Differential DNA methylation associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review

Abstract

Recent studies suggest that differential DNA methylation could play a role in the mechanism of cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Considering the significance of this matter and a lack of effective prophylaxis against DCI, we aim to summarize the current state of knowledge regarding their associations with DNA methylation and identify the gaps for a future trial. PubMed MEDLINE, Scopus, and Web of Science were searched by two authors in three waves for relevant DNA methylation association studies in DCI after aSAH. PRISMA checklist was followed for a systematic structure. STROBE statement was used to assess the quality and risk of bias within studies. This research was funded by the National Science Centre, Poland (grant number 2021/41/N/NZ2/00844). Of 70 records, 7 peer-reviewed articles met the eligibility criteria. Five studies used a candidate gene approach, three were epigenome-wide association studies (EWAS), one utilized bioinformatics of the previous EWAS, with two studies using more than one approach. Methylation status of four cytosine-guanine dinucleotides (CpGs) related to four distinct genes (ITPR3, HAMP, INSR, CDHR5) have been found significantly or suggestively associated with DCI after aSAH. Analysis of epigenetic clocks yielded significant association of lower age acceleration with radiological CVS but not with DCI. Hub genes for hypermethylation (VHL, KIF3A, KIFAP3, RACGAP1, OPRM1) and hypomethylation (ALB, IL5) in DCI have been indicated through bioinformatics analysis. As none of the CpGs overlapped across the studies, meta-analysis was not applicable. The identified methylation sites might potentially serve as a biomarker for early diagnosis of DCI after aSAH in future. However, a lack of overlapping results prompts the need for large-scale multicenter studies. Challenges and prospects are discussed.

Keywords: Aneurysmal subarachnoid hemorrhage; Cerebral vasospasm; DNA methylation; Delayed cerebral ischemia; Epigenetic changes; Intracranial aneurysm.

Fig. 1

Study selection process

Fig. 2

Direct acyclic graph (DAG) for aneurysmal subarachnoid hemorrhage, delayed cerebral ischemia and DNA methylation alterations. BNI – Barrows Neurological Institute grading scale. DMC – differentially methylated CpGs. DMR – differentially methylated regions. Solid lines indicate a causal path. Dashed lines indicate covariates, demographic variables, and listed genes with differential DNA methylation. Created with BioRender.com

Fig. 3

Conceptual diagram representing the epigenetic pathway from aneurysmal subarachnoid hemorrhage to delayed cerebral ischemia. Created with BioRender.com