Epigenetic Variation and Childhood Asthma in Puerto Ricans

描述（由申请人提供）：在美国所有种族群体中，波多黎各（PR）儿童哮喘的患病率、发病率和死亡率最高。最近的证据表明，在没有DNA序列改变的情况下发生的基因表达的遗传和/或从头变化（表观遗传）影响哮喘的发病机制。与大量的遗传学研究相反，很少有研究检查哮喘的表观遗传学。研究得最好的表观遗传机制是DNA甲基化，甲基共价加成到胞嘧啶残基上，主要发生在CpG位点（即，鸟嘌呤旁边有一个胞嘧啶的DNA序列）。我们推测PR儿童哮喘的发病机制可能与免疫应答和肺功能相关基因中或附近CpG位点的DNA甲基化有关。为了验证这一假设，我们将首先使用来自白色血细胞（WBC）和鼻上皮细胞（特异性目的1）的DNA，在40对6至14岁的PR单卵（MZ）双胞胎（20对MZ双胞胎哮喘不一致，20对MZ双胞胎哮喘一致）的80名成员中进行甲基化（GWM）和哮喘的全基因组研究。在这项双胞胎研究的同时，我们将进行一项GWM和哮喘及其中间表型的研究。（肺功能测量和过敏标志物）在a）760名患有（病例，n=380）和没有（对照，n=380）哮喘的PR儿童中使用来自WBC的DNA，和B）500名患有（n=250）和没有（n=250）哮喘的PR儿童中使用来自鼻上皮的DNA（具体目标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不足和母亲/儿童心理社会压力）是否与Sp. Aim 2（特定目标3a）的最高甲基化结果相关。最后，我们将通过在一部分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我们先前目标中选定的甲基化测量。然后，我们将在一个独立队列中进行重复研究（哮喘桥[特定目标3b]）。这项建议应确定新的表观遗传标记的哮喘（包括环境诱发的哮喘）在PR儿童。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.