Epigenetic Variation and Childhood Asthma in Puerto Ricans

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Puerto Rican (PR) children share a disproportionate burden from asthma in the U.S. We have demonstrated that in PR children, a variety of psychological stressors -including physical or sexual abuse, exposure to violence, and parental psychopathology- are associated with worse asthma outcomes. Puerto Rican children also have reduced response to bronchodilators (short-acting inhaled β2-agonists, the most commonly used medication for asthma worldwide). We have recently shown that high child stress is associated with reduced response to short-acting inhaled β2-agonists (bronchodilator response or BDR) in PR children with asthma, and our preliminary results also implicate genetic and epigenetic (DNA methylation) variation in genes involved in stress responses (e.g., ADCYAP1R1) on asthma and BDR. Moreover, external in vitro experiments show that high stress leads to reduced expression of the genes for the β2-adrenergic receptor (ADRB2) and the glucocorticoid receptor (NR3C1) in white blood cells of children with asthma. While it is known that stress reduces BDR, it is not known whether this can be prevented by treatment with inhaled corticosteroids (ICS), or whether stress reduces response to ICS in vivo. Moreover, we have very limited knowledge of the genetic or epigenetic mechanisms underlying treatment resistance in stressed children. Lack of such knowledge is an important problem, because, without it, gaining the ability to prevent or treat stress-induced asthma morbidity in underserved children is highly unlikely. On the basis of our novel preliminary results, we hypothesize that chronic stress reduces response to inhaled corticosteroids (ICS) and BDR in PR children with asthma, and that these effects are mediated by altered methylation of genes regulating responses to stress, corticosteroids and BDR. To test this hypothesis, we will first determine whether increased stress leads to reduced response to ICS or BDR (even after treatment with ICS) in 300 PR children with asthma (Sp. Aim 1). We will then test for association between high child stress and genome-wide DNA methylation in respiratory (nasal) epithelium in 550 Puerto Rican children with asthma (Sp. Aim 2). Next, we will examine whether methylation changes in the top 100 genes identified in Aim 2 are associated with response to ICS or BDR in 300 to 550 PR children with asthma (Sp. aim 3a). Finally, we will assess the effects of methylation changes identified in Aim 3a on gene expression (Sp. Aim 3b). This proposal should determine whether and how psychosocial stress leads to reduced response to common treatments for asthma control (ICS) and relief of asthma symptoms (short-acting inhaled β2-agonists) in a high-risk group (Puerto Rican children). To achieve this goal, we have assembled an outstanding multidisciplinary research team.