RESUMO
Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.
Assuntos
Alcoolismo/genética , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/genética , Adulto , Alcoolismo/fisiopatologia , Animais , LDL-Colesterol/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Etanol/efeitos adversos , Etanol/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos , Fenótipo , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 9/fisiologia , Ratos , Ratos WistarRESUMO
Postpartum depression (PPD) affects â¼10-18% of women in the general population and results in serious consequences to both the mother and offspring. We hypothesized that predisposition to PPD risk is due to an altered sensitivity to estrogen-mediated epigenetic changes that act in a cell autonomous manner detectable in the blood. We investigated estrogen-mediated epigenetic reprogramming events in the hippocampus and risk to PPD using a cross-species translational design. DNA methylation profiles were generated using methylation microarrays in a prospective sample of the blood from the antenatal period of pregnant mood disorder patients who would and would not develop depression postpartum. These profiles were cross-referenced with syntenic locations exhibiting hippocampal DNA methylation changes in the mouse responsive to long-term treatment with 17ß-estradiol (E2). DNA methylation associated with PPD risk correlated significantly with E2-induced DNA methylation change, suggesting an enhanced sensitivity to estrogen-based DNA methylation reprogramming exists in those at risk for PPD. Using the combined mouse and human data, we identified two biomarker loci at the HP1BP3 and TTC9B genes that predicted PPD with an area under the receiver operator characteristic (ROC) curve (area under the curve (AUC)) of 0.87 in antenatally euthymic women and 0.12 in a replication sample of antenatally depressed women. Incorporation of blood count data into the model accounted for the discrepancy and produced an AUC of 0.96 across both prepartum depressed and euthymic women. Pathway analyses demonstrated that DNA methylation patterns related to hippocampal synaptic plasticity may be of etiological importance to PPD.
