Maternal asthma and epigenomic modification in offspring with asthma

哮喘影响全球超过 3 亿人；孕产妇哮喘是最显着的风险之一 她的孩子患有哮喘，但这种影响的机制在很大程度上尚不清楚。的目标 该项目旨在揭示特征明确的受试者中这种风险的遗传和表观遗传机制 患有哮喘的患者在两个时间点（相隔大约 10 年）接受过评估。我们将结合 遗传、基因组和表观基因组方法来识别差异表达基因，以及遗传 及其在气道上皮细胞、PHA 刺激的 CD4 T 中差异表达的表观遗传机制 淋巴细胞和气道平滑肌细胞。我们的具体目标如下： (i) 发现显示出的 SNP 在一项全基因组关联研究中，母亲哮喘状况与儿童哮喘风险的相互作用； (二) 通过比较来识别患有和不患有哮喘的母亲的后代之间的差异表达基因 全基因组表达模式并识别导致个体差异的遗传变异 基因表达（eOTL）； (iii) 阐明差异基因表达背后的表观遗传机制 通过比较全基因组甲基化模式，在患有和不患有哮喘的母亲的后代之间进行研究 甲基化 DNA 免疫沉淀和测序 (MeDIP-seq) 并鉴定甲基化 QTL (meQTL) 导致甲基化模式的差异； (iv) 表征小 RNA 群体的差异 通过高通量 RNA 测序 (RNA-seq) 对患有和不患有哮喘的母亲的后代（包括 miRNA）进行分析， 绘制有助于 miRNA 丰度和靶向个体间差异的 eQTL，并执行 对目标 1-4 中生成的数据进行综合分析。据我们所知，这些研究将是第一个使用 全基因组方法阐明儿童哮喘风险增加的机制 患有哮喘的妈妈们。使用 4 种互补方法整合全基因组遗传、基因组和 对哮喘患者的哮喘相关原代细胞进行表观基因组研究应该揭示新的基因， 哮喘发病机制的调节途径和网络以及机制。

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.