Genetic Susceptibility to Asthma and Indoor Air Pollution in Peru

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DESCRIPTION (provided by applicant): Particulate matter (PM) has been associated with increased asthma morbidity and certain individuals likely have increased susceptibility. The parent R01 grant investigates genetic contributions to individual susceptibility to the adverse health effects of indoor air pollution. Preliminary data from the investigators' parent R01 suggests that outdoor pollutant concentrations are a major contributor to indoor air quality in our Peruvian community. In addition, proximity to traffic from a major roadway is associated with increased odds of asthma and atopy; highlighting the importance of traffic-related PM exposure. The aims of this proposal expand on the parent grant by focusing on traffic-related PM exposure and exploring underlying epigenetic and inflammatory mechanisms as well as dietary contributions (i.e., micronutrient levels) to susceptibility of adverse health consequences. Limited studies have shown that PM exposure may contribute to epigenetic changes, including changes in global hypermethylation and gene-specific methylation; however, the PM-induced methylation changes in individuals with asthma contributing to increased morbidity remains unknown. Furthermore, though PM induced inflammation has been implicated as contributing to these negative health effects, the mechanism remains unclear. The overall hypothesis of this ViCTER proposal is that traffic-related PM exposure leads to changes in methylation which are associated with systemic inflammatory profiles and asthma health and these changes may be modified by micronutrient (i.e., foliate) levels. The specific aims are as follows: Specific Aim 1: To determine the association between traffic related PM exposure and differential methylation and expression alterations using RNA sequencing and bisulfite methylation sequencing in children with asthma and to validate the sequencing results using real-time PCR (RT-PCR) and quantitative methylation-specific PCR (qMSP). Specific Aim 2: To identify the effect of traffic-related PM on peripheral blood proinflammatory response in children with asthma and to determine whether epigenomic alterations modify the proinflammatory response. Specific Aim 3: To determine whether micronutrient (i.e., vitamin D, foliate) levels modify individual response to traffic-related PM exposure in 300 children with asthma followed longitudinally and whether there is an association between micronutrient serum levels (i.e., vitamin D, foliate) and epigenomic alterations in children with asthma from Specific Aim 1. This proposal builds on an established interdisciplinary program, including pulmonologists, epidemiologists, environmental health scientists, statisticians and geneticists by bringing new investigators with expertise in epigenetics (Dr. Guerrero-Preston), toxicology (Project 2 Principal Investigator: Dr. Hartung) and micronutrient assessment (Project 3 Principal Investigator: Dr. Lima). The investigators have a unique opportunity to leverage resources and answer important questions regarding the epigenomic and inflammatory mechanisms underlying the adverse health effects of traffic-related PM exposure.