DNA Methylation of the Natriuretic Peptide System Genes and Ischemic Stroke

Abstract

Background and ObjectivesThe natriuretic peptide (NP) system has been considered an important regulator for ischemic stroke (IS) with a limited clinical implication. A better understanding of the underlying molecular mechanisms is urgent. Here, we aimed to examine the role of DNA methylation of NP system genes in IS.MethodsDNA methylation at promoter regions of 4 core NP system genes, e.g., CORIN, FURIN, NPPA, and NPPB, was measured by targeted bisulfite sequencing in 853 patients with IS and 918 controls. We first examined the association between DNA methylation at each single CpG and IS, followed by gene-based and gene set analyses to examine the joint associations of DNA methylation at multiple CpGs in a gene or all 4 genes as a pathway with IS.ResultsAfter control of covariates and multiple testing, DNA methylation at 19 of the 36 assayed CpGs was individually associated with IS at q < 0.05. Higher average methylation levels at the targeted regions of CORIN (odds ratio [OR] = 0.64, 95% confidence interval [CI]: 0.56–0.73), FURIN (OR = 0.78, 95% CI: 0.69–0.88), and NPPA (OR = 0.78, 95% CI: 0.69–0.88) were associated with a lower odds of IS (all q < 0.05). The truncated product method revealed the same gene-based associations (all q < 0.05) and found that DNA methylation at all 4 NP system genes together was jointly associated with IS (p = 0.0001).DiscussionDNA methylation at NP system genes was downregulated in patients with IS. Our results may unravel a molecular mechanism underlying the regulating effect of the NP system on IS and highlight the relevance of testing the joint effect of multiple CpGs in the epigenetic analysis.

Exploring Genetic Associations of 3 Types of Risk Factors With Ischemic Stroke: An Integrated Bioinformatics Study

“…28 FURIN was found to be upregulated 24 hours after brain ischemia in animal experiments, 50 and a case-control study showed lower DNA methylation levels in the IS region, suggesting its relevance to IS. 29 A genome-wide association study has shown that genetic variability in MAN2A2 is associated with blood pressure, which has been confirmed by us to have a causal relationship with IS. 30 ALDH2 plays a crucial role in clearing 4-hydroxy-2-nonenal through a process involving JNK (c-Jun N-terminal kinase)-mediated activation of cystathionine-β-synthase-3.…”

Epigenome-wide association study identifies novel genes associated with ischemic stroke

“…For participants in the Chinese cohorts, demographic and lifestyle information and disease history were collected using standard questionnaires, as previously described [ 18 ]. For CATIS participants, blood samples were collected within 48 h of stroke onset and then stored at -80 °C for biochemical and DNA methylation analysis.…”