Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 501, No. 17, Xu-Zhou Road, Taipei, 100, Taiwan.
Master of Public Health Degree Program, College of Public Health, National Taiwan University, Taipei, Taiwan.
Clin Epigenetics. 2023 Jun 3;15(1):94. doi: 10.1186/s13148-023-01512-x.
Smoking can lead to the deterioration of lung function and susceptibility to diabetes. Recently, smoking was found to induce DNA methylation (DNAm) changes in some cytosine-phosphate-guanine sites (CpGs). As linear combinations of DNAm levels of aging-related CpGs, five measures of epigenetic age acceleration (EAA) have received extensive attention: HannumEAA, IEAA, PhenoEAA, GrimEAA, and DunedinPACE. It is of interest to explore whether some measures of EAA can mediate the associations of smoking with diabetes-related outcomes and indices of ventilatory lung function.
In this study, we included self-reported smoking variables (smoking status, the number of pack-years, and years since smoking cessation), seven DNAm markers (HannumEAA, IEAA, PhenoEAA, GrimEAA, DNAm-based smoking pack-years, DNAm plasminogen activator inhibitor 1 [PAI-1] levels, and DunedinPACE), and four health outcomes (fasting glucose, hemoglobin A1C, forced expiratory volume in 1.0 s [FEV1], and forced vital capacity [FVC]) from 2474 Taiwan Biobank participants. Mediation analyses were conducted while adjusting for chronological age, sex, body mass index, drinking status, regular exercise status, educational attainment, and five cell-type proportions. We demonstrated that GrimEAA, DNAm-based smoking pack-years, DNAm PAI-1 levels, DunedinPACE, and PhenoEAA mediated smoking associations with diabetes-related outcomes. Moreover, current and former smoking both had an adverse indirect effect on FVC through DNAm PAI-1 levels. For former smokers, a long time since smoking cessation had a positive indirect impact on FVC through GrimEAA and on FEV1 through PhenoEAA.
This is one of the first studies to comprehensively investigate the role of five measures of EAA in mediating the associations of smoking with the health outcomes of an Asian population. The results showed that the second-generation epigenetic clocks (GrimEAA, DunedinPACE, and PhenoEAA) significantly mediated the associations between smoking and diabetes-related outcomes. In contrast, the first-generation epigenetic clocks (HannumEAA and IEAA) did not significantly mediate any associations of smoking variables with the four health outcomes. Cigarette smoking can, directly and indirectly, deteriorate human health through DNAm changes in aging-related CpG sites.
吸烟可导致肺功能恶化和易患糖尿病。最近，研究发现吸烟可诱导一些胞嘧啶磷酸鸟嘌呤位点（CpG）的 DNA 甲基化（DNAm）改变。作为与衰老相关的 CpG 中 DNAm 水平的线性组合，已有五种表观遗传年龄加速（EAA）测量方法备受关注：HannumEAA、IEAA、PhenoEAA、GrimEAA 和 DunedinPACE。探索某些 EAA 测量方法是否能介导吸烟与糖尿病相关结局和通气肺功能指标之间的关联，具有一定的意义。
本研究纳入了自我报告的吸烟变量（吸烟状况、吸烟包年数和戒烟年限）、七个 DNAm 标志物（HannumEAA、IEAA、PhenoEAA、GrimEAA、基于 DNAm 的吸烟包年数、DNAm 纤溶酶原激活物抑制剂 1[PAI-1]水平和 DunedinPACE）以及来自 2474 名台湾生物库参与者的 4 个健康结局（空腹血糖、糖化血红蛋白、1.0 秒用力呼气量[FEV1]和用力肺活量[FVC]）。在调整了实际年龄、性别、体重指数、饮酒状况、规律运动状况、教育程度和 5 种细胞比例后，进行了中介分析。结果表明，GrimEAA、基于 DNAm 的吸烟包年数、DNAm PAI-1 水平、DunedinPACE 和 PhenoEAA 介导了吸烟与糖尿病相关结局之间的关联。此外，目前吸烟和曾经吸烟均通过 DNAm PAI-1 水平对 FVC 产生不良间接影响。对于曾经吸烟者，戒烟年限较长时，GrimEAA 对 FVC、PhenoEAA 对 FEV1 有正向间接影响。
这是首次全面研究五种 EAA 测量方法在介导吸烟与亚洲人群健康结局关联中的作用的研究之一。结果表明，第二代表观遗传钟（GrimEAA、DunedinPACE 和 PhenoEAA）显著介导了吸烟与糖尿病相关结局之间的关联。相比之下，第一代表观遗传钟（HannumEAA 和 IEAA）并没有显著介导吸烟变量与 4 项健康结局之间的任何关联。吸烟可通过与衰老相关的 CpG 位点的 DNAm 改变，直接和间接损害人类健康。
