Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-11-01 Epub Date: 2024-10-05 DOI:10.1016/j.ebiom.2024.105383

Yue Zhao, Xiayan Li, Kai Wang, Gayatri Iyer, Stacey A Sakowski, Lili Zhao, Samuel Teener, Kelly M Bakulski, John F Dou, Bryan J Traynor, Alla Karnovsky, Stuart A Batterman, Eva L Feldman, Maureen A Sartor, Stephen A Goutman

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引用次数: 0

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival.

Methods: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes.

Findings: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons.

Interpretation: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS.

Funding: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.

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表观遗传年龄加速与肌萎缩侧索硬化症患者的职业暴露、性别和存活率有关。

背景：肌萎缩性脊髓侧索硬化症（ALS）与衰老、遗传和环境风险因素有关，但其潜在机制尚不完全清楚。我们旨在评估表观遗传年龄加速（EAA），即DNA甲基化（DNAm）年龄加速及其与ALS病例状态和存活率的关系：在这项研究中，我们纳入了 2011 年至 2021 年间采集的 428 例 ALS 和 288 例对照样本。我们使用 GrimAge 残差法计算了 ALS 和对照组血样的 EAA，并将 ALS 患者分为三个年龄组（快、正常、慢）。我们通过职业暴露评估、免疫细胞比例和转录组变化，将EAA与ALS病例状态和存活率联系起来，并将其与环境和生物因素联系起来：ALS患者的平均EAA值较高，为1.80 ± 0.30年（p 解释：EAA值与ALS患者的病情相关：EAA与肌萎缩性脊髓侧索硬化症的病例状态有关，至少对男性而言，EAA与确诊后的存活期缩短有关。职业暴露和免疫细胞比例以性别依赖的方式部分解释了 EAA 对 ALS 的影响。这些发现凸显了衰老和暴露在 ALS 中的复杂相互作用：美国国立卫生研究院（NIH）、美国疾病预防控制中心（CDC）/国家 ALS 登记处、ALS 协会、兰德尔-惠特科姆博士 ALS 遗传学基金、彼得-克拉克 ALS 研究基金、西奈医务人员基金会、斯科特-普兰格 ALS 诊疗基金、神经网络治疗发现基金、神经网络新兴疗法。

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

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.