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

表观遗传学在社会环境压力因素对慢性阻塞性肺病结局的不利影响中的作用

基本信息

批准号：
10052092
负责人：
Christine Ladd-Acosta
金额：
$ 58.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-13 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10052092
关键词：
Acceleration Address Adverse effects Affect Age Aging Algorithms Behavior Therapy Behavioral Biological Biological Markers Blood Body mass index Cause of Death Cell physiology Chronic Obstructive Airway Disease Chronology Communities Critical Care DNA DNA Methylation Data Data Collection Detection Discrimination Disease Disease Outcome Education Effectiveness of Interventions Epidemiology Epigenetic Process Exposure to Frequencies Gene Expression Goals Health Hospitalization Income Individual Intervention Knowledge Lead Longevity Low Income Population Low income Lung Lung diseases Measures Mediation Medicine Molecular Target Morbidity - disease rate Outcome Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Pharmacologic Substance Play Population Prevalence Protocols documentation Quality of life RNA Research Personnel Respiratory Signs and Symptoms Risk Factors Role Sampling Severities Smoking History Social Environment Social Sciences Socioeconomic Status Specimen Sputum Stress Testing Time United States Violence adverse childhood events biological adaptation to stress biomarker performance burden of illness data curation design effectiveness evaluation environmental stressor epigenomics genome-wide health disparity health disparity populations improved indexing insight inter-individual variation low socioeconomic status mortality perceived stress preventive intervention respiratory response social social stress social stressor stem stressor success treatment strategy

项目摘要

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.

项目概要慢性阻塞性肺疾病（COPD）是美国第四大死亡原因，死亡率很高发病率，包括生活质量差和呼吸系统恶化导致住院并增加死亡。没有针对慢性阻塞性肺病的疾病缓解药物。低收入人群比例过高受慢性阻塞性肺病影响，与收入较高的人相比，健康状况明显较差。我们的研究小组和其他人发现，暴露于社会环境压力源的增加与病情恶化有关 COPD 呼吸道症状和生活质量，与实际年龄、教育程度、BMI 和吸烟无关历史。然而，迄今为止，减少社会/行为风险因素的策略效率低下。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，可以对其进行干预，可以提供有希望的替代策略。强有力的平行证据支持表观遗传参与对社会压力的生物反应暴露和 COPD 发病机制。个体基因座和表观遗传衰老途径都受到影响。我们的初步结果进一步支持 DNA 甲基化（DNAm；一种表观遗传数据）与在低收入人群中，慢性阻塞性肺病的结果更差，社会压力更大。尽管如此证据，没有研究在社会压力源和慢性阻塞性肺病的背景下严格检验 DNAm 结果。因此，这项由 ESI 主导的提案检验了社会环境压力因素有助于这一假设通过表观遗传机制恶化慢性阻塞性肺病呼吸和生活质量结果，包括在表观遗传衰老途径和个体（非衰老）基因座。我们利用两项现有的慢性阻塞性肺病研究收集了整个生命周期的社会压力源、慢性阻塞性肺病健康结果以及血液和诱导痰生物样本具有适当的患病率以及暴露和结果的变异性。在目标 1 中，我们测试了社会压力对慢性阻塞性肺病健康影响的加速表观遗传衰老机制结果。在目标 2 中，我们测试一组目标位点（之前与慢性阻塞性肺病、社会经济地位或社会压力源）。对于每个目标，血液和诱导痰 DNAm 将并行测试，并对不同样本类型的结果进行比较，以进一步了解机制/生物标志物公用事业。要测试的社会压力包括过去不良的童年经历和最近的暴力，歧视、感知压力以及压力综合指数。慢性阻塞性肺病的结果有待测试包括 COPD 对健康和生活质量的影响（通过 SGRQ 和 CAT 评分）以及呼吸道症状严重程度（通过 mMRC 和恶化频率）。目标 3 将目标 1-2 的 DNAm 发现与诱导的痰基因表达水平以确定下游功能基因表达变化。我们的结果可以提供新的 DNA 和/或 RNA 生物靶标，可对其进行干预以改善 COPD 成果，特别是在低收入群体中。