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， 治疗进展是渐进的。据报道，在大基因组范围内， 哮喘和过敏性疾病的关联研究（GWAS），但它们的个体效应很小， 变异只占整体遗传风险的一小部分。此外，GWAS的研究结果中， 哮喘和过敏性疾病导致了致病变异或致病基因的发现， 哮喘和过敏性疾病的发病机制。后者特别具有挑战性，部分原因是 这些疾病的显著临床异质性，部分原因是强大的 统计，分子和免疫学工具，用于桥接从GWAS到基因发现的轨迹， 生物学翻译在这个应用程序中，我们提出了一个强大的和全面的战略， 哮喘和过敏性疾病相关基因座的候选致病变异体及其靶基因，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作用， 上皮细胞、气道平滑肌和肺免疫细胞，以及外周免疫细胞，都处于静息状态， 和激活状态;（ii）它们对两大类疾病组的下游表型效应， 英国生物库资源中的特征以及深度表型分析中特定哮喘和过敏性疾病的内在型 参与哮喘出生队列的不同种族受试者;（iii）他们在静息状态下的免疫学效应 和活化的肺淋巴细胞和骨髓细胞以及“人源化基因座”BAC工程小鼠模型。 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，它们将共同连接从GWAS到 通过具有遗传学专业知识的杰出研究人员团队的高度综合研究进行翻译， （EPI）基因组学、统计遗传学和免疫学。实现这些目标将最终确定新药 目标和个人最有可能作出反应，为精准医疗提供了一个框架， 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.