Abstract
Aberrant DNA methylation profiles have been implicated in numerous cardiovascular diseases; however, few studies have investigated how these epigenetic modifications contribute to stroke recurrence. The aim of this study was to identify methylation loci associated with the time to recurrent cerebro- and cardiovascular events in individuals of European and African descent. DNA methylation profiles were generated for 180 individuals from the Vitamin Intervention for Stroke Prevention clinical trial using Illumina HumanMethylation 450K BeadChip microarrays, resulting in beta values for 470,871 autosomal CpG sites. Ethnicity-stratified survival analyses were performed using Cox Proportional Hazards regression models for associations between each methylation locus and the time to recurrent stroke or composite vascular event. Results were validated in the Vall d'Hebron University Hospital cohort from Barcelona, Spain. Network analyses of the methylation loci were generated using weighted gene coexpression network analysis. Primary analysis identified four significant loci, cg04059318, ch.2.81927627R, cg03584380, and cg24875416, associated with time to recurrent stroke. Secondary analysis identified three loci, cg00076998, cg16758041, and cg02365967, associated with time to composite vascular endpoint. Locus cg03584380, which is located in an intron of ZDHHC6, was replicated in the Vall d'Hebron University Hospital cohort. The results from this study implicate the degree of methylation at cg03584380 is associated with the time of recurrence for stroke or composite vascular events across two ethnically diverse groups. Furthermore, modules of loci were associated with clinical traits and blood biomarkers including previous number of strokes, prothrombin fragments 1 + 2, thrombomodulin, thrombin-antithrombin complex, triglyceride levels, and tissue plasminogen activator. Ultimately, these loci could serve as potential epigenetic biomarkers that could identify at-risk individuals in recurrence-prone populations.
Highlights
Ischemic strokes account for 87% of all strokes and are heterogeneous, multifactorial diseases comprising genetic and environmental contributions
Abnormal DNA methylation patterns have been implicated in a number of cardiovascular diseases [5, 6]; few studies have investigated these epigenetic contributions to stroke recurrence [7,8,9]
In the African descent (AFR) individuals, the average baseline age of those experiencing a recurrent stroke was five years older compared to those not having a recurrent stroke (65 years versus 60 years; p = 0.047). Those individuals having a Vitamin Intervention for Stroke Prevention (VISP) recurrent stroke had a more severe enrollment stroke compared to the nonrecurrent control group, as measured on the modified Rankin stroke scale (RSS)
Summary
Ischemic strokes account for 87% of all strokes and are heterogeneous, multifactorial diseases comprising genetic and environmental contributions. A proportion of the estimated 37.9% heritability for ischemic stroke [2] is accounted for from genetic variants identified in genome-wide association studies, suggesting other mechanisms, such as epigenetic modifications, could comprise some of the remaining heritability for ischemic stroke and stroke recurrence risk. Epigenetics, such as DNA methylation, refer to chemical modifications of DNA structure that can be maintained over cellular generations [3] and serve to propagate cellular memory [4]. Findings from this study support the utility of epigenetic marks as potential biomarkers and may lead to improved prognosis or prevention of recurrent stroke and cardiovascular events
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