Asthma is a chronic disease of the airways, with heritability estimates ranging from 20-80%1,2. Although many common risk alleles have been identified in genome-wide association studies (GWAS) of asthma, together they explain very little of its heritability. The genetic architecture of asthma is complex, involving interplay betwen genetic and environmental factors. Human rhinovirus (HRV) is one of the most common causes of exacerbations in asthma and in other chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF)3,4. HRV accounts for approximately 60% of asthma exacerbations in children5 and although it has great public health importance, the genetic architecture of HRV response is still poorly understood. In this study, I propose to bridge this gap by characterizing inter-individual variation in gene expression response to HRV in monocytes from 120 Hutterites. The Hutterites are a founder population of European descent who live communally6-8. The Hutterites in our studies are related to each other in a 13- generation pedigree with 64 founders who were born between the early 1700s and the early 1800s7,8. The small number of founders reduces genetic heterogeneity while their communal farming lifestyle minimizes heterogeneity in environmental exposures between individuals, both of which should facilitate gene discovery. In this application, an in vitro model of gene-environment interactions will be developed to map the genetic architecture of gene expression response to HRV in monocytes from subjects with and without asthma.
The specific aims of this proposal are 1) to characterize transcriptional abundance in HRV-treated and untreated monocytes from well characterized asthmatic and non-asthmatic Hutterites, 2) to identify HRV response genes and map expression quantitative trait loci (eQTLs) associated with variation in response to HRV and 3) to further investigate the role of genetic variation that influences response to HRV by assessing their associations with asthma and asthma-associated phenotypes. Studies of the genetic basis of response to pathogens implicated in asthma pathogenesis have been lacking. To address this gap in knowledge and to overcome some of the inherent limitations of GWAS, I will use the wealth of genetic and phenotypic information already collected on this unique population resource. Understanding the genetic architecture of HRV response may ultimately lead to a better understanding of gene-environment interactions, and to the development of novel prevention strategies in asthma and potentially other complex lung diseases.
Asthma is a common complex disease that is influenced by both environmental and genetic risk factors, as well as interactions between them. In this application, I propose to use an in vitro model of gene-environment interactions to identify genetic variation that is associated with response to human rhinovirus (HRV), a pathogen that is associated with both the development and exacerbation of asthma symptoms. This work will ultimately contribute towards a better understanding of asthma pathogenesis and of gene-environment interactions.