Clinical Genomics and Experimental Therapeutics

点击翻译按钮获取中文摘要

I. Epigenomics and multi-omics in AUD: Alcohol may influence disease outcomes through epigenetic modifications and is known to affect the acetylation and methylation of histones and the methylation of DNA (Zakhari, 2013). DNA methylation involves the addition of a methyl group, donated by the metabolite, S-adenosylmethionine (SAM), to the C of CpG dinucleotides. Chronic alcohol consumption leads to a reduction in SAM, which can lead to hypomethylation across the epigenome (Lu et al., 2000). Alcohol also impacts the folate cycle which is necessary for the generation of methionine for the synthesis of methyl groups (Mason and Choi, 2005) and the highly reactive alcohol metabolite acetaldehyde can induce inhibition of DNA methyltransferases, the family of enzymes that catalyze CpG methylation, to reduce methylation (Jangra et al., 2016, Garro et al., 1991). Alcohol metabolism also acutely depletes molecules needed for re-methylation by increasing reactive oxygen species (ROS) formation, which results in decreased production of methionine and SAM (Chen et al., 2011). Epigenome-wide association studies (EWAS) have identified CpGs that are associated with alcohol consumption and AUD (Lohoff et al., 2018, Lohoff et al., 2020, Longley et al., 2021). However, prior studies were somewhat limited by small sample sizes and lower capture arrays (Longley et al., 2021). In addition, only a few studies exist linking alcohol consumption and AUD EWAS data with detailed biological validation. To address these gaps in the literature, we conducted the largest EWAS analyses of alcohol consumption in a single cohort of individuals (n=8161) and we are continuing to follow up top findings in AUD relevant phenotypes using a translational cross-tissue/cross-phenotypic approach to identify novel potential targets relevant to AUD. Various other computational genomic approaches are applied to identify new drug targets for AUD, including Mendelian Randomization and multi-omics studies (Mavromatis et al., 2022). II. Aging in AUD Studies have shown that individuals with AUD die earlier than healthy controls and are at a significantly increased risk for all-cause mortality (Westman et al., 2015, Larame et al., 2015). Given the potential role of AUD in the aging process, it is important to understand this relationship on a molecular, epigenetic level. To better assess biological age, several epigenetic clocks that robustly correlate with chronological age have been developed. These clocks are algorithms that take the weighted average of methylation levels at specific CpG sites to calculate DNA methylation age (DNAm age), which is highly correlated with chronological age. We have previously shown that AUD is associated with epigenetic age acceleration (Rosen et al., 2018) and confirmed our finding in a larger sample. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 10-5)(Luo et al., 2020). We continue to work on epigenetic biomarkers of aging in individuals with AUD and have developed a methylation score of stress that tracks stress exposure in individuals with AUD (Jung et al., 2022). In addition, we have conducted multi-omic analyses of aging and identified several novel targets (Mavromatis et al., 2023)(Rosoff et al., 2023). III. PCSK9 in AUD Approximately 50% of all liver disease mortality is currently attributable to alcohol misuse (Gao and Bataller, 2011, Rehm et al., 2013, Seitz et al., 2018), yet there are no FDA approved treatment options for alcohol-associated liver disease (ALD). Thus, a substantial and increasing need is emerging for new therapeutic options capable of reducing alcohol-associated liver damage. We have recently shown that the PCSK9 inhibitor alirocumab attenuates alcohol-induced hepatic triglyceride accumulation, hepatocellular injury and hepatic inflammation in a rat model of chronic alcohol exposure (Lee et al., 2019). Given the unmet clinical need for novel treatment options for ALD, we started a safety and tolerability study of alirocumab in heavy social drinkers. We hypothesize that alirocumab will be well tolerated and safe in this new target population and alirocumab will attenuate alcohol-induced liver damage and inflammatory biomarkers. We are currently conducting this clinical trial entitled A Phase I, Randomized, Double-Blind, Placebo-Controlled, Study of Safety, Tolerability, and Bioeffects of alirocumab in Non-treatment Seeking Heavy Drinkers (ClinicalTrials.gov Identifier: NCT04781322). Additional preclinical work is ongoing on the mechanisms by which PCSK9 inhibition attenuates ALD and inflammation. We have also recently shown that PCSK9 inhibition appears to have a neutral effect on neurocognitive outcomes using a drug-target Mendelian Randomization approach (Rosoff et al., 2022).