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

doi:10.3969/j.issn.1674-8115.2025.08.011

Abstract

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

CLC Number:

R541

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.

Figures/Tables 9

TrendMD

References 29

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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

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

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

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