| Popis: |
Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used cultured upper airway (sinonasal) epithelial cell models to assess transcriptional and epigenetic responses to a virus (rhinovirus [RV]) and a bacterium (Staphylococcus aureus [SA]) and provide context-specific functional annotations to variants discovered in GWASs of asthma. Using genome-wide genetic, gene expression, and DNA methylation data in RV-, SA- and vehicle-treated cells from 115 individuals, we mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each condition. Co-localization analyses of these airway epithelial cell molecular QTLs with asthma GWAS variants revealed potential molecular disease mechanisms of asthma for GWAS variants, including QTLs at the TLSP locus that were common both to exposure conditions and childhood onset and adult onset asthma and at the 17q12-21 asthma locus that were specific to both RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. Overall, our study provides information on functional effects of asthma risk variants in airway epithelial cells and provides insight into disease-relevant microbial exposures that modulate genetic effects on transcriptional and epigenetic responses in cells and on risk for asthma in GWAS. Author Summary Both genetic and environmental factors influence asthma. Genome-wide association studies have identified thousands of genetic variants associated with asthma but do not provide information on their functional effects, tissue specificity, or environmental context. To address these limitations, we used an upper airway epithelial cell model to study responses to microbes that potentially influence airway disease inception and/or symptoms, and to understand the functional relevance of asthma risk variants. To this end, we mapped genetic variation associated with gene expression and DNA methylation in cells exposed to a virus (rhinovirus) or a bacterium (Staphylococcus aureus) compared to vehicle controls and tested for co-localization of these molecular traits with variants associated with adult onset and childhood onset asthma in GWAS. We report putative disease mechanisms of asthma and associated genes and DNA methylation sites in airway epithelial cells exposed to disease-promoting risk factors. |
