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率和死亡率有关。这些关联的因果污染物成分和生理机制尚不完全清楚。这项研究的目的是提高人们对空气颗粒污染对老年冠状动脉疾病高危人群全血基因表达重要性的认识。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物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可用数据联系起来。我们收集了重复的测量来评估暴露于PM对急性心血管健康的影响，重点是超细颗粒。纳入的受试者有完整的家庭暴露和健康结果数据，包括60名居住在洛杉矶空气盆地高污染地区退休社区的不吸烟老年人。研究人员对每位受试者进行了长达7个月的随访，抽取了12次全血总RNA，同时采集了炎症和氧化应激生物标志物的血液样本。具体目的如下：1)评估CAD受试者外周血中炎症和氧化应激反应的关键基因是否与室内和室外家居场所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学途径相关的基因表达水平将在较高的PM暴露后发生改变。这将通过定量PCR来检测42个关键基因的表达，这些基因在空气污染物的影响下被上调或下调。基因将包括那些涉及氧化应激，抗氧化防御，外源代谢，炎症，凝血和内质网应激。重复测量分析将用于确定选定的基因是否会因空气污染而改变其表达，并根据细胞的变化进行调整。我们将在受试者的退休社区使用详细测量来评估基因表达与PM组成和来源的关系。我们期望找到与超细PM和交通相关空气污染标志物的最强关联。2)评估受试者基因型对Aim 1中参与空气污染物暴露的氧化应激或抗氧化反应的蛋白质的影响。我们假设，氧化应激相关的多态性将改变一组基因的表达，以响应空气污染物暴露。这一探索性目标将产生初步数据，为更大规模的研究制定计划，旨在确定可能对空气污染不利影响更敏感的人群。这项研究的结果将为进一步的流行病学研究奠定基础，包括重复测量，以获得暴露时间依赖性基因和蛋白质表达的信息。公共卫生相关性：我们将分析暴露于城市空气污染与有冠心病史的老年人高危人群外周血关键基因表达之间的关系。我们将评估这种基因-环境设计的潜力，以成为人口研究中一个强大的新工具，旨在测量对环境应激源的生物反应，包括空气污染物诱导的系统性氧化应激和炎症，这些应激源在不良心血管结果中起作用。与公共卫生相关的是，数据将来自易感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.