Gene expression responses to air pollution and modification by genetic variation

基因表达对空气污染的反应和遗传变异的改变

• 批准号: 8890158
• 负责人: Sharine Wittkopp
• 金额: $ 4.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890158
• 关键词: Accounting; Acute; Address; Adverse effects; Air Pollutants; Air Pollution; Antioxidants; Area; Arrhythmia; Atherosclerosis; Biological; Biological Markers; Blood Platelets; Blood Pressure; Blood Vessels; Caliber; Cardiac; Cardiopulmonary; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Chemicals; Clinical; Code; Cohort Studies; Complement; Coronary heart disease; Cross-Sectional Studies; Cultured Cells; DNA Sequence; DNA copy number; Data; Diesel Exhaust; Direct Costs; Drug Metabolic Detoxication; EKG ST Segment Depression; Elderly; Epidemiologic Studies; Epithelial; Exposure to; Facilities and Administrative Costs; Fossil Fuels; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Goals; Grant; Heart Diseases; Human; Human Cell Line; In Vitro; Individual; Inflammation; Inflammatory; Inherited; Knowledge; Link; Los Angeles; Measures; Messenger RNA; Mitochondria; Mitochondrial DNA; Modification; Molecular; Morbidity - disease rate; Mutation; Myocardial Infarction; Nuclear; Outcome; Oxidative Stress; Oxidative Stress Pathway; Parents; Particulate; Particulate Matter; Pathway interactions; Peripheral; Persons; Platelet Activation; Pollution; Population; Predisposition; Production; Proteins; Reactive Oxygen Species; Regulatory Pathway; Relative Risks; Reporting; Research; Risk; Risk Factors; Role; Signal Transduction Pathway; Source; Testing; Thrombosis; Toxic Environmental Substances; Training; Ultrafine; United States; Up-Regulation; Variant; Vascular Endothelial Cell; Weather; Whole Blood; Work; biological adaptation to stress; cardiovascular health; cardiovascular risk factor; cohort; differential expression; epidemiologic data; exposed human population; gene environment interaction; genetic information; genetic variant; heart rate variability; in vivo; mitochondrial DNA mutation; mortality; mouse model; peripheral blood; research study; response; traffic-related air pollution; trafficking; ultrafine particle

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in the United States. In 2009, direct and indirect costs associated with coronary heart disease (CHD) were estimated to total $165 billion. Therefore, there is substantial need for research to enhance our understanding of risk factors for CHD morbidity and mortality. Epidemiological studies have shown that exposure to ambient particulate matter (PM) air pollution is associated with increases in cardiovascular morbidity and mortality. Though exact mechanisms are unknown, elevated PM levels have been associated with increased levels of circulating biomarkers of inflammation and thrombosis. There is little data regarding gene expression in relevant biological pathways in relation to PM exposure in humans at potentially increased cardiac risk. Similarly, there is limited information in humans on whether individual genetic variation produces observable changes in gene expression relevant to pathophysiological mechanisms involved in acute peripheral vascular responses to particulate air pollutants. The aims of this study are to evaluate relations between peripheral blood gene expression and air pollution exposures in a cohort panel of elderly subjects with CHD, and to test effect modification of these relations by variants of nuclear and mitochondrial genes that may confer increased cardiovascular risk to air pollution. Air pollution is of considerable importance in the Los Angeles (LA) basin due to a unique combination of weather, topography and traffic. The Cardiovascular Health and Air Pollution Study (CHAPS, parent study of this project) has shown associations of traffic-related PM components with ischemic ST-segment depression, systemic inflammation and increases in blood pressure among a susceptible population of older adults in the LA area. In vitro evidence from CHAPS indicates that components of PM induce reactive oxygen species generation. Additionally, recent experiments showed an up regulation of genes in detoxification pathways in cultured human airway epithelial and vascular endothelial cells exposed to PM. Previous in vitro research has shown ultrafine PM (diameter <0.1 �m) localizes to and damages the mitochondria. A recent cross-sectional study showed mitochondrial DNA (mtDNA) copy number was associated with increased PM exposure, indicating mitochondrial damage. I hypothesize that exposure to PM air pollution will be associated with changes in nuclear gene expression levels and that polymorphisms in nuclear and mitochondrial genes and somatic mtDNA mutations will modify this association as well as the previously established associations with biomarkers of systemic inflammation. I will examine this hypothesis using q-PCR and sequencing of DNA from whole blood from the CHAPS cohort. Genetic information may reveal plausible molecular mechanisms that account for the significant biomarker responses previously seen. Investigating these relationships may elucidate potential mechanisms for the cardiovascular effects of air pollution exposure.

描述（由申请人提供）：心脏病是美国的主要死亡原因。2009年，与冠心病（CHD）相关的直接和间接费用估计为1650亿美元。因此，有大量的研究，以提高我们对冠心病发病率和死亡率的危险因素的认识是必要的。流行病学研究表明，暴露于环境颗粒物（PM）空气污染与心血管疾病发病率和死亡率的增加有关。尽管确切的机制尚不清楚，但PM水平升高与炎症和血栓形成的循环生物标志物水平升高有关。几乎没有数据显示，人类暴露于PM可能会增加心脏病风险，相关生物学途径中的基因表达与PM暴露有关。同样，在人类中，关于个体遗传变异是否产生与对颗粒空气污染物的急性外周血管反应所涉及的病理生理机制相关的基因表达的可观察变化的信息有限。本研究的目的是评估外周血基因表达和空气污染暴露之间的关系，在一个队列面板的老年受试者冠心病，并测试这些关系的核和线粒体基因的变体，可能会增加心血管疾病的风险，空气污染的影响修改。 由于天气、地形和交通的独特组合，空气污染在洛杉矶（LA）盆地中相当重要。心血管健康和空气污染研究（CHAPS，本项目的母研究）显示，在洛杉矶地区的老年人易感人群中，交通相关PM成分与缺血性ST段压低、全身炎症和血压升高相关。来自CHAPS的体外证据表明，PM的组分诱导活性氧产生。此外，最近的实验表明，在培养的人气道上皮细胞和血管内皮细胞暴露于PM的解毒途径的基因上调。以前的体外研究表明，超细PM（直径<0.1 μ m）定位于线粒体并损害线粒体。最近的一项横断面研究表明，线粒体DNA（mtDNA）拷贝数与PM暴露增加相关，表明线粒体损伤。我假设暴露于PM空气污染将与核基因表达水平的变化相关，核和线粒体基因的多态性以及体细胞mtDNA突变将改变这种关联以及先前建立的与全身性炎症生物标志物的关联。我将使用来自CHAPS队列的全血的q-PCR和DNA测序来检验这一假设。遗传信息可能会揭示合理的分子机制，这些机制可以解释之前观察到的显着生物标志物反应。调查这些关系可能阐明空气污染暴露对心血管影响的潜在机制。