Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

• Published in: Scientific reports 2020-07, Vol.10 (1), p.11419-11419, Article 11419
• Main Authors: Kim, Bong Jun, Kim, Youngmi, Youn, Dong Hyuk, Park, Jeong Jin, Rhim, Jong Kook, Kim, Heung Cheol, Kang, Keunsoo, Jeon, Jin Pyeong
• Format: Article
• Language: English
• Subjects: 692/308; 692/617; Adult; Aged; Antigens, CD - genetics; Biomarkers; Bisulfite; Brain Ischemia - genetics; Cadherins - genetics; CpG Islands; Deoxyribonucleic acid; DNA; DNA Methylation; Epigenesis, Genetic; Epigenome; Female; Gene expression; Genes; Genome-Wide Association Study; Genomes; Humanities and Social Sciences; Humans; Ischemia; Male; Middle Aged; multidisciplinary; Polymerase chain reaction; Real-Time Polymerase Chain Reaction; Receptor, Insulin - genetics; Replication; RNA, Messenger - genetics; Science; Science (multidisciplinary); Stroke; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - genetics; Vasospasm, Intracranial - complications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-68325-3

Little is known about the epigenetic changes associated with delayed cerebral ischemia (DCI) pathogenesis after subarachnoid hemorrhage (SAH). Here, we investigated genome-wide DNA methylation profiles specifically associated with DCI, which is a major contributor to poor clinical outcomes. An epigenome-wide association study (EWAS) and quantitative real-time PCR (qRT-PCR) were conducted in 40 SAH patients (DCI, n = 13; non-DCI, n = 27). A replication study using bisulfite modification and methylation-specific PCR was further performed in 36 patients (DCI, n = 12; non-DCI, n = 24). The relative degree of methylation was described as the median and 25th–75th percentile. No significant differences in clinical characteristics between DCI and non-DCI groups were observed. Among the top 10 differentially methylated genes analyzed via EWAS, two aberrantly methylated CpG sites of cg00441765 ( INSR gene) and cg11464053 ( CDHR5 gene) were associated with decreased mRNA expression (2 −ΔCt ). They include INSR [0.00020 (0.00012–0.00030) in DCI vs. 0.00050 (0.00030–0.00068) in non-DCI] and CDHR5 [0.114 (0.053–0.143) in DCI vs. 0.170 (0.110–0.212) in non-DCI]. Compared with non-DCI cases, patients with DCI exhibited an increased degree of methylation in the replication study: INSR , 0.855 (0.779–0.913) in DCI vs. 0.582 (0.565–0.689) in non-DCI; CDHR5 , 0.786 (0.708–0.904) in DCI vs. 0.632 (0.610–0.679) in non-DCI. Hypermethylation of two novel genes, INSR and CDHR5 may serve as a biomarker for early detection of DCI following SAH.