Asthma is the most common chronic respiratory lung disease, affecting more than 17 million people in the US;identification of its molecular determinants remains an important priority in translational science. Four years ago, we proposed an integrative genomic approach that combined genome-wide genetic and expression studies (so-called expression quantitative trait locus (eQTL) mapping) to facilitate the identification of novel regulatory genetic variation contributing to the pathogenesis and natural history of asthma. Using this approach, we identified novel regulatory genetic variants that confer susceptibility to asthma at four distinct genomic regions: the chromosome 17q locus (that includes the genes ZPBP2, GSDMB and ORMDL3);the Fatty Acid Desaturase locus (FADS1 &FADS2);the N-acetyl galactosaminidase (NAGA) locus, and the factor XIII A subunit (F13A1) locus. We now propose to extend these studies with the goals of (1) mapping additional regulatory variants that contribute to the pathogenesis of asthma;(2) identifying the specific functional regulatory variants underlying the genetic associations with asthma;and (3) characterizing the functional role of these candidate genes in the development of asthma.
In Specific Aim 1 we will extend our previous work in the integrative genomics by performing a first of its kind eQTL meta-analysis using data from four large existing datasets of more than 4,000 subjects of diverse ancestry. Results from this effort will be used to reinterpret a meta-analysis of asthma genome-wide association studies. Associations will be replicated in three additional asthma cohorts (n E12,000).
In Specific Aim 2, we will perform functional fine-mapping of three of the novel asthma loci (FADS2, NAGA and F13A1) in human bronchial epithelial cells and related cell types by means of allelic imbalance screens, chromatin-based DNA-DNA and DNA-protein interaction studies, and allele specific reporter assays. Confirmed functional variants will be tested for genetic association with asthma in the EVE Consortium cohorts.
In Specific Aim 3, we will conduct a functional evaluation of the FADS2 gene in an established murine model, with confirmation of the molecular mechanisms using in vitro cellular assays in both murine- and human-derived human bronchial epithelial cells. This project has high potential to precisely localize functional genetic variants contributing to the pathogenesis of asthma, and provide a better understanding of the role of these genes in the pathogenesis of asthma, thereby establishing a solid foundation for new drug development aimed at modifying their aberrant gene expression.
Asthma is the most common chronic respiratory lung disease;identification of its molecular determinants remains an important priority in translational science. The asthma-associated regulatory genetic variants identified through this application will provide novel insights into the pathogenesis of asthma. The studies of FADS2 will confirm it as a potential target for therapeutic development or environmental modification through dietary modification of fatty acid intake.
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|Kothari, Parul H; Qiu, Weiliang; Croteau-Chonka, Damien C et al. (2018) Role of local CpG DNA methylation in mediating the 17q21 asthma susceptibility gasdermin B (GSDMB)/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression quantitative trait locus. J Allergy Clin Immunol 141:2282-2286.e6|
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|McGeachie, Michael J; Wu, Ann C; Tse, Sze Man et al. (2015) CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies. J Allergy Clin Immunol 136:1503-1510|
|Croteau-Chonka, Damien C; Rogers, Angela J; Raj, Towfique et al. (2015) Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation. PLoS One 10:e0140758|
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