Rhinovirus (RV) is the main cause of the common cold and as an exacerbator of chronic airway diseases. Yet, little is known about the genetic and epigenetic responses to this virus, or to the molecular mechanisms that contribute to airway disease after RV infection. This thesis addresses these questions by identifying molecular responses, pathways, and mechanisms of RV infection in a relevant tissue of two chronic airway diseases, chronic rhinosinusitis (CRS) and asthma, and through genome wide association studies (GWAS). In chapter 2, I used an airway epithelial cell (AEC) model of RV infection to identify differential DNA methylation (DNAm) and transcriptional responses to RV infection in CRS cases compared to non-CRS controls. Weighted gene co-expression network analysis (WGCNA) assigned differential molecular responses to co-expression/co-methylation modules enriched in known pathways of CRS pathogenesis and of immune response to viral infection. To study potential genetic causes of CRS, in chapter 3, I used a two-stage genome-wide association study (GWAS) in 2,540 European American adults (483 CRS cases, 2,057 non-CRS controls). Variation at two loci were identified as potentially involved in CRS; the known functions of a gene at one of these loci, WSB2, supported the role of the upper airway mucosal immune surface as a key site in disease development. Finally, because of the role of the upper airway epithelium as the primary site of RV infection and in asthma inception, in chapter 4, I leveraged the AEC model of RV infection to identify RV-response mechanisms that contribute to asthma risk. Expression and DNAm quantitative trait loci (eQTLs, meQTLs) were mapped in the vehicle- and RV-treated AECs and integrated with three asthma GWASs. Co-localization analyses of airway epithelial cell molecular QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both exposure conditions and in all three asthma GWASs, as well as QTLs at the 17q12-21 asthma locus, the most replicated and most significant asthma susceptibility locus in childhood onset asthma, that were specific to RV exposure and to childhood onset asthma. The results of the combined data at this locus indicated that gene expression of ERBB2, a gene associated with asthma severity, may be modulated by RV via an epigenetic mechanism involving long-range chromatin looping. These findings were supported by promoter capture Hi-C data from ex vivo bronchial epithelial cells. Together, these results not only highlight the broad regulatory landscape at this important asthma locus, but they also show the importance of context-specificity in identifying molecular mechanisms that contribute to disease risk.




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