PROJECT SUMMARY In this new R01 application entitled “Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB,” the overarching hypothesis is that common genetic polymorphisms alter the airway responses to environmental cues thus influencing the risk of type 2 inflammation in asthma. The investigators address the limitations of traditional genetic epidemiological studies in identifying how heritable risk loci influence the development of disease. They suggest that common genetic variants interact to increase the risk of type 2 inflammation, the dominant pathology present in the airway of asthmatics. The investigators have developed methods to characterize the degree of type 2 inflammation present in the airways of asthmatics and use these measures to classify subjects as type 2 high or low for the purposes of defining the genetic contribution to molecular disease endotypes. This application proposes in three aims to: 1) identify the causal genetic variants that are associated with asthma in the IL1RL1 gene using CRISPR-Cas9 DNA deletion, 2) to explore the cell biology of IL-33 release and the role of gasdermin proteins in this cellular process, and 3) to explore the expression genetics of IL33 and GSDMB in airway epithelial cells in order to fine-map the observed “expression quantitative trait loci” and relate these SNPs to risk of type 2 high asthma. Together these studies will serve to 1) further define the genetic risk polymorphisms that influence the development of type 2 high asthma, 2) will elucidate novel pathways for therapeutic intervention, and 3) to define genetically the target population most likely to benefit from novel therapeutics.