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| Página principal > Artículos > Artículos publicados > Altered methylation pattern in EXOC4 is associated with stroke outcome : |
(Institut d'Investigació Biomèdica Sant Pau) (NeuroGenomics and Informatics. Washington University School of Medicine) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institució Catalana de Recerca i Estudis Avançats) (Programa de Epigenética y Biología del Cáncer (PEBC)) (Instituto de Biomedicina de Sevilla) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Institut d'Investigació Biomèdica Sant Pau) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut d'Investigació Biomèdica Sant Pau)| Fecha: | 2022 |
| Resumen: | Background and purpose: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. Results: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8. 4 × 10) and in MERTK (p value = 1. 56 × 10). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1. 14 × 10 and p value = 1. 3 × 10, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = − 4. 91) and showed a tendency towards a decrease in EXOC4 expression (rho = − 0. 469, p value = 0. 091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. Conclusions: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation. |
| Ayudas: | Instituto de Salud Carlos III PI17/02089 Instituto de Salud Carlos III PI18/01338 Instituto de Salud Carlos III PI20/00678 Instituto de Salud Carlos III CP12/03298 Instituto de Salud Carlos III FI19/00309 Instituto de Salud Carlos III CD20/00043 Instituto de Salud Carlos III CM18/00198 Agència de Gestió d'Ajuts Universitaris i de Recerca 2019_FI_B 00853 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR-1427 |
| Nota: | Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); La Marató de TV3; Fundació MútuaTerrassa; Eranet-Neuron; European research grants; Boehringer Ingelheim; Pfizer/Bristol Myers; Fons Social Europeu (FSE). |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Brain Ischemia ; C-mer Tyrosine Kinase ; CpG Islands ; DNA Methylation ; Epigenesis, Genetic ; Epigenome ; Genome-Wide Association Study ; Humans ; RNA ; Stroke |
| Publicado en: | Clinical Epigenetics, Vol. 14 Núm. 1 (december 2022) , p. 124, ISSN 1868-7083 |
