The model shown describes different stages of alcohol exposure and subsequent PCSK9 methylation and expression findings. Consistent with mild use are our finding of alcohol exposure leading to hypomethylation (discovery data sets, Fig. 1a-e, plasma data set, Fig. 2f) with lower expression initially. Chronic alcohol use eventually leads to higher methylation and higher expression (rat data set, Supplementary Fig. 4) whereas alcohol liver toxicity (acute – NIAAA mouse model or chronic – liver transplant cases) leads to high methylation with ultimately low protein expression, consistent with end-stage liver disease (Fig. 4 and Supplementary Fig. 2, 5). Low expression and high methylation might also be affected by changes in cell type composition of tissue, as shown in end-stage liver disease tissue that varies greatly from healthy liver tissue on a global scale (Supplementary Fig. 3, 5). The early mild stage might be due to direct effects on transcription factor binding in the promoter regions (Supplementary Fig. 7), while later might be caused by liver toxicity effects and tissue composition changes (Supplementary Fig. 2, 3, 5).