"PIK"ing Out New Epigenetic Markers in Lung Disease.
"PIK"ing Out New Epigenetic Markers in Lung Disease.
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“PIK”找出肺部疾病的新表观遗传标记。
DOI：
10.1164/rccm.202002-0295ed
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发表时间：
2020
影响因子：
24.7
通讯作者：
Zacharias,William
中科院分区：
文献类型：
--
作者：
Swarr,Daniel;Putcha,Nirupama;Zacharias,William
在过去的10年里，全基因组关联研究已经成功地确定了与慢性阻塞性肺疾病(COPD)风险相关的一些特定基因座的基因变异。仅COPD基因(COPD遗传流行病学)研究就发现了20个风险基因(1)。除了COPD的这些遗传因素外，各种外部因素，包括围产期暴露、反复感染和慢性环境刺激物(如吸烟、污染和生物质燃料)，显然也导致了这种疾病的发病。这些暴露导致疾病的机制仍然是一个积极关注的领域。表观遗传机制被广泛定义为不是由于DNA序列变化而导致的基因转录调节，已被假设为疾病发病机制中基因-环境相互作用的关键中介[2]。DNA的甲基化模式被广泛认为受到环境刺激的影响，形成对过去损伤的细胞记忆，从而影响未来的反应。DNA甲基化模式可能在遗传风险因素和环境暴露之间形成一座重要的生物学桥梁，这是许多复杂医疗条件的特征(3，4)。到目前为止，对大型队列的表观遗传学研究已经证明，在既往吸烟者中，患COPD的风险与特定的DNA甲基化模式之间存在重要的关联(5)。DNA甲基化的改变也与总死亡率的增加有关(6-8)。在本期杂志上发表的一项研究中，Morrow和他的同事(pp.1099-1109)分析了来自两项大型多中心研究的患者的外周血DNA甲基化情况，这些患者来自两项关于患有或有COPD风险的个人的大型多中心研究。他们报告了与死亡率变化相关的七个CpG位点的DNA甲基化。这些位点是在COPD基因研究的样本中确定的，并在ECLIPSE(COPD纵向评估以确定预测性替代终点研究)队列中重复。效应大小最大且最具生物学可信度的两个重复位点--cg03971555和cg12033075--位于PIK3CD(磷脂酰肌醇-3-激酶催化亚单位d)附近的CpG岛的“海岸区域”。这两个位点的高甲基化与存活率降低、登记时肺功能降低以及COPD风险增加相关。这些结果是有影响的，因为它们暗示了广泛研究的PI3K信号通路是吸烟者疾病表型和死亡风险的潜在介体。
Over the past 10 years, genome-wide association studies have successfully identified genetic variation at a number of specific loci associated with chronic obstructive pulmonary disease (COPD) risk. The COPDGene (Genetic Epidemiology of COPD) study alone has led to the discovery of 20 risk loci (1). In addition to these genetic contributions to COPD, a variety of external factors, including exposures during the perinatal period, recurrent infections, and chronic environmental irritants (eg, smoking, pollution, and biomass fuel), clearly contribute to the pathogenesis of this disease. The mechanisms by which these exposures predispose to disease remain an area of active interest. Epigenetic mechanisms, broadly defined as regulation of gene transcription that does not result from changes in DNA sequence, have been hypothesized to be key mediators of gene–environment interactions in disease pathogenesis (2). Methylation patterns of DNA are widely recognized to be impacted by environmental stimuli, forming a cellular memory of past injuries that condition future responses. DNA methylation patterns may form an important biological bridge between genetic risk factors and environmental exposures that are characteristic of many complex medical conditions (3, 4). To date, epigenetic studies of large cohorts have demonstrated important associations between the risk of developing COPD and specific DNA methylation patterns in former smokers (5). DNA methylation changes have also been associated with increased overall mortality (6–8). However, the association between DNA methylation and mortality in current and former smokers with or without COPD has not previously been examined.In a study presented in this issue of the Journal, Morrow and colleagues (pp. 1099–1109) analyzed peripheral blood for genome-wide DNA methylation in a subset of patients from two large multicenter studies of individuals with or at risk for COPD (9). They report DNA methylation at seven CpG sites that were associated with changes in mortality. These sites were identified in samples from the COPDGene study and were replicated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study) cohort. The two replicated sites with the largest effect sizes and arguably with the most supporting biological plausibility—cg03971555 and cg12033075—are located in the “shore region” of a CpG island adjacent to PIK3CD (phosphatidylinositol-3-kinase catalytic subunit d). Hypermethylation at both sites was associated with decreased survival, lower lung function at enrollment, and increased risk of COPD. These results are impactful in that they implicate the well-studied PI3K signaling pathway as a potential mediator of disease phenotypes and mortality risk in smokers.