Air Pollution and Peripheral Blood Gene Expression in Subjects with Coronary Arte

描述(由申请人提供)：大量研究表明，环境颗粒物(PM)空气污染与心血管住院和死亡率之间存在关联。这些联系的因果污染物成分和生理机制还没有完全了解。这项拟议研究的目的是提高人们对空气颗粒物污染对冠心病(CAD)高危人群全血基因表达的重要性的认识。我们建议从一项正在进行的小组研究中确定候选基因转录本在受试者中的表达水平，并将表达结果与密集暴露和健康结果评估的现有数据联系起来。我们收集了多次评估PM暴露对急性心血管健康影响的措施，重点是超细颗粒物。拥有完整的家庭暴露和健康结果数据的登记受试者包括60名老年不吸烟者，他们生活在洛杉矶空气盆地空气污染水平较高地区的退休社区。每个受试者都接受了长达7个月的跟踪调查，抽取了多达12次全血总RNA，同时采集了血液样本，以检测炎症和氧化应激的生物标志物。具体目的如下：1)评估炎症和氧化应激反应的关键基因在冠心病患者外周血中的表达是否与室内和室外家庭场所测量的空气污染物暴露有关。我们假设，与心血管急性反应和疾病进展相关的生物通路中涉及的基因的表达水平将随着PM暴露的增加而改变。这将通过定量聚合酶链式反应来测试42个关键基因的表达，这些基因预计会因空气污染物而上调或下调。基因将包括与氧化应激、抗氧化防御、异体代谢、炎症、凝血和内质网应激有关的基因。重复测量分析将被用来确定选定的基因是否会因空气污染而改变表达，并根据细胞转移进行调整。我们将使用受试者退休社区的详细测量来评估基因表达与PM组成和来源的关系。我们预计会发现与超细颗粒物和与交通相关的空气污染标志物之间的最强联系。2)评估对空气污染物暴露中参与氧化应激或抗氧化反应的蛋白质的受试者基因型对目标1中关系的影响修正。我们假设氧化应激相关的多态将改变选定的一组基因的表达，以响应空气污染物的暴露。这一探索性目标将产生初步数据，以计划进行更大规模的研究，旨在确定人们对空气污染不利影响的潜在易感性。这项研究的结果将为进一步的流行病学研究奠定基础，这些研究涉及重复测量，以产生关于暴露时间依赖的基因和蛋白质表达的信息。公共卫生相关性：我们将分析有冠心病病史的高危老年人暴露于城市空气污染与外周血细胞关键基因表达的关系。我们将评估这种基因-环境设计成为人口研究中一种强大的新工具的潜力，该研究旨在测量对环境应激的生物反应，包括空气污染物诱导的全身氧化应激和炎症，这些因素在不利的心血管结果中发挥作用。与公共卫生相关的是，数据将来自易受影响的城市人口的日常生活。

DESCRIPTION (provided by applicant): Numerous studies have shown associations of ambient particulate matter (PM) air pollution with cardiovascular hospital admissions and mortality. The causal pollutant components and physiologic mechanisms for these associations are not fully understood. The objective of the proposed study is to advance knowledge on the importance of particulate air pollution on whole blood gene expression in a high-risk population of elderly people with coronary artery disease (CAD). We propose to determine the expression levels of candidate gene transcripts in subjects from an ongoing panel study, and link the expression results to available data from intensive exposure and health outcome assessments. We collected repeated measures to evaluate acute cardiovascular health effects of exposure to PM, with a focus on ultrafine particles. Enrolled subjects with complete home exposure and health outcome data include 60 elderly nonsmokers living in retirement communities in areas of the Los Angeles air basin with high air pollution levels. Each subject has been followed over a 7-month period with up to 12 blood draws for whole blood total RNA at the same time blood samples were taken for biomarkers of inflammation and oxidative stress. Specific aims are as follows: 1) To assess whether key genes of inflammatory and oxidative stress responses are differentially expressed in peripheral blood of subjects with CAD in relation to air pollutant exposures measured at indoor and outdoor home sites. We hypothesize that the expression level of genes involved in biological pathways relevant to cardiovascular acute responses and disease progression will be altered following higher PM exposures. This will be accomplished with quantitative PCR to test the expression of 42 key genes expected to be up- or down-regulated in response to air pollutants. Genes will include those involved in oxidative stress, antioxidant defense, xenobiotic metabolism, inflammation, coagulation, and endoplasmic reticulum stress. Repeated measures analysis will be used to determine if selected genes change their expression in response to air pollution, adjusted for cell shifts. We will evaluate the relation of gene expression to PM composition and source using detailed measurements at the subjects' retirement communities. We anticipate finding the strongest associations with ultrafine PM and markers of traffic-related air pollution. 2) To evaluate effect modification of relationships in Aim 1 by subject genotypes for proteins involved in oxidative stress or antioxidant responses to air pollutant exposures. We hypothesize that oxidative stress-related polymorphisms will alter the expression of the selected set of genes in response to air pollutant exposures. This exploratory aim will generate preliminary data to plan for larger studies aiming to identify people at potentially heightened susceptibility to adverse effects of air pollution. Results of this study will establish a foundation for additional epidemiologic research involving repeated measurements to yield information about exposure time-dependent gene and protein expression. PUBLIC HEALTH RELEVANCE: We will analyze the relation between exposure to urban air pollution and expression of key genes in peripheral blood cells of a high-risk population of elderly people with a history of coronary heart disease. We will assess the potential of this gene-environment design to become a powerful new tool in population studies aiming to measure biological response to environmental stressors, including air pollutant-induced systemic oxidative stress and inflammation that play a role in adverse cardiovascular outcomes. The relevance to public health is that data will come from the everyday life of a susceptible urban population.