Alcohol-Induced Changes in Methylation Status of Individual CpG Sites, and Serum Levels of Vasopressin and Atrial Natriuretic Peptide in Alcohol-Dependent Patients during Detoxification Treatment

Abstract

Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification.

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

“…Of the candidate gene studies reviewed, two featured repeated measures of DNAm, comparing alcohol-dependent cases versus controls at baseline, day 7 and day 14 posttreatment admission. While the first found significant differences in DNAm of volume-regulating neuropeptides AVP and ANP both at baseline and between day 7 and 14 of withdrawal [48], the second [49] reported increased nerve growth factor (NGF) methylation in cases versus controls, but only between day 7 and 14.…”

The Epigenetic Regulation of GATA4-Dependent Brain Natriuretic Peptide Expression during Alcohol Withdrawal

“…In alcohol dependence, several recent studies describe alterations not only in hypothalamus-pituitary-adrenocortical (HPA)-dependent stress regulation, but also in the levels of volume-regulating hormones such as the neuropeptides atrial natriuretic peptide (ANP) and vasopressin (AVP) [1,2,3,4,5,6]. Referring to alcohol dependence, both neuropeptides have received extensive interest as they are known to exert direct effects on central nervous endocrinological pathways [1,2,4].…”

“…Referring to alcohol dependence, both neuropeptides have received extensive interest as they are known to exert direct effects on central nervous endocrinological pathways [1,2,4]. ANP has strong anxiolytic properties specifically on different levels of the HPA axis, such as inhibition of corticotropin-releasing factor, adrenocorticotropic hormone, and cortisol secretion.…”

“…Surprisingly, the association of epigenetic BNP regulation in the context of alcohol consumption has not been investigated although, in recent studies, epigenetic mechanisms regarding volume-regulating/natriuretic peptides like ANP and AVP have been investigated in the context of alcohol dependence. Our group demonstrated that epigenetic control and gene transcription of AVP and ANP were altered in the blood of alcohol-dependent patients compared to healthy controls [1,3,13]. While observing a significant hypermethylation of the gene promoter region for vasopressin, mRNA transcription levels were unaltered.…”

“…In contrast, ANP mRNA transcription was significantly elevated in the patient group and was associated with a significant hypomethylation of the corresponding promoter region. Moreover, we describe a significant correlation between promoter-related DNA methylation of the ANP precursor gene and the extent of craving, as measured with the Obsessive Compulsive Drinking Scale (OCDS) [1,3,13]. Also, genome-wide association studies recently showed alcohol dependence to be associated with a single-nucleotide polymorphism (rs13273672) located on a gene (GATA4) that encodes a transcription factor of ANP [14].…”