Immunometabolic Pathways: Investigating Mediators of Major Depressive Disorder and Atherosclerotic Cardiovascular Disease Comorbidity

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science Pub Date : 2025-05-08 DOI:10.1016/j.bpsgos.2025.100528

Angela Koloi , Nabila P.R. Siregar , Rick Quax , Antonis I. Sakellarios , Femke Lamers , Arja Rydin , Kevin Dobretz , Costas Papaloukas , Dimitrios I. Fotiadis , Jos A. Bosch

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Abstract

Background

Major depressive disorder (MDD) and cardiovascular diseases (CVDs) often co-occur whereby comorbidity results in poorer clinical outcomes, presumably due to shared immunometabolic pathways. Identifying shared biomarkers for MDD-CVD comorbidity may provide targets for prevention or treatment.

Methods

Using data from the NESDA (Netherlands Study of Depression and Anxiety) (n = 2256, 66.3% female, mean age 41.86 ± 13.08 years at baseline), validated with the UK Biobank (UKB) data (n = 35,668, 56.14% female, mean age 63.95 ± 7.74 years), this study aimed to identify 1) biomarkers, closely associated with current MDD, and 2) longitudinal pathways linking MDD and atherosclerotic CVD. Plasma metabolites (nuclear magnetic resonance) and inflammatory markers were used as exposures within a machine learning framework. Influential biomarkers were integrated into a temporal network analysis linking MDD to subsequent CVDs, exploring longitudinal pathways through causal discovery, validated by sensitivity analysis and centrality assessment. External validation included mediation and regression analysis adjusting for covariates.

Results

Network analysis identified stable direct paths from MDD to CVDs via tumor necrosis factor α (TNF-α), tyrosine, and fatty acids and indirect paths via acetate, high-density lipoprotein (HDL) diameter, interleukin 6, AGP, high-sensitivity C-reactive protein, and low-density lipoprotein triglycerides. Among these, acetate, tyrosine, AGP (α₁-acid glycoprotein), and HDL diameter potentially mediated the MDD-CVD connection, given that these were identified as key nodes within the network. UKB validation confirmed HDL diameter (β = 0.004) and AGP (β = 0.003) as significant depression-CVD mediators (both p < .001), after adjusting for age, sex, deprivation index, alcohol consumption, smoking status, physical activity, and body mass index.

Conclusions

These analyses identified biomarkers shared in MDD and CVDs and may drive comorbid pathology risk.

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免疫代谢途径：研究重度抑郁症和动脉粥样硬化性心血管疾病合并症的介质

背景：重度抑郁症（MDD）和心血管疾病（cvd）经常同时发生，其中共病导致较差的临床结果，可能是由于共享的免疫代谢途径。确定MDD-CVD共病的共同生物标志物可能为预防或治疗提供靶点。方法使用NESDA（荷兰抑郁和焦虑研究）的数据（n = 2256, 66.3%女性，基线时平均年龄41.86±13.08岁），并通过英国生物银行（UKB）数据（n = 35668, 56.14%女性，平均年龄63.95±7.74岁）验证，本研究旨在确定1)与当前MDD密切相关的生物标志物，以及2)MDD与动脉粥样硬化性CVD之间的纵向通路。血浆代谢物（核磁共振）和炎症标志物被用作机器学习框架内的暴露。有影响力的生物标志物被整合到将MDD与随后的cvd联系起来的时间网络分析中，通过因果发现探索纵向途径，并通过敏感性分析和中心性评估进行验证。外部验证包括调节协变量的中介和回归分析。结果网络分析发现，MDD通过肿瘤坏死因子α (TNF-α)、酪氨酸和脂肪酸等直接途径转化为cvd，通过醋酸酯、高密度脂蛋白（HDL）直径、白细胞介素6、AGP、高敏c反应蛋白和低密度脂蛋白甘油三酯等间接途径转化为cvd。其中，醋酸、酪氨酸、AGP （α1-酸性糖蛋白）和HDL直径可能介导MDD-CVD连接，因为这些被确定为网络中的关键节点。UKB验证证实HDL直径（β = 0.004）和AGP （β = 0.003）是显著的抑郁- cvd介质(p <；.001)，在调整了年龄、性别、剥夺指数、饮酒、吸烟状况、身体活动和体重指数之后。这些分析确定了MDD和cvd共有的生物标志物，并可能驱动共病的病理风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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