Epigenetic Variation and Childhood Asthma in Puerto Ricans

在美国，波多黎各（PR）儿童的哮喘负担不成比例。 在PR儿童中，各种心理压力源-包括身体或性虐待，接触暴力， 和父母的精神病理学-与更糟糕的哮喘结果有关。波多黎各儿童也有 对支气管扩张剂（短效吸入性β2受体激动剂，最常用的药物）的反应降低 全球哮喘）。我们最近的研究表明，儿童的高压力与儿童对 短效吸入性β2受体激动剂（支气管扩张反应或BDR）在PR哮喘儿童中的应用，以及我们的研究 初步结果也暗示了与压力有关的基因的遗传和表观遗传（DNA甲基化）变异 响应（例如，ADCYAP 1 R1）对哮喘和BDR的作用。此外，外部体外实验表明， 应激导致β2-肾上腺素能受体（ADRB 2）和糖皮质激素基因表达减少 哮喘儿童白色血细胞中NR 3C 1受体的表达。虽然已知压力会降低BDR，但这是不可能的。 目前尚不清楚是否可以通过吸入性皮质类固醇（ICS）治疗来预防，或者是否可以通过压力来预防。 降低了体内对ICS的反应。此外，我们对遗传或表观遗传的知识非常有限， 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，获得预防或治疗压力引起的哮喘发病率的能力， 得不到充分服务的儿童是极不可能的。根据我们新的初步结果，我们假设， 慢性应激降低了PR哮喘儿童对吸入性皮质类固醇（ICS）和BDR的反应， 这些作用是由调节应激反应的基因甲基化改变、皮质类固醇和 BDR。为了验证这一假设，我们将首先确定压力的增加是否会导致对 ICS或BDR（即使在ICS治疗后）在300例PR哮喘儿童中（Sp. Aim 1）。然后我们将测试 高儿童压力与儿童呼吸道（鼻）上皮细胞全基因组DNA甲基化之间的关系 550名波多黎各哮喘儿童（Sp. Aim 2）。接下来，我们将检查甲基化是否在 Aim 2中确定的前100个基因与300至550名PR儿童对ICS或BDR的反应相关， 哮喘（Sp. aim 3a）。最后，我们将评估Aim 3a中鉴定的甲基化变化对基因表达的影响。 表达（Sp. Aim 3b）。这项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）的常用治疗的反应降低 吸入性β2受体激动剂）。为了实现这一目标，我们组建了一个 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.