Promoter hypomethylation of CDH7: a novel epigenetic marker associated with cerebral small vessel disease

Abstract

Introduction: Cerebral small vessel disease (SVD), manifesting as white matter hyperintensities (WMH), lacunar infarctions, and cerebral microbleeds on magnetic resonance imaging (MRI), has been linked to developmental epigenetic alterations. This study aimed to identify and validate gene-specific promoter methylation changes as epigenetic markers associated with SVD, using MRI-defined imaging features and blood inflammatory cells. Methods: Genome-wide promoter methylation was profiled using the Infinium MethylationEPIC v2.0 array in peripheral inflammatory cells from 16 patients without SVD and 16 patients with all three imaging features, including WMH, lacunes, and microbleeds on MRI. Candidate CpGs were defined as consensus DMPs detected by both minfi and SeSAMe (nominal P < 0.05 in both pipelines with concordant direction), filtered by absolute delta beta > 0.10 and promoter proximity (TSS200/TSS1500). Validation was performed to determine whether these gene-specific promoter methylations could serve as independent variables predicting the presence of SVD imaging features when combined with established cardiovascular risk factors, using data from 766 patients with ischemic stroke (53 [6.9%] without SVD and 713 [93.1%] with ≥1 SVD imaging feature). Hierarchical logistic regression analysis and a deep learning model were applied. Subgroup analyses using multinomial logistic regression were performed to assess whether gene-specific promoter methylation could independently predict WMH or lacunes. Results: EPIC profiling identified 17 promoter regions with significant differences between groups, corresponding to CDH7, ZNF234, OR51A4, DEFB126, MAP3K8, TMCO6, TMEM191B, MMUT, TEX26, ZNF600, FAM240C, S100A13, S100A14, FLG2, MIR3667HG, RECK, and MIR662. Among these, CDH7hypomethylation emerged as an independent predictor of any SVD imaging feature when combined with advanced age and hyperhomocysteinemia in both hierarchical logistic regression and deep learning analyses. Subgroup analysis demonstrated that CDH7 hypomethylation independently predicted the presence of a isolated lacune, whereas no association was observed for isolated WMH. Conclusion: CDH7 hypomethylation was identified and validated as an epigenetic marker predictive of MRI-defined SVD imaging features using blood inflammatory cells. This finding highlights the potential of epigenetic profiling for improving risk stratification in patients with cerebral SVD.