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

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.