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

Autor:	Zhao Y; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Li X; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Wang K; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Iyer G; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Sakowski SA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA., Zhao L; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA., Teener S; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA., Bakulski KM; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Dou JF; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Traynor BJ; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Karnovsky A; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Batterman SA; Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA., Feldman EL; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA., Sartor MA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. Electronic address: sartorma@umich.edu., Goutman SA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA. Electronic address: sgoutman@med.umich.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Nov; Vol. 109, pp. 105383. Date of Electronic Publication: 2024 Oct 05.
DOI:	10.1016/j.ebiom.2024.105383
Abstrakt:	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. Competing Interests: Declaration of interests YZ: None. XL: None. KW: None. GI: None. SAS: Listed as inventors on a patent, Issue number US10660895, held by University of Michigan titled “Methods for Treating Amyotrophic Lateral Sclerosis” that targets immune pathways for use in ALS therapeutics. SAS has received unrelated research funding from NIH R01DK129320, which has no competing interest with this work. LZ: None. ST: None. KMB: None. JFD: None. BJT: Holds patents on the diagnostic and therapeutic implications of the C9orf72 repeat expansion. BJT has received unrelated research funding from Cerevel Therapeutics and ALS Association, which have no competing interest with this work. BJT holds leadership role in Scientific Advisory Committee and American Neurological Association. BJT serves on the editorial board of EClinicalMedicine, JNNP, NBA, and is an associate editor for Brain. BJT also has collaborative research agreement with Ionis Pharmaceuticals, Roche, and Optimeos. AK: None. SAB: None. ELF: Listed as inventor on a patent, Issue number US10660895, held by University of Michigan titled “Methods for Treating Amyotrophic Lateral Sclerosis” that targets immune pathways for use in ALS therapeutics. ELF has received unrelated funding from NIH, CDC/ATSDR, DoD, JDRF, which have no competing interest with this work. ELF serves on the scientific advisory boards for the Foundation for Peripheral Neuropathy, Peripheral Nerve Society Diabetes Neuropathy, NIH Blueprint Neurotherapeutics Network for Biologics (BPN-Biologics) External Oversight Committee, National Advisory Neurological Disorders and Stroke (NANDS) Council Neural Exposome Top Priorities (NEXT) Working Group. ELF also serves on the editorial advisory boards for Experimental Neurology; Nature Reviews Neurology; Neurobiology of Disease; Journal of Neurology, Neurosurgery and Psychiatry; JAMA Neurology; Oxford University Press, Contemporary Neurology Series (Editor-in-Chief); The Lancet Neurology; Scientific Reports; Med (Cell Press Journal); Annals of Neurology (Associate Editor). ELF holds leadership positions in International Congress on Neuromuscular Disease, Scientific Program Committee National Academy of Medicine, Chair of Section 07, 2020–2022, National Academy of Medicine, Membership Committee, 2020–2022, American Neurological Association, Annals/ACTN Oversight Committee, 2021–2023, American Neurological Association, Chair of Governance Committee, National Academy of Medicine, Neuroscience Forum National Academy of Medicine, Council Member National Academy of Sciences, Engineering, and Medicine, Committee on Making ALS a Livable Disease ONETOX-OSPP Neural Exposome Strategic Planning, Member. MAS: None. SAG: Listed as inventor on a patent, Issue number US10660895, held by University of Michigan titled “Methods for Treating Amyotrophic Lateral Sclerosis” that targets immune pathways for use in ALS therapeutics. Scientific consulting for Evidera. Payment from American Academy of Neurology. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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