Abstract
Background and Objectives The 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.
Methods DNA 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.
Results After 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).
Discussion DNA 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.
Glossary
- ANP=
- atrial natriuretic peptide;
- BMI=
- body mass index;
- BNP=
- brain natriuretic peptide;
- CATIS=
- China Antihypertensive Trial in Acute Ischemic Stroke;
- CI=
- confidence interval;
- CNP=
- C-type natriuretic peptide;
- CVD=
- cardiovascular disease;
- DBP=
- diastolic blood pressure;
- EWAS=
- epigenome-wide association study;
- FDR=
- false discovery rate;
- GTEx=
- Genotype-Tissue Expression;
- HDL-C=
- high-density lipoprotein cholesterol;
- IS=
- ischemic stroke;
- LDL-C=
- low-density lipoprotein cholesterol;
- NP=
- natriuretic peptide;
- OR=
- odds ratio;
- PMMS=
- Prevention of Metabolic syndrome and Multi-metabolic disorders Study;
- SBP=
- systolic blood pressure;
- wTPM=
- weighted truncated product method
Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
↵* These authors contributed equally to this work and should be considered as co–first authors.
Submitted and externally peer reviewed. The handling editor was Alexandra Durr, MD, PhD.
- Received January 7, 2022.
- Accepted in final form March 18, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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