Maternal asthma and epigenomic modification in offspring with asthma

哮喘影响全世界超过3亿人;孕产妇哮喘是最重要的风险之一， 她的孩子患哮喘，但这种影响的机制在很大程度上是未知的。的目标 该项目旨在揭示这种风险的遗传和表观遗传机制， 哮喘患者在两个时间点进行评估，大约相隔10年。我们将联合收割机 遗传学、基因组学和表观基因组学方法来鉴定差异表达的基因， 以及它们在气道上皮细胞中差异表达的表观遗传机制，PHA刺激的CD 4 + T细胞 淋巴细胞和气道平滑肌细胞。我们的具体目标如下：（i）发现显示 在全基因组关联研究中，母亲哮喘状态与儿童哮喘风险的相互作用;（ii） 通过比较确定患有和不患有哮喘的母亲的后代之间差异表达的基因 全基因组表达模式，并确定解释个体间差异的遗传变异 基因表达（eOTL）;（iii）阐明差异基因表达的表观遗传机制 通过比较全基因组甲基化模式， 甲基化DNA免疫沉淀和测序（MeDIP-seq），并确定甲基化QTL（meQTL） 导致甲基化模式差异的因素;以及（iv）表征小RNA群体中的差异 通过高通量RNA测序（RNA-seq）， 绘制eQTL，这些eQTL有助于miRNA丰度和靶向的个体间变异， 综合分析目标1-4中产生的数据。据我们所知，这些研究将是第一个使用 全基因组方法来阐明儿童哮喘风险增加的潜在机制 患有哮喘的母亲使用4种互补的方法，整合全基因组遗传学，基因组学和 在来自哮喘受试者的哮喘相关原代细胞中的表观基因组研究应该揭示新的基因， 调节途径和网络，以及哮喘发病机制。

Asthma affects >300 million people worldwide; maternal asthma is among the most significant risks for the development of asthma in her child, but the mechanisms for this effect are largely unknown. The objectives of this project are to uncover the genetic and epigenetic mechanisms for this risk in well-characterized subjects with asthma who have been evaluated at two time points, approximately 10 years apart. We will combine genetic, genomic, and epigenomic approaches to identify differentially expressed genes, and the genetic and epigenetic mechanisms for their differential expression in airway epithelial cells, PHA-stimulated CD4+ T lymphocytes, and airway smooth muscle cells. Our specific aims are as follows: (i) Discover SNPs that show interactions with maternal asthma status on asthma risk in the child in a genome-wide association study; (ii) Identify differentially expressed genes between offspring of mothers with and without asthma by comparing genome-wide expression patterns and identify genetic variants that account for inter-individual differences in gene expression (eOTLs); (iii) Elucidate epigenetic mechanisms underlying differential gene expression between offspring of mothers with and without asthma by comparing genome-wide methylation patterns using methylated DNA immunoprecipitation and sequencing (MeDIP-seq) and identify methylation QTLs (meQTLs) that contribute to differences in methylation patterns; and (iv) Characterize differences in small RNA populations (including miRNA) in offspring of mothers with and without asthma by high throughput RNA-sequencing (RNA-seq), map eQTLs that contribute to inter-individual variation in miRNA abundance and targeting, and perform integrated analyses of the data generated in Aims 1-4. To our knowledge, these studies will be the first to use genome-wide approaches to elucidate mechanisms underlying the increased risk for asthma in children of mothers with asthma. Using 4 complimentary approaches that integrate genome-wide genetic, genomic, and epigenomic studies in asthma-relevant, primary cells from subjects with asthma should reveal novel genes, regulatory pathways and networks, and mechanisms for asthma pathogenesis.