10.6084/M9.FIGSHARE.C.6226794.V1
Natalia Cullell
Natalia
Cullell
Hospital de Sant Pau
University Hospital Mútua de Terrassa
University of Barcelona
Carolina Soriano-Tárraga
Carolina
Soriano-Tárraga
Cristina Gallego-Fábrega
Cristina
Gallego-Fábrega
Hospital de Sant Pau
Jara Cárcel-Márquez
Jara
Cárcel-Márquez
Hospital de Sant Pau
Elena Muiño
Elena
Muiño
Hospital de Sant Pau
Laia Llucià-Carol
Laia
Llucià-Carol
Hospital de Sant Pau
Miquel Lledós
Miquel
Lledós
Hospital de Sant Pau
Manel Esteller
Manel
Esteller
Manuel Castro de Moura
Manuel Castro
de Moura
Joan Montaner
Joan
Montaner
Vall d'Hebron Institut de Recerca
University of Seville
Anna Rosell
Anna
Rosell
Vall d'Hebron Institut de Recerca
Pilar Delgado
Pilar
Delgado
Vall d'Hebron Institut de Recerca
Joan Martí-Fábregas
Joan
Martí-Fábregas
Hospital de Sant Pau
Jerzy Krupinski
Jerzy
Krupinski
Manchester Metropolitan University
University Hospital Mútua de Terrassa
Jaume Roquer
Jaume
Roquer
Jordi Jiménez-Conde
Jordi
Jiménez-Conde
Israel Fernández-Cadenas
Israel
Fernández-Cadenas
Hospital de Sant Pau
Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study
Abstract 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 < 10–06) 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 × 10–08) and in MERTK (p value = 1.56 × 10–07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10–06 and p value = 1.3 × 10–02, 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.
Genetics
figshare
2022
2022-10-01
2022-10-01
Collection
10.6084/m9.figshare.c.6226794
CC BY 4.0