The Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA, 01702, USA.
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Clin Epigenetics. 2021 Mar 22;13(1):60. doi: 10.1186/s13148-021-01041-5.
DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases.
We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data.
Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
DNA 甲基化是一种关键的表观遗传修饰，可直接影响基因调控。DNA 甲基化受环境因素（如吸烟）的影响很大，而吸烟与慢性阻塞性肺疾病（COPD）和肺癌有因果关系。迄今为止，针对 DNA 甲基化和基因表达及其与肺部疾病的相互关系，进行的大规模联合分析较少。
我们对来自四个队列的~6000 个人的全血基因表达进行了全基因组关联研究。我们发现并复制了许多与每个 CpG 500kb 内顺式基因表达相关的 CpG，在各个队列中鉴定了 148 至 1741 个顺式 CpG-转录物对。我们发现，CpG 越靠近转录起始位点，其效应大小越大，36%的顺式 CpG-转录物对共享相同的因果遗传变异。孟德尔随机化分析表明，CHRNA5 的低甲基化和低表达（编码与吸烟相关的烟碱受体）与 COPD 和肺癌风险增加有关。这一推测的因果关系在肺组织数据中得到了进一步验证。
我们的研究结果提供了全血 DNA 甲基化与基因表达的大型综合关联研究。表达平台的差异而非人群的差异对于顺式 CpG-转录物对的复制至关重要。跨 CpG-转录物对的低重现性表明，DNA 甲基化调节附近而非远程基因表达。CHRNA5 甲基化和表达与 COPD 和肺癌的关系表明，吸烟相关表观遗传变异模式与肺部疾病之间存在潜在的机制联系，并突出了肺部疾病和戒烟治疗的潜在治疗靶点。
