Asthma is the most common chronic disease among children. Results from gene mapping studies of complex human diseases including asthma have indicated that most associated variants are non-coding, rather than protein coding. Many of these non-coding risk variants likely reside in regulatory elements that affect gene expression. This suggests expression quantitative trait loci (eQTL) variants identified in a relevant tissue will present a variant pool enriched for asthma disease variants. The bronchial airway epithelium contributes to asthma pathogenesis by affecting airway immune responses, through the production of mucus that plugs airways, and by signaling to the airway mesenchyme which influences airway remodeling. Our goal is to identify airway epithelium eQTLs which confer risk of childhood asthma in diverse populations. The nasal airway epithelium is an easily accessible alternative to bronchial airway epithelium and the nasal airway transcriptome closely approximates the bronchial airway transcriptome. We hypothesize the functional underpinnings of many asthma genetic susceptibility loci involve cis-regulation of airway epithelium gene expression. We will test our hypothesis with three specific aims:
Aim 1 : Identify cis-regulated genes and their eQTLs within asthma GWAS loci in primary airway epithelium from Puerto Rican childhood asthmatics and controls. We will use targeted RNA-seq to determine total/allelic expression levels of all 159 genes localized to the 21 identified asthma GWAS loci in the nasal airway epithelium of 750 Puerto Rican asthmatics and controls. Cis-regulated genes will be determined by eQTL analyses using genome-wide genotype data and allelic imbalance analyses. Finemapping of eQTLs will be accomplished with complete variant data from targeted DNA-seq of all subjects.
Aim 2 : Identify novel asthma-related eQTLs by whole transcriptome eQTL analysis of primary airway epithelium from Puerto Rican childhood asthmatics and controls. Whole transcriptome expression on all 750 subjects will be used to identify genes that are both differentially expressed in asthma and are cis-regulated, as in Aim 1. DNA-seq will be used to generate complete variant data at the asthma-related, cis-regulated genes to perform eQTL finemapping.
Aim 3 : Characterize the lower airway, clinical, and biological significance of identified nasal asthma eQTLs in diverse populations of asthmatics. We will characterize the strongest nasal asthma eQTLs in the bronchial airway epithelium of 100 asthmatics. We will determine if the strongest finemapped airway eQTLs identified in Aims 1 and 2 predispose to asthma and related traits in 7200 Puerto Rican, Mexican, and African American children. Altered biologic mechanisms will be identified by pathway analysis of asthma-associated genes regulated by airway eQTLs.
Dysfunction of the airways contributes greatly to the development and severity of childhood asthma. Our goal here is to determine the genetic factors controlling the function of cells that line the airways of childhood asthmatics, and whether these genetic factors influence the development of childhood asthma. Results from this proposal may identify new targets for asthma therapy.
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