Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases

摘要 哮喘和过敏性疾病是儿童和成人最常见的慢性疾病， 我们的医疗保健系统每年超过800亿美元。在过去的40年里，利率一直在上升， 治疗方面的进展是渐进的。在全基因组的大样本中已经报道了超过150个基因座 哮喘和过敏性疾病的联合研究，但它们的个体影响很小，这些 变异只占总遗传风险的一小部分。此外，全球气候变化网络的研究结果中很少有 哮喘和过敏性疾病导致了因果变异或因果基因的发现，这些变异或因果基因有助于 哮喘和过敏性疾病的发病机制。后者尤其具有挑战性，部分原因是 这些疾病具有明显的临床异质性，部分原因是发展滞后。 统计、分子和免疫学工具，为从GWAS到基因发现的轨迹搭建桥梁 从生物学到翻译。在此应用程序中，我们提出了一种稳健而全面的策略来识别 哮喘和过敏性疾病相关基因的候选因果变异及其靶基因，以及 表征(I)它们在哮喘和过敏性疾病相关细胞类型中的功能效应，包括支气管 上皮细胞、呼吸道平滑肌和肺免疫细胞以及外周免疫细胞均处于静息状态 和激活状态；(2)它们对广泛类别的疾病组和 英国生物库资源中的特征和深度表型中特定哮喘和过敏性疾病内型的研究 参与哮喘出生队列的不同种族受试者；以及(Iii)他们在休息时的免疫效果 并激活肺淋巴细胞和髓系细胞，并在“人源化位点”BAC工程小鼠模型中进行研究。 这些目标将通过一个高度协作和协同的计划来实现，该计划包括两个 项目、服务核心和管理核心，它们将共同架起从GWAS到 翻译是由一支具有遗传学专业知识的特殊研究团队进行的高度整合的研究， (EPI)基因组学、统计遗传学和免疫学。实现这些目标将最终发现新药 目标和最有可能做出反应的个人，为精准医疗和 哮喘和过敏性疾病的个性化治疗。

ABSTRACT Asthma and allergic diseases are among the most common chronic diseases in children and adults, costing our health care system over $80 billion per year. Rates have been increasing over the past 40 years and therapeutic advances have been incremental. Over 150 loci have been reported in large genome-wide association studies (GWAS) of asthma and allergic diseases, but their individual effects are small and these variants account a small fraction of the overall genetic risk. Moreover, remarkably few of the GWAS findings for asthma and allergic diseases have led to discoveries of causal variants or causal genes that contribute to asthma and allergic disease pathogenesis. The latter has been particularly challenging due in part to the significant clinical heterogeneity of these diseases, and in part to the lag in the development of powerful statistical, molecular, and immunologic tools for bridging the trajectory from GWAS to gene discovery to biology to translation. In this application, we propose a robust and comprehensive strategy for identifying candidate causal variants and their target genes at asthma and allergic disease-associated loci, and for characterizing (i) their functional effects in asthma and allergic disease-relevant cells types, including bronchial epithelial cells, airway smooth muscle and lung immune cells, as well as peripheral immune cells, all in resting and activated states; (ii) their downstream phenotypic effects on both broad categories of disease groups and traits in the UK Biobank resource and on specific asthma and allergic disease endotypes in deeply phenotyped ethnically-diverse subjects participating in asthma birth cohorts; and (iii) their immunologic effects in resting and activated lung lymphocytes and myeloid cells and in “humanized locus” BAC-engineered mouse models. These goals will be accomplished through a highly collaborative and synergistic program that includes two projects, a service core, and an administrative core that together will that bridge the trajectory from GWAS to translation through highly integrated studies by an exceptional team of investigators with expertise in genetics, (epi)genomics, statistical genetics, and immunology. Achieving these goals will ultimately identify novel drug targets and the individuals most likely to respond, providing a framework for precision medicine and personalized treatment of asthma and allergic diseases.