Exposure to violence, epigenetic variation, and asthma in Puerto Rican children

在美国，波多黎各儿童的哮喘负担不成比例。 波多黎各儿童，各种心理压力源-包括身体或性虐待，父母 精神病理学和暴露于暴力-与哮喘和更严重的哮喘结果有关。在 特别是，我们已经表明，暴露于暴力与儿童哮喘在波多黎各人。 此外，我们已经报道，暴露于暴力与基因的DNA甲基化有关， 垂体腺苷酸环化酶激活多肽1型受体（ADCYAP 1 R1），以及这种甲基化 和ADCYAP 1 R1的遗传变异都与波多黎各儿童的哮喘有关。而 暴露于暴力与哮喘和儿童哮喘发病率增加有关， 关于这种联系背后的表观遗传机制的知识非常有限。缺乏这种知识是一种 这是一个重要的问题，因为如果没有它，获得预防或治疗服务不足儿童哮喘的能力 接触暴力的可能性很小根据我们新的初步发现，我们假设， 暴露于暴力通过改变基因甲基化增加哮喘和哮喘发病率的风险 调节对压力的行为、自主神经、神经内分泌和免疫反应。为了验证这个假设， 我们将首先测试暴露于暴力和全基因组DNA甲基化变化之间的关联， 500名波多黎各儿童的呼吸道（鼻）上皮（Sp. Aim 1）。接下来，我们将研究 Aim 1中确定的顶级基因的甲基化变化与哮喘相关， 哮喘严重程度或控制（严重哮喘急性发作、肺功能降低和支气管扩张剂减少 在250至500名波多黎各儿童（SP.目标2）。最后，我们将评估甲基化的影响， Aim 2中鉴定的基因变化对波多黎各儿童鼻上皮中基因表达的影响（Sp. 目的3a），以及在原代人支气管上皮细胞（SP。 目标3b）。该提案应确定暴露于暴力如何导致哮喘风险增加， 哮喘发病率在服务不足的少数民族儿童，如波多黎各人。为了实现这一目标，我们 组建了一支优秀的多学科研究团队。

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.