Abstract
IntroductionVascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It is known for its high heritability (> 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. Large GWAS studies have already assessed polymorphisms related to VEGF-A. However, no previous research has provided epigenome-wide insight in regulation of VEGF-A.MethodsVEGF-A concentrations of healthy participants from the STANISLAS Family Study (n = 201) were comprehensively assessed for association with DNA methylation. Genome-wide DNA methylation profiles were determined in whole blood DNA using the 450K Infinium BeadChip Array (Illumina). VEGF-A concentration in PBMC extracts was detected using a high-sensitivity multiplex Cytokine Array (Randox Laboratories, UK).ResultsEpigenome-wide association analysis identified 41 methylation sites significantly associated with VEGF-A concentrations derived from PBMC extracts. Twenty CpG sites within 13 chromosomes reached Holm-Bonferroni significance. Significant values ranged from P = 1.08 × 10−7 to P = 5.64 × 10−15.ConclusionThis study exposed twenty significant CpG sites linking DNA methylation to VEGF-A concentration. Methylation detected in promoter regions, such as TPX2 and HAS-1, could explain previously reported associations with the VEGFA gene. Methylation may also help in the understanding of the regulatory mechanisms of other genes located in the vicinity of detected CpG sites.
Highlights
Vascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis
Methylation detected in promoter regions, such as TPX2 and HAS-1, could explain previously reported associations with the VEGFA gene
Methylation may help in the understanding of the regulatory mechanisms of other genes located in the vicinity of detected CpG sites
Summary
Vascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis It is known for its high heritability (> 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. DNA methylation forms 5-methylcytosine on the CpG (cytosine-phosphate-guanine) site of a genome and normally results in silencing of the gene that is encoded in the sequence [2]. This particularity was researched in various epigenome-wide methylation studies (EWAS), which managed to relate individual CpGs with cardiovascular diseases [3], cancer [4] and other pathologies [5, 6]. Intergenic regions with CpG islands are systematically studied to elucidate the role of methylation in genomic regions distant from protein-coding regions [8]
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