Epigenomics of asthma risk factors and clinical subtypes in minority children

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PROJECT SUMMARY Asthma is the most common chronic disorder of children, with an estimated 300 million cases worldwide and with significant increases in incidence since the early 1980s. In the United States (U.S.), asthma prevalence, morbidity, mortality, and drug response vary substantially among racial and ethnic groups. While asthma was previously regarded as being a single clinical entity with a number of diagnostic criteria, it is now widely recognized that asthma represents multiple different pathobiological and clinical subtypes, which may underlie observed racial and ethnic variation. Furthermore, an individual's risk of developing asthma reflects a summation of genetic as well as various clinical risk factors. Importantly, clinical risk factors are not randomly distributed across racial and ethnic groups, and certain populations are more burdened than others. Our goal in this work is to identify cell types, genes, and pathways altered by exposure to clinical risk factors, thereby improving mechanistic understanding of asthma subtypes and elucidating the underlying networks by which these risk factors affect asthma disparities. To achieve this goal, we will determine the epigenetic profiles of patients with and without known asthma risk factors (Aim 1), identify common and unique epigenetic profiles associated with known and novel clinical asthma subtypes (Aim 2), and examine the contribution of common and unique epigenetic changes to the association of clinical risk factors with clinical asthma subtypes (Aim 3). We hypothesize that DNA methylation will provide the bridge that ties clinical risk factors with asthma disease subtypes and that this relationship may be modified by self-identified race/ethnicity and genetic ancestry thereby contributing to asthma disparities. Strong preliminary data from our group and others have shown that methylation, a long lasting but dynamic measure of cellular states, is highly correlated with exposure to clinical asthma risk factors, including early life respiratory infection, obesity, and maternal history of asthma. To execute this research program, we have assembled an interdisciplinary team with complementary expertise in epidemiology, clinical asthma, genetics, epigenetics, and statistical methods. Our team will study a unique cohort of minority children at the extremes of asthma prevalence and mortality (high risk Puerto Ricans and African Americans, and low risk Mexican Americans), who have existing demographic data, clinical exposures, genotypes, and RNA/DNA sequences. To our knowledge, there are no other groups within or outside the U.S. with populations as detailed as ours that are large enough to be well powered for these analyses. Therefore, we are the only group with the population needed and track record to successfully complete this project. Findings from our work will help: (i) provide the clinical and biomedical research communities with the largest methylation dataset on minority children produced to date, with a substantially increased value due to existing clinical, socio-environmental, and genetic data, (ii) improve risk profiling, especially for minority children, and (iii) precisely treat patients by selecting interventions using epigenetic markers accounting for clinical risk factors.