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.
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.
| Wittkopp, Sharine; Staimer, Norbert; Tjoa, Thomas et al. (2016) Nrf2-related gene expression and exposure to traffic-related air pollution in elderly subjects with cardiovascular disease: An exploratory panel study. J Expo Sci Environ Epidemiol 26:141-9 |
| 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 |
