
张翠翠
陈欢语
于俏
黄宇轩
姚耿圳
邹旭
Zhang Cuicui;Chen Huanyu;Yu Qiao;Huang Yuxuan;Yao Gengzhen;Zou Xu(Guangzhou University of Chinese Medicine,Guangzhou 510000,Guangdong Province,China;Guangdong Provincial Hospital of Traditional Chinese Medicine,Guangzhou 510000,Guangdong Province,China)
出处
《中国组织工程研究》
北大核心
2026年第5期1331-1340,共10页
Chinese Journal of Tissue Engineering Research
基金
国家中医药管理局高水平中医药重点学科建设项目-中医药人才培养重点学科建设项目“中医心病学”(国中医药人教函[2023]85号zyyzdxk-2023160),项目负责人:邹旭
国家中医药管理局重点研究室建设项目(国中医药科技发[2012]27号),项目参与人:邹旭
广东省中医药局项目(粤中医办函[2020]1号),项目负责人:邹旭
广东省中医药局项目(20223011),项目负责人:邹旭
广州市科技计划项目(202201020290),项目负责人:邹旭
广州市科技计划项目(2023A03J0230),项目参与人:邹旭
广州市科技计划项目(2024A03J0040),项目负责人:姚耿圳
广东省中医院中医学术流派传承工作室建设项目(中医二院[2013]233号),项目参与人:邹旭。
关键词
动脉型肺动脉高压
血浆蛋白
蛋白质数量性状位点
孟德尔随机化
因果关系
药物靶点
蛋白互作
pulmonary arterial hypertension
plasma proteins
protein quantitative trait loci
Mendelian randomization
causality
drug targets
protein interactions
