目的·通过孟德尔随机化（Mendelian randomization，MR）分析探讨血浆蛋白锌-α2-糖蛋白1（zinc-alpha-2-glycoprotein 1，AZGP1）与心力衰竭（heart hailure，HF）之间的因果关系，并结合实验验证AZGP1与HF的关联。方法·采用双样本MR分析，整合血浆蛋白和HF的大规模全基因组关联研究（genome-wide association study，GWAS）数据，评估AZGP1与HF的因果关系。采用逆方差加权（inverse-variance weighted，IVW）作为主要分析方法，辅以MR-Egger回归、加权中位数法和简单中位数法，评估AZGP1对HF的因果效应。通过MR-PRESSO整体测试和MR-Egger截距分析检验水平多效性，利用共定位分析验证遗传位点重叠性。进一步整合临床样本（84例HF患者与68例健康对照），采用酶联免疫吸附分析（enzyme-linked immunosorbent assay，ELISA）检测血浆AZGP1水平。结果·MR分析显示AZGP1水平升高显著降低HF风险（OR=0.82，95%CI 0.75~0.90，P=1.70×10^-5）。共定位分析表明AZGP1表达与HF受相同遗传变异调控（H4的后验概率=0.69）。敏感性分析和反向MR分析结果显示结果具有稳健性。ELISA实验结果显示HF患者血浆AZGP1水平显著低于健康对照组。结论·AZGP1对HF具有保护性因果效应，可作为HF治疗的潜在生物标志物。

Objective ·To investigate the causal relationship between plasma zinc-alpha-2-glycoprotein 1 (AZGP1) and heart failure (HF) by using Mendelian randomization (MR) analysis and experimental validation. Methods ·A two-sample MR analysis was performed to assess the causal relationship between AZGP1 and HF by integrating large-scale genome-wide association study (GWAS) data on plasma proteins and HF. The inverse-variance weighted (IVW) method was employed as the primary analytical approach, supplemented by MR-Egger regression, weighted median, and simple median methods. Horizontal pleiotropy was tested by using MR-PRESSO global test and MR-Egger intercept analysis. Colocalization analysis was conducted to validate genetic locus overlap. Additionally, a clinical cohort (84 HF patients and 68 healthy controls) was analyzed, with plasma AZGP1 levels quantified by enzyme-linked immunosorbent assay (ELISA). Results ·MR analysis showed that elevated plasma AZGP1 levels were significantly associated with reduced HF risk (OR=0.82, 95%CI 0.75‒0.90, P=1.70×10^-5). Colocalization analysis confirmed that AZGP1 expression and HF shared causal genetic variants (posterior probability for H4=0.69). Sensitivity and reverse MR analyses supported the robustness of the results. ELISA confirmed that plasma AZGP1 levels were significantly lower in HF patients compared to healthy controls, reinforcing its protective role in HF. Conclusion ·This study demonstrates AZGP1 exerts a protective causal effect on HF and may serve as a potential biomarker for HF treatment.