Epigenetic Variation and Childhood Asthma in Puerto Ricans

波多黎各(PR)儿童在美国因哮喘而分担不成比例的负担。我们已经证明 在公关儿童中，各种心理应激源--包括身体或性虐待、接触暴力、 以及父母的精神病理--与更糟糕的哮喘结局相关。波多黎各儿童也有 对支气管扩张剂(短效吸入β2-激动剂，最常用的药物)的反应减少 世界各地的哮喘患者)。我们最近的研究表明，儿童压力大与对 短效吸入β-2激动剂(支气管扩张剂反应或BDR)治疗PR哮喘儿童，以及我们的 初步结果还表明，与压力有关的基因存在遗传和表观遗传(DNA甲基化)变异 对哮喘和BDR的反应(例如，ADCYAP1R1)。此外，体外实验表明，高 应激导致β2肾上腺素能受体和糖皮质激素基因表达减少 哮喘患儿白细胞中NR3C1受体的表达虽然众所周知，压力会降低BDR，但事实并非如此 不知道这是否可以通过吸入皮质类固醇(ICS)治疗来预防，或者是否压力 减少体内对ICS的反应。此外，我们对遗传或表观遗传学的了解非常有限。 应激儿童治疗抵抗的潜在机制。缺乏这样的知识是一个重要的 问题，因为如果没有它，就有能力预防或治疗应激性哮喘的发病率 服务不足的儿童是极不可能的。根据我们新的初步结果，我们假设 慢性应激降低哮喘PR儿童对吸入皮质类固醇(ICS)和BDR的反应 这些效应是通过调节对压力、皮质类固醇和 BDR。为了验证这一假设，我们将首先确定增加的压力是否会导致对 300名患有哮喘的PR儿童的ICS或BDR(即使在ICS治疗后)(SP。目标1)。然后我们将测试 儿童高应激与呼吸道(鼻)上皮全基因组DNA甲基化的关系 550名波多黎各哮喘儿童(SP.目标2)。接下来，我们将检查甲基化是否改变了 在AIM 2中发现的前100个基因与300至550名PR儿童对ICS或BDR的反应有关 哮喘(sp.目标3a)。最后，我们将评估目标3a中确定的甲基化变化对基因的影响。 表达式(Sp.目标3b)。这一建议应该确定心理社会压力是否以及如何导致 对哮喘控制(ICS)和缓解哮喘症状(短效)的常见治疗反应降低 吸入β-2激动剂)的高危人群(波多黎各儿童)。为了实现这一目标，我们已经组建了一个 优秀的多学科研究团队。

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.