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.

蛛网膜下腔出血（SAH）后与迟发性脑缺血（DCI）发病机制有关的表观遗传学改变知之甚少。在这里，我们研究了与DCI特别相关的全基因组DNA甲基化谱，这是导致不良临床结果的主要原因。在40名SAH患者中进行了表观基因组关联研究（EWAS）和实时定量PCR（qRT-PCR）（DCI，n = 13；非DCI，n = 27）。在36例患者中进一步进行了使用亚硫酸氢盐修饰和甲基化特异性PCR的复制研究（DCI，n = 12；非DCI，n = 24）。甲基化的相对程度描述为中位数和25％至75％。DCI组和非DCI组之间在临床特征上没有显着差异。在通过EWAS分析的前10个差异甲基化基因中，INSR基因）和cg11464053（CDHR5基因）与mRNA表达下降（2-- ^ΔCt）相关。它们包括INSR [DCI中的0.00020（0.00012-0.00030）与非DCI中的0.00050（0.00030-0.00068）]和CDHR5 [ DCI中的0.114（0.053-0.143）对非DCI中的0.170（0.110-0.212）]。与非DCI病例相比，DCI患者在复制研究中显示出更高的甲基化程度：DSR的INSR为0.855（0.779-0.913），非DCI的为0.582（0.565-0.689）；DCI中的CDHR5为0.786（0.708-0.904），非DCI中的CDHR5为0.632（0.610-0.679）。两个新基因INSR和CDHR5的超甲基化 可以作为SAH后早期检测DCI的生物标记。