ABSTRACT

Cigarette smoking impacts DNA methylation, but the investigation of sex-specific features of lung tissue DNA methylation in smokers has been limited. Women appear more susceptible to cigarette smoke, and often develop more severe lung disease at an earlier age with less smoke exposure. We aimed to analyse whether there are sex differences in DNA methylation in lung tissue and whether these DNA methylation marks interact with smoking. We collected lung tissue samples from former smokers who underwent lung tissue resection. One hundred thirty samples from white subjects were included for this analysis. Regression models for sex as a predictor of methylation were adjusted for age, presence of COPD, smoking variables and technical batch variables revealed 710 associated sites. 294 sites demonstrated robust sex-specific methylation associations in foetal lung tissue. Pathway analysis identified 6 nominally significant pathways including the mitophagy pathway. Three CpG sites demonstrated a suggested interaction between sex and pack-years of smoking: GPR132, ANKRD44 and C19orf60. All of them were nominally significant in both male- and female-specific models, and the effect estimates were in opposite directions for male and female; GPR132 demonstrated significant association between DNA methylation and gene expression in lung tissue (P < 0.05). Sex-specific associations with DNA methylation in lung tissue are wide-spread and may reveal genes and pathways relevant to sex differences for lung damaging effects of cigarette smoking.

摘要

吸烟会影响 DNA 甲基化，但对吸烟者肺组织 DNA 甲基化的性别特异性特征的研究有限。女性似乎更容易受到香烟烟雾的影响，并且往往在较年轻时接触烟雾较少而患上更严重的肺部疾病。我们的目的是分析肺组织中 DNA 甲基化是否存在性别差异，以及这些 DNA 甲基化标记是否与吸烟相互作用。我们从接受肺组织切除术的前吸烟者那里收集了肺组织样本。本次分析纳入了来自白人受试者的一百三十个样本。作为甲基化预测因子的性别回归模型根据年龄、COPD 的存在、吸烟变量和技术批次变量进行了调整，揭示了 710 个相关位点。294 个位点显示胎儿肺组织中存在强大的性别特异性甲基化关联。通路分析确定了 6 个名义上重要的通路，包括线粒体自噬通路。三个 CpG 位点显示了性别和吸烟包年数之间的相互作用：GPR132、ANKRD44 和 C19orf60。所有这些在男性和女性特定模型中都名义上显着，并且男性和女性的效果估计方向相反；GPR132 显示 DNA 甲基化与肺组织基因表达之间存在显着相关性 ( P < 0.05)。肺组织中 DNA 甲基化与性别特异性的关联广泛存在，可能揭示与吸烟对肺部造成损害的性别差异相关的基因和途径。