Pollution, Epigenetics, and Serologic Markers of Rheumatoid Arthritis
Abstract
Rationale: The proposed research focusses on the Peer Reviewed Medical Research Program Topic Area of rheumatoid arthritis (RA), a serious disease that often affects people of work force age. RA affects 1% of individuals with a career in the military, as well as members of military families. Since military personnel are often exposed to environmental pollutants, the role of pollution in RA onset is of special interest for this group. RA is a disease that can result in joint damage disability, and even early death. The exact reasons why certain people develop RA are poorly understood. Though inherited genetic material may be important, increasingly researchers are focusing on "epigenetics," that is, how gene expression is controlled. There is an increasing interest in the epigenetics of diseases like RA. Among the events that could increase the risk of a disease like RA, changes in DNA methylation may cause a cascade of events, which could eventually trigger the symptoms and findings of diseases like RA. There are important potential environmental factors that affect DNA methylation, in particular, air pollution. Important types of air pollution include fine particulate matter, PM2.5; sulfur dioxide, SO2; and nitrogen dioxide, NO2. Decreased methylation of cytosine bases throughout the DNA ("global hypomethylation") is likely an important potential pathway for reported associations between pollution, inflammation, and many chronic diseases. Though particulate air pollution has been linked to many chronic diseases, there are very few data in RA. This is the rationale for the current study. Problem to Be Addressed: The study aims to study if air pollution exposures are linked with DNA hypomethylation and with Anti-Cyclic Citrullinated Peptide (CCP) antibodies, a specific marker of RA that may actually predate RA symptoms. Innovation of the Idea: To date, no one has studied links between exposure to air pollution, DNA hypomethylation, and RA. The study will overcome limitations within existing literature by using pioneering approaches to exposure assignment. Also, DNA methylation will be performed using novel methods (representing great improvements over standard methods). This innovative strategy is a considerable strength. Impact of the Research: This study will improve the existing body of evidence on pollution and autoimmune disease, with high-quality data. Since pollution can be influenced by policy, there are clear opportunities to translate this research into a reduction of RA burden, particularly for military populations. Study Design: This project will occur in a large population-based cohort of over 20,000 residents, containing environmental, demographic, and health data, as well as serum and DNA. This project will make use of baseline data on these subjects, who report lifetime residential location by postal codes. The data will be used to construct, for each subject, cumulative exposures to traffic density and residential proximity to industrial PM2.5 emissions. On baseline DNA samples, methylation will be quantified using novel methods developed by a team member. Baseline serum anti-CCP antibodies will be determined. Multivariate linear regression model will be performed, one assessing global DNA methylation density as the outcome and one assessing anti-CCP antibody levels. The models will include continuous variables summarizing average traffic density exposures, a categorical variable capturing residence to an important industrial emitter, and cumulative residential PM2.5. To explore statistical mediation of a relationship between anti-CCP antibodies and pollution exposures, one can introduce into this model DNA methylation as a covariate, monitoring the result for attenuation of pollution variable effects. Expected Results: The proposal represents an innovative use of unique resources. It will produce novel estimates of how environment, epigenetics, and serology ar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610367
Entities
People
- Sasha Bernatsky
Organizations
- McGill University Health Centre
- United States Army