Changes in DNA methylation persist over time in males with severe alcohol use disorder—A longitudinal follow‐up study

Abstract

Treatment strategies for alcohol use disorder (AUD) aim for abstinence or harm reduction. While deranged biochemical parameters reverse with alcohol abstinence, whether molecular changes at the epigenetic level reverse is not clearly understood.We investigated whether the reduction from high alcohol use reflects DNA methylation at the gene-specific and global level. In subjects seeking treatment for severe AUD, we assessed gene-specific (aldehyde dehydrogenase [ALDH2]/methylene tetrahydrofolate reductase [MTHFR]) and global (long interspersed elements [LINE-1]) methylation across three-time points (baseline, after detoxification and at an early remission period of 3 months), in peripheral blood leukocytes. We observed that both gene-specific and global DNA methylation did not change over time, irrespective of the drinking status at 3 months (52% abstained from alcohol). Further, we also compared DNA methylation in AUD subjects with healthy controls. At baseline, there was a significantly higher gene-specific DNA methylation (ALDH2: p < .001 and MTHFR: p = .001) and a significant lower global methylation (LINE-1: p = .014) in AUD as compared to controls. Our results suggest that epigenetic changes at the DNA methylation level associated with severe AUD persist for at least 3 months of treatment. K E Y W O R D Salcohol abstinence, alcohol use disorder, DNA methylation, long interspersed nucleotide elements, pyrosequencing | INTRODUCTIONAlcohol use accounts for 13.5% of total deaths among young adults worldwide (WHO, 2018). About 29% of men aged 15-54 years consume alcohol in India, with significant numbers using it daily (12%) or weekly (41%) (NFHS-4, 2015(NFHS-4, -2016. alcohol use disorder (AUD) is a chronic relapsing disorder, with only 15-16% of former users in India abstaining from alcohol over the past year (WHO, 2018). With the focus on abstinence and harm reduction approaches in treating AUD, whether molecular adaptations associated with chronic alcohol use reverse with alcohol abstinence poses an intriguing question.Among the molecular adaptations associated with chronic alcohol use, epigenetic changes are significant because of the associated downstream effects on gene expression (Ponomarev, Wang, Zhang, Harris, & Mayfield, 2012). These epigenetic changes are associated with onset, progression to, and persistence of dependence states (Cecil, Walton, & Viding, 2016;Jangra et al., 2016). It is well established that epigenome-wide, global, and gene-specific studies indicate differential methylation related to alcohol consumption

Genetics and Epigenetics of Aldehyde Dehydrogenase (ALDH2) in Alcohol Related Liver Disease

“…In the current study we found hypomethylation of ALDH2 gene in AUD with cirrhosis (3.8±0.8) compared to AUD without cirrhosis (5.1±1.9). In a previous study we had reported ALDH2 methylation in a set of controls (4.2±0.7) (Soundararajan et al, 2021). Thus, cirrhosis and HCC (which is often its sequel) both appear to be associated with hypomethylation while the noncirrhotic phenotype of AUD has a higher methylation level.…”

“…Consumption of excessive amounts of alcohol is also known to influence global DNA methylation, though studies have shown inconsistent findings (Zhang and Gelernter, 2017). Our earlier work looking at global DNA methylation using LINE1 (Long-Interspersed Nuclear Elements-1) loci showed hypomethylation in patients with AUD compared to controls (Soundararajan et al, 2021).…”

Pyrosequencing: Current forensic methodology and future applications—a review

“…A longitudinal study by Soundararajan et al. on males with severe alcohol use disorder show that the changes in DNA methylation persist over time, even at remission period of 3 months [111]. A close‐up investigation of the NR3C1 gene methylation in relation to alcohol consumption, depression, and obesity in a Brazilian population shows that NR3C1 hypomethylation is associated with alcohol consumption and obesity, whereas its hypermethylation is related to depression [112].…”

Global DNA methylation patterns in Alcohol Use Disorder

“…In this sense, a slight disparity of 0.1% in GMe levels between two groups - cases and controls - could represent a significant difference of over 28,000 cytosines that are methylated distinctly throughout the human genome (which contains more than 28 million CpG sites) ( Luo et al, 2014 ). However, up to now, only AUD studies using GMe proxy-based approaches were performed, observing both hypermethylation ( Bönsch et al, 2004 ; Kim et al, 2016 ) or hypomethylation in individuals with AUD compared to controls ( Soundararajan et al, 2021 ).…”