Maternal asthma and epigenomic modification in offspring with asthma

哮喘影响着全球3亿人；母亲哮喘是全球最大的风险之一 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 该项目旨在揭示这种风险的遗传和表观遗传机制在特征良好的受试者中 哮喘患者在两个时间点进行了评估，大约相隔10年。我们将联合起来 确定差异表达基因的遗传、基因组和表观基因组学方法，以及基因 PHA刺激的CD4T在呼吸道上皮细胞中差异表达的表观遗传学机制 淋巴细胞和呼吸道平滑肌细胞。我们的具体目标如下：(一)发现表现出 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； 比较哮喘母亲与非哮喘母亲子代的差异表达基因 全基因组表达模式和识别可解释个体间差异的遗传变异 基因表达(EOTLS)；(Iii)阐明差异基因表达的表观遗传学机制 通过比较全基因组甲基化模式来比较患有和不患有哮喘母亲的后代 甲基化DNA免疫沉淀和测序(MeDIP-seq)及甲基化QTL鉴定(MeQTL) 有助于甲基化模式的差异；以及(Iv)表征小RNA群体的差异 (包括miRNA)在患有和不患有哮喘的母亲的后代中进行高通量RNA测序(RNA-seq)， 定位导致miRNA丰度和靶向性个体间差异的eQTL，并执行 对目标1-4中产生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潜在机制 患有哮喘的母亲。使用4种免费的方法，将全基因组范围的遗传、基因组和 来自哮喘患者的与哮喘相关的原代细胞的表观基因组研究应该揭示新的基因， 哮喘发病机制的调控途径和网络。

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.