The impact of blood MCP-1 levels on Alzheimer's disease with genetic variation at the NAV3 and UNC5C loci.

IF 6.2 1区医学 Q1 PSYCHIATRY

Translational Psychiatry Pub Date : 2025-08-19 DOI:10.1038/s41398-025-03542-w

Jinghan Huang, Yixuan Wang, Thor D Stein, Ting Fang Alvin Ang, Yibo Zhu, Qiushan Tao, Kathryn L Lunetta, Jesse Mez, Rhoda Au, Lindsay A Farrer, Wei Qiao Qiu, Xiaoling Zhang

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Abstract

Monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in peripheral inflammation, has been shown to modulate established Alzheimer's disease (AD) loci. In this study, we hypothesized that blood MCP-1 levels may impact the associations of other genetic variants with AD risk beyond the well-established AD loci. We performed a genome-wide association study (GWAS) using logistic regression with the generalized estimating equation (GEE) and Cox proportional hazards models to examine the combined effects of single nucleotide polymorphisms (SNPs) and blood MCP-1 levels on AD. Three datasets were used: the Framingham Heart Study (FHS), Religious Orders Study/Memory and Aging Project (ROSMAP), and Alzheimer's Disease Neuroimaging Initiative (ADNI). We identified SNPs in two genes in the meta-analysis, namely, neuron navigator 3 (NAV3, also named unc-53 homolog 3, rs696468) (p < 7.55 × 10^-9) and the homolog unc-5 netrin receptor c (UNC5C rs72659964) (p < 1.07 × 10^-8), which are modified by blood MCP-1 concentration for AD risk. Elevated blood MCP-1 concentrations increased AD risk and brain AD pathology in individuals with NAV3 (rs696468-CC) and UNC5C (rs72659964-AT + TT) genotypes. Given that NAV3 and UNC5C are involved in regulating neurite outgrowth and guidance, increased MCP-1 levels may disturb the functions of vulnerable gene carriers to increase AD risk.

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血液MCP-1水平对NAV3和UNC5C基因座遗传变异的阿尔茨海默病的影响

单核细胞趋化蛋白-1 （MCP-1）是一种参与外周炎症的细胞因子，已被证明可以调节阿尔茨海默病（AD）基因座。在这项研究中，我们假设血液MCP-1水平可能影响其他遗传变异与AD风险的关联，而不是已知的AD位点。我们进行了一项全基因组关联研究（GWAS），使用逻辑回归与广义估计方程（GEE）和Cox比例风险模型来检验单核苷酸多态性（snp）和血液MCP-1水平对AD的联合影响。使用了三个数据集：弗雷明汉心脏研究（FHS）、宗教秩序研究/记忆和衰老项目（ROSMAP）和阿尔茨海默病神经影像学倡议（ADNI）。我们在meta分析中发现了两个基因的snp，即神经元导航3 (NAV3，也称为unc-53同源物3，rs696468) （p -9）和unc-5网络蛋白受体c (UNC5C rs72659964) (p -8)，它们被血液MCP-1浓度修饰，与AD风险有关。在NAV3 （rs696468-CC）和UNC5C （rs72659964-AT + TT）基因型个体中，血液MCP-1浓度升高会增加AD风险和脑AD病理。鉴于NAV3和UNC5C参与调节神经突起生长和引导，MCP-1水平升高可能干扰易感基因携带者的功能，增加AD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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来源期刊

Translational Psychiatry PSYCHIATRY-

CiteScore

11.50

自引率

2.90%

发文量

484

审稿时长

23 weeks

期刊介绍： Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.