Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts

DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV1, FEF25–75%) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.

DNA甲基化作为一种表观遗传调控基因转录的机制，在人类队列研究中被发现具有亚稳态和变异性。截至目前，针对与人类纵向肺功能下降相关的亚稳态DNA甲基化生物标志物的识别研究尚显不足。此类生物标志物的识别对于筛查易感人群具有重要意义。我们假设，可量化的基于血液的DNA甲基化改变将作为肺功能下降和衰老的亚稳态生物标志物，有助于发现与肺病发生机制相关的新路径和新机制。通过线性混合模型，我们进行了全基因组表观遗传关联研究（EWAS），探讨了CpG二核苷酸DNA甲基化与纵向肺功能（FVC、FEV1、FEF25–75%）下降及衰老之间的关联，首次发现于“标准化衰老研究”，并在“奥古斯塔堡区域合作健康研究”队列中进行验证。我们识别出两个与肺功能下降和衰老相关的亚稳态表观遗传位点，分别为cg05575921（AHRR基因）和cg06126421（IER3基因），这些位点可能揭示了与肺功能、病理发生及衰老相关的基本机制。人类表观基因组变异可能有助于解释肺功能下降及相关病理生理学特征，这些特征无法仅通过DNA序列来解释，例如吸烟者、前吸烟者以及可能是不吸烟者的肺功能加速下降。因此，我们在两个队列中进行的EWAS研究，可能对整个人群而非仅是老年人产生重要影响。