DNA methylation of the natriuretic peptides system genes and ischemic stroke: gene-based and gene-set analyses

Background The natriuretic peptides (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 NP system genes
methylation in IS. Methods and Results DNA methylation at promoter regions
of four core NP system genes, e.g., CORIN, FURIN, NPPA, and NPPB, was
measured by targeted bisulfite sequencing in 853 IS patients and 918
healthy 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 four genes as a pathway with IS. After control of
covariates and multiple testing, DNA methylation at 19 of the 36 assayed
CpGs were individually associated with IS at q<0.05. The average
methylation levels at the targeted regions of CORIN (OR=0.64, 95%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 inversely associated with 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 four NP system genes
together was jointly associated with IS (P=0.0001). Conclusions DNA
methylation at NP system genes was downregulated in IS patients. 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.