Jiménez-Balado, JoanFernández-Pérez, IsabelGallego-Fabrega, CristinaLazcano, UxueSoriano Tarraga, CarolinaVallverdú-Prats, MartaMola Caminal, MarinaRey Álvarez, LucíaMacias-Gómez, AdriàSuárez-Pérez, AntoniGiralt-Steinhauer, EvaRodríguez-Campello, AnaCuadrado-Godia, ElisaOis Santiago, Angel JavierEsteller, ManelRoquer, JaumeFernández-Cadenas, IsraelJiménez Conde, Jordi2025-04-112025-04-112024Jiménez-Balado J, Fernández-Pérez I, Gallego-Fábrega C, Lazcano U, Soriano-Tárraga C, Vallverdú-Prats M, et al. DNA methylation and stroke prognosis: an epigenome-wide association study. Clin Epigenetics. 2024 Jun 6;16(1):75. DOI: 10.1186/s13148-024-01690-21868-7075http://hdl.handle.net/10230/70132Background and aims: Stroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis. Methods and results: To that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N = 316] and St. Pau [replication, N = 92]). Functional outcome was assessed using the modified Rankin Scale (mRS) at three months after stroke, being poor outcome defined as mRS > 2. DNAm was determined using the 450K and EPIC BeadChips in whole-blood samples collected within the first 24 h. We searched for differentially methylated positions (DMPs) in 370,344 CpGs, and candidates below p-value < 10-5 were subsequently tested in the replication cohort. We then meta-analyzed DMP results from both cohorts and used them to identify differentially methylated regions (DMRs). After doing the epigenome-wide association study, we found 29 DMPs at p-value < 10-5 and one of them was replicated: cg24391982, annotated to thrombospondin-2 (THBS2) gene (p-valuediscovery = 1.54·10-6; p-valuereplication = 9.17·10-4; p-valuemeta-analysis = 6.39·10-9). Besides, four DMRs were identified in patients with poor outcome annotated to zinc finger protein 57 homolog (ZFP57), Arachidonate 12-Lipoxygenase 12S Type (ALOX12), ABI Family Member 3 (ABI3) and Allantoicase (ALLC) genes (p-value < 1·10-9 in all cases). Discussion: Patients with poor outcome showed a DMP at THBS2 and four DMRs annotated to ZFP57, ALOX12, ABI3 and ALLC genes. This suggests an association between stroke outcome and DNAm, which may help identify new stroke recovery mechanisms.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/s13148-024-01690-2DNA methylationEpigeneticsStroke outcomeThrombospondin-2info:eu-repo/semantics/openAccess