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

空气污染与冠心病患者外周血基因表达

• 批准号: 7846833
• 负责人: RALPH J DELFINO
• 金额: $ 11.48万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846833
• 关键词: Acute; Address; Admission activity; Adverse effects; Age; Air; Air Pollutants; Air Pollution; Alleles; Animal Model; Antioxidants; Archives; Area; Biological; Biological Assay; Biological Markers; Biological Process; Blood; Blood Cells; Blood Vessels; Blood specimen; C-reactive protein; CYP1A1 gene; CYP2E1 gene; Caliber; Candidate Disease Gene; Carbon; Cardiac; Cardiovascular system; Cells; Clinical Research; Coagulation Process; Communities; Complex; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Cytochrome P450; Data; Disease Progression; EPHX1 gene; Elderly; Enrollment; Ensure; Environment Design; Enzymes; Epidemiologic Studies; Epidemiology; Exposure to; Foundations; Functional disorder; Funding; Future; Gases; Gene Expression; Gene Proteins; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Glutathione S-Transferase; Health; Home environment; Hospitals; Human; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-6; Investigation; Knowledge; Lead; Life; Link; Longitudinal Studies; Los Angeles; Manganese Superoxide Dismutase; Measurement; Measures; Mediator of activation protein; Messenger RNA; Microsomal Epoxide Hydrolase; Modification; Morbidity - disease rate; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NQO1 gene; Outcome; Outcome Assessment; Oxidative Stress; Paraoxonase 1; Particle Size; Particulate; Particulate Matter; Pathway interactions; Patients; Peripheral; Peroxidases; Physiological; Platelet Activation; Play; Population; Population Study; Predisposition; Proteins; Public Health; RNA; Recording of previous events; Recruitment Activity; Research; Research Methodology; Retirement; Risk; Role; Sample Size; Sampling; Site; Source; Testing; Thrombosis; Time; Tracer; Transcript; Transcriptional Regulation; Tube; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ultrafine; United States National Institutes of Health; Urban Population; Variant; Whole Blood; Work; Xenobiotic Metabolism; biological adaptation to stress; catalase; clinically relevant; cytokine; endoplasmic reticulum stress; environmental particulate; environmental stressor; gene environment interaction; glutathione peroxidase; heme oxygenase-1; high risk; mRNA Expression; mortality; non-smoker; novel; particle; peripheral blood; pollutant; protein expression; public health relevance; response; tool; trafficking; ultrafine particle

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.

描述（由申请人提供）：许多研究表明，周围颗粒物（PM）空气污染与心血管住院和死亡率相关。这些协会的因果污染物成分和生理机制尚未完全理解。这项研究的目的是进一步了解颗粒物空气污染对冠心病（CAD）老年人高危人群全血基因表达的重要性。我们建议从正在进行的小组研究中确定受试者中候选基因转录本的表达水平，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。我们收集了重复的措施，以评估暴露于PM的急性心血管健康影响，重点是超细颗粒。具有完整的家庭暴露和健康结果数据的入组受试者包括60名居住在洛杉矶空气盆地高空气污染水平地区退休社区的老年非吸烟者。每名受试者都被随访了7个月，最多抽取12次血液用于全血总RNA，同时采集血液样本用于炎症和氧化应激的生物标志物。具体目标如下：1）评估炎症和氧化应激反应的关键基因是否在患有CAD的受试者的外周血中差异表达，其与在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，参与心血管急性反应和疾病进展相关的生物学途径的基因表达水平将在更高的PM暴露后改变。这将通过定量PCR来完成，以测试42个关键基因的表达，这些基因预计将在对空气污染物的反应中上调或下调。基因将包括参与氧化应激、抗氧化防御、异生物质代谢、炎症、凝血和内质网应激的基因。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，并根据细胞变化进行调整。我们将评估基因表达与PM成分和来源的关系，使用受试者退休社区的详细测量。我们希望找到与超细PM和与交通有关的空气污染标志物的最强关联。2)评估目标1中受试者基因型对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关系的影响。我们假设，氧化应激相关的多态性将改变所选择的一组基因的表达，以应对空气污染物暴露。这一探索性的目标将产生初步数据，以计划进行更大规模的研究，旨在确定对空气污染不利影响可能更敏感的人。本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，以获得有关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细胞中关键基因表达之间的关系。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，这些研究旨在测量对环境应激因素的生物反应，包括空气污染引起的全身氧化应激和炎症，这些因素在不良心血管结局中发挥作用。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。