孟德尔随机化解析AZGP1在心力衰竭中的保护作用

doi:10.3969/j.issn.1674-8115.2025.08.011

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (8): 1035-1045.doi: 10.3969/j.issn.1674-8115.2025.08.011

孟德尔随机化解析AZGP1在心力衰竭中的保护作用

李龙¹^,², 赵霞¹^,², 金珊¹, 李泽莹¹^,², 吕福强¹, 庞丽娟¹^,²(), 刘克坚¹()

^1.石河子大学第一附属医院，国家卫生健康委员会中亚高发病防治重点实验室，石河子 832000
^2.广东省湛江中心人民医院病理科，湛江 524000

收稿日期:2025-03-20 接受日期:2025-05-09 出版日期:2025-08-28 发布日期:2025-08-20
通讯作者: 刘克坚，教授，博士；电子信箱：25931884@qq.com
庞丽娟，教授，博士；电子信箱：ocean123456@163.com。
作者简介:第一联系人：为共同第一作者（co-first authors）。
基金资助:
国家自然科学基金(82060054);新疆生产建设兵团科技计划项目(2023AB018-12);湛江市科技发展专项资金(2023A214);湛江市疾病防治重点项目专题(2022A01103);湛江中心人民医院高层次人才科研启动经费项目(2022A15);2024人才发展基金-天山英才医药卫生中青年骨干人才(CZ001216);石河子大学博士基金项目(BS202205)

Deciphering the protective role of AZGP1 in heart failure through Mendelian randomization

LI Long¹^,², ZHAO Xia¹^,², JIN Shan¹, LI Zeying¹^,², LÜ Fuqiang¹, PANG Lijuan¹^,²(), LIU Kejian¹()

^1.National Health Commission Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction by Province and Ministry), The First Affiliated Hospital of Shihezi University, Shihezi 832000, China
^2.Department of Pathology, Central People's Hospital of Zhanjiang, Guangdong Province, Zhanjiang 524000, China

Received:2025-03-20 Accepted:2025-05-09 Online:2025-08-28 Published:2025-08-20
Contact: LIU Kejian, E-mail: 25931884@qq.com
PANG Lijuan: E-mail: ocean123456@163.com.
Supported by:
National Natural Science Foundation of China(82060054);Science and Technology Program of Xinjiang Production and Construction Corps(2023AB018-12);Zhanjiang Municipal Science and Technology Development Special Funds(2023A214);Zhanjiang Municipal Key Project for Disease Prevention and Control(2022A01103);Scientific Research Startup Funding Project for High-Level Talents at Central People's Hospital of Zhanjiang(2022A15);2024 Talent Development Fund-Tianshan Talent Program for Young and Middle-aged Medical Backbones(CZ001216);Doctoral Research Foundation of Shihezi University(BS202205)

摘要/Abstract

摘要：

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。

关键词: 心力衰竭, AZGP1, 血浆蛋白, 孟德尔随机化, 生物标志物

Abstract:

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.

Key words: heart failure, AZGP1, plasma protein, Mendelian randomization, biomarker

中图分类号:

R541

李龙, 赵霞, 金珊, 李泽莹, 吕福强, 庞丽娟, 刘克坚. 孟德尔随机化解析AZGP1在心力衰竭中的保护作用[J]. 上海交通大学学报（医学版）, 2025, 45(8): 1035-1045.

LI Long, ZHAO Xia, JIN Shan, LI Zeying, LÜ Fuqiang, PANG Lijuan, LIU Kejian. Deciphering the protective role of AZGP1 in heart failure through Mendelian randomization[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 1035-1045.

图/表 9

图1 MR研究设计主要假设概述Note： IEU GWAS—Integrative Epidemiology Unit GWAS Database; deCODE Healthy Study—The Icelandic deCODE Health and Genetic Epidemiology Study; IVW—inverse-variance weighted; cis-MR—cis-acting Mendelian randomization; Cis-pQTL—cis-acting protein quantitative trait locus.

Fig 1 Overview of key assumptions in MR studies

图2 血浆蛋白与HF的MR分析结果的火山图Note： FC—fold change.

Fig 2 Volcano plot of results of MR analysis of plasma proteins versus HF

图3 77种血浆蛋白浓度与HF发病风险之间的因果关系的IVW系统评估

Fig 3 Systematic evaluation of the causal relationships between plasma concentrations of 77 proteins and HF risk by IVW method

图4 血浆蛋白水平与HF发病风险的反向因果关系分析

Fig 4 Reverse causality analysis between plasma protein levels and HF risk

图5 AZGP1与HF的遗传共定位分析Note： Larger colored dots highlight significant associations. Chromosome 7 gene positions (Mb) vs -log10 (P value), with colors scaled by significance. Gradient colors indicate strength, with zoomed gene associations at 99.0‒100.5 Mb.

Fig 5 Genetic co-localization analysis of AZGP1 with HF

图6 血浆蛋白AZGP1与HF的MR因果关联分析Note： A. Scatter plot of SNP effects. B. Forest plot of causal estimates. C. Leave-one-out sensitivity analysis of the AZGP1-HF association. D. Funnel plot for pleiotropy assessment. IV—instrumental variable.

Fig 6 MR causal association analysis of plasma protein AZGP1 with HF

表 1 临床样本的基线特征

Tab 1 Baseline characteristics of clinical samples

Characteristic	Control group (n=68)	HF group (n=84)	χ²/Z value	P value
Gender/n(%)			0.030	0.862
Male	39 (57.4)	47 (56.0)
Female	29 (42.6)	37 (44.0)
Age/year	72.00 (63.00, 81.00)	77.50 (69.25, 82.00)	-1.383	0.167
BMI/(kg·m^-2)	24.15 (22.99, 26.41)	24.61 (22.31, 27.51)	-0.715	0.474
FPG/(mmol·L^-1)	5.46 (5.11, 6.02)	5.50 (4.81, 6.58)	-0.009	0.993
TAG/(mmol·L^-1)	1.40 (1.07, 1.93)	0.99 (0.77, 1.27)	-4.056	<0.001
TC/(mmol·L^-1)	4.49 (3.69, 5.16)	3.30 (2.69, 3.83)	-6.283	<0.001
LDL/(mmol·L^-1)	2.83 (2.28, 3.58)	1.88 (1.37, 2.32)	-6.181	<0.001
HDL/(mmol·L^-1)	1.19 (0.99, 1.47)	0.90 (0.77, 1.11)	-5.691	<0.001

表2 HF危险因素的多因素Logistic分析结果

Tab 2 Multivariate Logistic regression analysis results of risk factors for HF

Factor	β value	SE	χ² value	OR (95%CI)	P value
TAG	-0.694	0.366	3.596	0.500 (0.244‒1.024)	0.058
LDL	-1.092	0.274	15.830	0.336 (0.196‒0.575)	<0.001
HDL	-2.182	0.616	12.542	0.113 (0.034‒0.377)	<0.001
AZGP1	-0.115	0.043	7.278	0.891 (0.820‒0.969)	0.007

图7 ELISA检测HF患者AZGP1的表达情况

Fig 7 Expression of AZGP1 in HF patients detected by ELISA

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孟德尔随机化解析AZGP1在心力衰竭中的保护作用

Deciphering the protective role of AZGP1 in heart failure through Mendelian randomization

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