The role of epigenetics in the adverse effects of social environmental stressors on COPD outcomes

项目总结 慢性阻塞性肺疾病(COPD)是美国第四大主要死亡原因，其发病率较高 发病率，包括生活质量差和导致住院和增加的呼吸恶化 死亡率。目前还没有治疗慢性阻塞性肺疾病的疾病修饰药物。低收入个人的比例不成比例 受慢性阻塞性肺病影响，与收入较高的人相比，他们的健康状况明显更差。我们的 团队和其他人发现，暴露在社会环境压力源中的更多与更糟糕的情况有关 COPD呼吸道症状和生活质量，与年龄、教育程度、体重指数和吸烟无关 历史。然而，到目前为止，减少社会/行为风险因素的战略一直效率低下。因此， 需要采取补充战略来减轻疾病负担；生物机制，例如表观遗传学， 这可能会被干预，可能会提供一种有前途的替代战略。 强有力的平行证据支持表观遗传学参与对社会压力的生物反应 暴露和慢性阻塞性肺疾病的发病机制。个体基因座和表观遗传衰老途径都与此有关。 我们的初步结果进一步支持DNA甲基化(dNaM；一种表观遗传学数据)与两者相关 在低收入人群中，COPD结果更差，社会压力暴露增加。尽管如此 证据表明，没有研究在社会应激源和慢性阻塞性肺病的背景下严格检查dNaM 结果。因此，这项由ESI领导的提案检验了社会环境压力因素对 通过表观遗传机制恶化COPD的呼吸和生活质量，包括在 表观遗传衰老途径和个体(非衰老)基因座。我们利用了两项现有的慢性阻塞性肺病研究 收集社会压力源的统一测量，包括寿命、COPD健康结局以及 血液和诱导痰生物样本具有适当的流行率和暴露和结果的可变性。 在目标1中，我们测试了社会压力对COPD健康的影响中的加速表观遗传衰老机制 结果。在目标2中，我们在一组目标基因座(以前与 与慢性阻塞性肺病、社会经济地位或社会压力源有关)。对于每个目标，血液和诱导痰dNaM将 平行测试，并比较不同样本类型的结果，以进一步了解机制/生物标记物 实用程序。接受测试的社会压力暴露包括过去的不良童年经历和最近的暴力事件， 辨别力、感知压力以及压力的综合指数。慢性阻塞性肺疾病的结果有待检测 包括COPD对健康和生活质量(通过SGRQ和CAT评分)和呼吸道症状影响 严重程度(通过MMRC和恶化频率)。目标3将目标1-2中的dNaM发现与诱导 以痰中基因表达水平识别下游功能基因表达的变化。我们的结果可以 提供可干预以改善COPD的新的DNA和/或RNA生物靶点 结果，特别是在低收入群体中。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States with high morbidity, including poor quality of life and respiratory exacerbations leading to hospitalization and increased mortality. There are no disease modifying drugs for COPD. Low-income individuals are disproportionately affected by COPD and have significantly worse health outcomes compared to those with higher income. Our team, and others, found that increased exposure to social environmental stressors is associated with worse COPD respiratory symptoms and quality of life, independent of chronologic age, education, BMI, and smoking history. However, strategies to reduce social/behavioral risk factors have, to date, been inefficient. Thus, complementary strategies to reduce the burden of disease are needed; biologic mechanisms, e.g. epigenetics, that could be intervened upon, could provide a promising alternative strategy. Strong parallel lines of evidence support epigenetic involvement in the biologic response to social stress exposures and for COPD pathogenesis. Both individual loci and the epigenetic aging pathway are implicated. Our preliminary results further support DNA methylation (DNAm; a type of epigenetic data) is related to both worse COPD outcomes and increased social stress exposure, in a low-income population. Despite this evidence, no studies have rigorously examined DNAm in the context of both social stressors and COPD outcomes. Therefore, this ESI-led proposal tests the hypothesis that social environment stressors contribute to worsened COPD respiratory and quality of life outcomes through epigenetic mechanisms, including in the epigenetic aging pathway and at individual (non-aging) loci. We leverage two existing COPD studies that collected unified measures of social stressors, from across the lifespan, COPD health outcomes, as well as blood and induced sputum biosamples with suitable prevalence and variability in exposures and outcomes. In Aim 1, we test for accelerated epigenetic aging mechanisms in social stress effects on COPD health outcomes. In Aim 2, we test for DNA methylation mechanisms at a targeted set of loci (previously associated with COPD, socioeconomic position, or social stressors). For each aim, blood and induced sputum DNAm will be tested in parallel, and results compared across specimen types to further inform mechanism/biomarker utility. Social stress exposures to be tested include past adverse childhood experience and recent violence, discrimination, and perceived stress as well as a composite index of stress. COPD outcomes to be tested include impact of COPD on health and life quality (via SGRQ and CAT score) and respiratory symptom severity (via mMRC and exacerbation frequency). Aim 3 will relate DNAm findings from Aims 1-2 to induced sputum gene expression levels to identify downstream functional gene expression changes. Our results can provide new DNA and/or RNA biologic targets that could be intervened upon to improve COPD outcomes, particularly in low-income groups.