Epigenetic Regulation of the Promotor Region of Vascular Endothelial Growth Factor-A and Nerve Growth Factor in Opioid-Maintained Patients

Abstract

Aims: The nerve growth factor (NGF) and the vascular endothelial growth factor-A (VEGF-A) may be of importance for psychiatric diseases including substance use disorders. The aim of the study was to identify differences in the regulation of both neuropeptides via the DNA-methylation status of the promotor regions of NGF and VEGF-A in different forms of maintenance therapy for opioid dependence and the related stress regulation via the hypothalamic-pituitary-adrenal axis. Methods: We compared methylation levels of opioid-dependent patients receiving treatment with diamorphine (n = 28) or levomethadone (n = 54) and similar levels in a healthy control group (n = 72). Results: There was a significantly higher methylation of VEGF-A in opioid-maintained patients with levomethadone compared to that in the control group (estimated marginal means [EMM] [SE]): 0.036 [0.003] vs. 0.020 [0.003]; p < 0.001). We performed a cluster analysis for NGF, splitting up the results in 4 clusters. We found significant changes in methylation rates of the opioid-maintained patients compared to the controls in cluster I ([EMM] [SE]: 0.064 [0.005] vs. 0.084 [0.006]; p = 0.03), cluster II ([EMM] [SE]: 0.133 [0.013] vs. 0.187 [0.014]; p < 0.001) and cluster III ([EMM] [SE]: 0.190 [0.014] vs. 0.128 [0.016]; p < 0.001). Conclusions: The results are of importance, as they indicate that long-term changes in stress regulation regulated by neurotrophines are a crucial part of the symptomatology of opioid dependence, thus influencing drug consumption and the different forms of opioid-maintenance therapies.

Epigenome-wide association study in healthy individuals identifies significant associations with DNA methylation and PBMC extract VEGF-A concentration

“…DNA methylation occurs mostly on cytosine residues positioned in CpG islands (high density of CG dinucleotides) within a promoter region, transcription start site (TSS), first or second exons of a gene, in an enhancer region, or upstream from genes with CpG island shores (2 kb) or CpG shelves (2-4 kb) [2]. Previous studies have shown that epigenetics plays an important role in the regulation of promoter regions of VEGFA [22,23] and VEGFR genes [24,25], but no previous research studies have performed an EWAS of VEGF-A concentration to determine the methylation sites responsible for the regulation of VEGFA. As VEGF-A plays a distinct role in the development of several chronic diseases, the discovery of its epigenetic regulation mechanisms may contribute to a better understanding of these disorders and contribute in the research of new therapeutic possibilities.…”