Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension

Tobacco, alcohol, and marijuana consumption is an important public health problem because of their high use worldwide and their association with the risk of mortality and many health conditions, such as hypertension, which is the commonest risk factor for death throughout the world. A likely pathway of action of substance consumption leading to persistent hypertension is DNA methylation. Here, we evaluated the effects of tobacco, alcohol, and marijuana on DNA methylation in the same cohort (<i>N</i> = 3,424). Three epigenome-wide association studies (EWAS) were assessed in whole blood using the InfiniumHumanMethylationEPIC BeadChip. We also evaluated the mediation of the top CpG sites in the association between substance consumption and hypertension. Our analyses showed 2,569 CpG sites differentially methylated by alcohol drinking and 528 by tobacco smoking. We did not find significant associations with marijuana consumption after correcting for multiple comparisons. We found 61 genes overlapping between alcohol and tobacco that were enriched in biological processes involved in the nervous and cardiovascular systems. In the mediation analysis, we found 66 CpG sites that significantly mediated the effect of alcohol consumption on hypertension. The top alcohol-related CpG site (cg06690548, P-value = 5.9·10⁻⁸³) mapped to SLC7A11 strongly mediated 70.5% of the effect of alcohol consumption on hypertension (P-value = 0.006). Our findings suggest that DNA methylation should be considered for new targets in hypertension prevention and management, particularly concerning alcohol consumption. Our data also encourage further research into the use of methylation in blood to study the neurological and cardiovascular effects of substance consumption. The consumption of tobacco, alcohol, and marijuana is very high worldwide and is associated with common diseases, like cardiovascular and neurological disorders.This study found that tobacco and alcohol have large effects on genome wide DNA methylation while marijuana consumption has nonsignificant effects.The genes differentially methylated were enriched in pathways related to neurodevelopment, suggesting the mediation between recreational drug consumption and neurological disorders.More remarkably, 66 alcohol related CpG sites significantly mediated the association between heavy drinking and hypertension.Our findings suggest that DNA methylation changes should be considered for new targets in disease prevention for recreational drug consumers. The consumption of tobacco, alcohol, and marijuana is very high worldwide and is associated with common diseases, like cardiovascular and neurological disorders. This study found that tobacco and alcohol have large effects on genome wide DNA methylation while marijuana consumption has nonsignificant effects. The genes differentially methylated were enriched in pathways related to neurodevelopment, suggesting the mediation between recreational drug consumption and neurological disorders. More remarkably, 66 alcohol related CpG sites significantly mediated the association between heavy drinking and hypertension. Our findings suggest that DNA methylation changes should be considered for new targets in disease prevention for recreational drug consumers.

烟草、酒精及大麻的使用是一项重要的公共卫生问题：其在全球范围内的普及率居高不下，且与死亡风险及多种健康病症（如高血压）密切相关——而高血压是全球范围内最常见的致死危险因素。物质使用引发持续性高血压的潜在作用通路之一为DNA甲基化（DNA methylation）。本研究针对同一队列（样本量N=3424）评估了烟草、酒精及大麻使用对DNA甲基化的影响。研究采用InfiniumHumanMethylationEPIC BeadChip芯片对全血样本开展了3项表观全基因组关联研究（epigenome-wide association study, EWAS），同时分析了CpG位点（CpG site）在物质使用与高血压关联中的介导作用。
分析结果显示，饮酒可导致2569个CpG位点发生差异甲基化，吸烟则可导致528个CpG位点发生差异甲基化。经多重比较校正后，未发现大麻使用与差异甲基化存在显著关联。本研究共发现61个同时受饮酒和吸烟影响的差异甲基化基因，这些基因显著富集于神经系统与心血管系统相关的生物学过程。
介导效应分析结果显示，共有66个CpG位点可显著介导饮酒对高血压的影响。与饮酒关联度最高的CpG位点cg06690548（P值=5.9×10⁻⁸³）位于SLC7A11基因区域，该位点可显著介导70.5%的饮酒对高血压的影响（P值=0.006）。本研究结果提示，DNA甲基化可作为高血压预防与管理的新型靶点，尤其针对饮酒人群。本研究数据同时推动了后续研究：可通过血液甲基化检测探究物质使用对神经系统与心血管系统的影响。
全球范围内烟草、酒精及大麻的使用量居高不下，且与心血管疾病、神经系统疾病等常见病症密切相关。本研究发现，烟草与酒精对全基因组DNA甲基化具有显著影响，而大麻使用则未表现出显著效应。差异甲基化基因显著富集于神经发育相关通路，提示休闲性药物使用与神经系统疾病之间存在甲基化介导的关联。尤为值得关注的是，66个与饮酒相关的CpG位点可显著介导过量饮酒与高血压之间的关联。本研究结果提示，DNA甲基化改变可作为休闲性药物使用者疾病预防的新型靶点。
全球范围内烟草、酒精及大麻的使用量居高不下，且与心血管疾病、神经系统疾病等常见病症密切相关。本研究发现，烟草与酒精对全基因组DNA甲基化具有显著影响，而大麻使用则未表现出显著效应。差异甲基化基因显著富集于神经发育相关通路，提示休闲性药物使用与神经系统疾病之间存在甲基化介导的关联。尤为值得关注的是，66个与饮酒相关的CpG位点可显著介导过量饮酒与高血压之间的关联。本研究结果提示，DNA甲基化改变可作为休闲性药物使用者疾病预防的新型靶点。