Puerto Rican children share a disproportionate burden from asthma in the U.S. We have demonstrated that in Puerto Rican children, a variety of psychological stressors -including physical or sexual abuse, parental psychopathology, and exposure to violence- are associated with asthma and worse asthma outcomes. In particular, we have shown that exposure to violence is associated with childhood asthma in Puerto Ricans. Moreover, we have reported that exposure to violence is associated with DNA methylation of the gene for the pituitary adenylate cyclase activating polypeptide 1 type 1 receptor (ADCYAP1R1), and that such methylation and a genetic variant in ADCYAP1R1 are each associated with asthma in Puerto Rican children. While exposure to violence has been implicated in asthma and increased morbidity from asthma in children, we have very limited knowledge about the epigenetic mechanisms underlying this link. Lack of such knowledge is an important problem, because, without it, gaining the ability to prevent or treat asthma in underserved children exposed to violence is highly unlikely. On the basis of our novel preliminary findings, we hypothesize that exposure to violence increases the risk of asthma and asthma morbidity through altered methylation of genes regulating behavioral, autonomic, neuroendocrine and immunologic responses to stress. To test this hypothesis, we will first test for association between exposure to violence and genome-wide DNA methylation changes in respiratory (nasal) epithelium in 500 Puerto Rican children (Sp. Aim 1). Next, we will examine whether methylation changes in the top genes identified in Aim 1 are associated with asthma and measures of worse asthma severity or control (severe asthma exacerbations, reduced lung function, and reduced bronchodilator response) in 250 to 500 Puerto Rican children (Sp. Aim 2). Finally, we will assess the effects of methylation changes in the genes identified in Aim 2 on gene expression in nasal epithelium of Puerto Rican children (Sp. Aim 3a), as well as on gene expression and protein abundance in primary human bronchial epithelial cells (Sp. Aim 3b). This proposal should determine how exposure to violence leads to increased risk of asthma and asthma morbidity in underserved minority children, such as Puerto Ricans. To achieve this goal, we have assembled an outstanding multidisciplinary research team.