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.
Exposure to air pollution linked to fossil fuel combustion is associated with adverse cardiovascular outcomes including myocardial infarction, elevations in blood pressure, and the progression of atherosclerosis. Genetically susceptible populations may include people with reduced capacity to protect against oxidative stress that is induced by key air pollutant chemicals. This proposal examines how inherited and acquired genetic differences modify human gene expression changes in genes coding for proteins involved in oxidative stress, inflammatory and cardiovascular clinical responses to these environmental toxins.
|Wittkopp, Sharine; Staimer, Norbert; Tjoa, Thomas et al. (2013) Mitochondrial genetic background modifies the relationship between traffic-related air pollution exposure and systemic biomarkers of inflammation. PLoS One 8:e64444|