Epigenetic Variation and Childhood Asthma in Puerto Ricans

描述(申请人提供)：波多黎各(PR)儿童是美国所有种族中哮喘患病率、发病率和死亡率最高的。最近的证据表明，发生在没有DNA序列改变(表观遗传学)的基因表达的可遗传和/或从头开始的改变影响哮喘的发病。与大量的遗传学研究相比，很少有研究研究哮喘的表观遗传学。研究得最好的表观遗传机制是DNA甲基化，即甲基与胞嘧啶残基的共价加成，主要发生在CpG位点(即DNA序列中胞嘧啶与鸟嘌呤相邻)。我们推测，与免疫反应和肺功能相关的基因中/附近的CpG位点的DNA甲基化影响PR儿童哮喘的发病。为了验证这一假设，我们将首先使用白细胞(WBC)和鼻腔上皮细胞(特定目标1)的DNA，对40对6至14岁的PR单合子(MZ)双胞胎中的80名成员进行甲基化(GWM)和哮喘的全基因组研究(其中20对MZ双胞胎与哮喘不一致，20对MZ双胞胎与哮喘一致)。在这项双生子研究的同时，我们将使用WBC的DNA对760例有哮喘的PR儿童(n=380)和500名有哮喘的PR儿童(n=250)进行GWM和哮喘及其中间表型(肺功能测量和过敏标记物)的研究(特定目标2)。然后，我们将评估选定的环境/生活方式(EL)暴露(环境烟草烟雾、维生素D不足和母子心理社会压力)是否与Sp的最高甲基化结果有关。目标2(具体目标3a)。最后，我们将通过在一组研究参与者中进行焦磷酸测序分析和基因表达研究，来验证从我们先前的目标中选择的甲基化测量结果。然后，我们将在一个独立的队列中进行复制研究(哮喘桥[特定目标3b])。这项建议应该确定PR儿童中哮喘(包括环境诱导性哮喘)的新的表观遗传学标记。为了实现这一目标，我们组建了一支经验丰富的多学科研究团队。

DESCRIPTION (provided by applicant): Puerto Rican (PR) children have the highest prevalence, morbidity and mortality from asthma of all ethnic groups in the United States. Recent evidence suggests that heritable and/or de novo changes in gene expression that occur without alterations in DNA sequence (epigenetic) influence the pathogenesis of asthma. In contrast to a large number of genetic studies, few studies have examined the epigenetics of asthma. The best studied epigenetic mechanism is DNA methylation, the covalent addition of a methyl group to a cytosine residue occurring mostly in a CpG site (i.e., DNA sequence with a cytosine next to a guanine). We hypothesize that DNA methylation of CpG sites in/near genes relevant to immune response and lung function influence the pathogenesis of asthma in PR children. To test this hypothesis, we will first conduct a genome-wide study of methylation (GWM) and asthma in 80 members of 40 pairs of PR monozygotic (MZ) twins ages 6 to 14 years (20 pairs of MZ twins discordant for asthma and 20 pairs of MZ twins concordant for asthma) using DNA from white blood cells (WBCs) and nasal epithelial cells (Specific Aim 1). In parallel with this twin study, we will conduct a GWM and asthma and its intermediate phenotypes (lung function measures and allergy markers) in a) 760 PR children with (cases, n=380) and without (controls, n=380) asthma using DNA from WBCs, and b) 500 PR children with (n=250) and without (n=250) asthma using DNA from nasal epithelium (Specific Aim 2). We will then assess whether selected environmental/lifestyle (EL) exposures (environmental tobacco smoke, vitamin D insufficiency and maternal/child psychosocial stress) are associated with the top methylation findings from Sp. Aim 2 (Specific Aim 3a). Finally, we will validate selected methylation measurements from our prior aims by conducting pyrosequencing assays and gene expression studies in a subset of study participants. We will then then conduct replication studies in an independent cohort (Asthma BRIDGE [Specific Aim 3b]). This proposal should identify novel epigenetic markers of asthma (including environmentally-induced asthma) in PR children. To achieve this goal, we have assembled an experienced multidisciplinary research team.