【摘要】 目的：通过两样本、双向孟德尔随机化（MR）分析方法，评估血浆蛋白质与心肌梗死之间的因果关系，筛选关键生物标志物并进行表达验证。方法：以公开的4 907种血浆蛋白质的全基因组关联研究（GWAS）数据作为暴露因素，单核苷酸多态性（SNP）作为工具变量，以4个心肌梗死数据集为结局。采用逆方差加权法（IVW），辅以简单模型、加权模型、加权中位数估计法（WME）和MR-Egger回归法进行两样本MR分析，评估暴露因素与结局之间的因果关系；采用韦恩图和词云图筛选出与心肌梗死相关的蛋白质作为候选生物标志物；采用反向MR分析评估反向因果关系；采用敏感性分析判断结果稳健性；采用免疫组织化学实验（IHC）验证蛋白酶体激活亚基1(PSME1)和膜囊泡蛋白分选相关蛋白29(VPS29)在小鼠主动脉中的表达；采用酶联免疫吸附试验（ELISA）验证PSME1和VPS29在急性心肌梗死患者血浆中的表达。结果：两样本MR分析表明，PSME1在4个数据集中均与心肌梗死呈显著负关联，OR(95%CI)分别为0.684(0.557～0.839)、0.990(0.987～0.993)、0.579(0.448～0.748)、0.993(0.990～0.996),P均<0.001；同样VPS29在4个数据集中也均与心肌梗死呈显著负关联，OR(95%CI)分别为0.902(0.862～0.945)、0.998(0.997～0.999)、0.866(0.808～0.929)、0.998(0.997～0.999),P均<0.001。反向MR分析未发现因果关系的反向性，敏感性分析表明结果稳健。IHC结果表明，与对照组小鼠相比，动脉粥样硬化背景的急性心肌梗死小鼠主动脉中PSME1和VPS29表达水平显著降低（P均<0.05）。ELISA结果表明，与正常对照人群相比，PSME1和VPS29在急性心肌梗死患者血浆中显著降低（P均<0.05）。结论：较高水平PSME1和VPS29与心肌梗死发生风险负相关，PSME1和VPS29可能是心血管疾病的保护性生物标志物。更多还原

【Abstract】 Objectives:This study aims to evaluate the causal relationship between plasma proteins and myocardial infarction(MI) using two-sample bidirectional Mendelian randomization(MR) analysis,identify key bio markers,and validate their expression.Methods:The study utilized publicly available genome-wide association study(GWAS) data of 4 907 plasma proteins as the exposure factor,with single nucleotide polymorphisms(SNPs) as instrumental variables,and four MI datasets as outcomes.Two-sample MR analysis was performed using the inverse variance weighted(IVW) method,complemented by simple model,weighted model,weighted median estimator(WME),and MR-Egger regression methods to assess the causal relationship between exposure factors and outcomes.Venn diagrams and word clouds were used to screen proteins associated with MI as candidate biomarkers.Reverse MR analysis was conducted to evaluate reverse causality.Sensitivity analysis was performed to assess the robustness of the results.Immunohistochemistry(IHC) was used to validate the expression of proteasome activator subunit 1(PSME1) and vacuolar protein sorting 29(VPS29) in the aorta of mice,and enzyme-linked immunosorbent assay(ELISA) was used to verify the expression of PSME1 and VPS29 in plasma from patients with acute myocardial infarction(AMI).Results:The two-sample MR analysis indicated that PSME1 was significantly negatively associated with myocardial infarction in all four datasets,with OR(95% CI) of 0.684(0.557-0.839),0.990(0.987-0.993),0.579(0.448-0.748),and 0.993(0.990-0.996),respectively,with all P<0.001.Similarly,VPS29 also showed a significant negative association with MI in all four datasets,with OR(95%CI) of 0.902(0.862-0.945),0.998(0.997-0.999),0.866(0.808-0.929),and 0.998(0.997-0.999),respectively,with all P<0.001.Reverse MR analysis did not detect reverse causality,and sensitivity analysis confirmed the robustness of the results.IHC results showed significantly reduced expression of PSME1 and VPS29 in the aortas of AMI mice with an atherosclerotic background compared to control mice(both P<0.05).ELISA results indicated significantly lower plasma levels of PSME1 and VPS29 in AMI patients compared to healthy controls(both P<0.05).Conclusions:Higher levels of PSME1 and VPS29 are negatively associated with the risk of MI,suggesting that PSME1and VPS29 may serve as protective biomarkers for cardiovascular diseases.更多还原