Exploring the role of gene-environment interactions in asthma.

摘要

Human rhinovirus (HRV) is the most frequent causative pathogen of the common cold and is also involved in the inception and morbidity of several upper and lower respiratory illnesses including bronchiolitis in infancy, childhood pneumonia, and acute exacerbations of chronic respiratory diseases such as asthma, chronic obstructive lung disease, and cystic fibrosis. In this dissertation, I aimed to uncover the genetic and gene expression contributions to inter-individual variation in response to human rhinovirus infection (HRV) in relation to asthma and lung function phenotypes. In Chapter 2, I explored the suitability of lymphoblastoid cell lines (LCLs) for functional genomics studies. I found evidence suggesting that LCLs may be a faithful model for expression quantitative trait loci (eQTL) mapping studies but not for studies of perturbations that affect immune and stress response. In Chapter 3, I studied the main and interactive effects of the genotype at the 17q21 asthma susceptibility locus and HRV wheezing illnesses in early life on inception of asthma in children. I found that variation at the 17q21 locus is associated with the risk and number of HRV wheezing illnesses in the first three years of life. I also showed that 17q21 locus is associated with asthma only in children who had had HRV wheezing illness in early life, suggesting an interaction between a common genetic risk factor (17q21 genotype) and a common environmental risk factor (HRV wheezing illness) with respect to childhood-onset asthma. In Chapter 4, I integrated genome-wide gene expression and genotype data in uninfected and HRV-infected peripheral blood mononuclear cells (PBMCs). I identified local genetic variation that affects gene expression in uninfected and HRV-infected PBMCs. Additionally, I discovered genotype x HRV interactions that influence the expression levels of 32 genes, and showed that HRV-interacting regulatory variations are promising QTLs for pulmonary function phenotypes.