title: Leveraging gene-environment interactions and endotypes for asthma gene discovery.
abstract: Asthma is a heterogeneous clinical syndrome that includes subtypes of disease with different underlying causes and disease mechanisms. Asthma is caused by a complex interaction between genes and environmental exposures; early-life exposures in particular play an important role. Asthma is also heritable, and a number of susceptibility variants have been discovered in genome-wide association studies, although the known risk alleles explain only a small proportion of the heritability. In this review, we present evidence supporting the hypothesis that focusing on more specific asthma phenotypes, such as childhood asthma with severe exacerbations, and on relevant exposures that are involved in gene-environment interactions (GEIs), such as rhinovirus infections, will improve detection of asthma genes and our understanding of the underlying mechanisms. We will discuss the challenges of considering GEIs and the advantages of studying responses to asthma-associated exposures in clinical birth cohorts, as well as in cell models of GEIs, to dissect the context-specific nature of genotypic risks, to prioritize variants in genome-wide association studies, and to identify pathways involved in pathogenesis in subgroups of patients. We propose that such approaches, in spite of their many challenges, present great opportunities for better understanding of asthma pathogenesis and heterogeneity and, ultimately, for improving prevention and treatment of disease.
authors.affiliation: COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: kb@copsac.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bønnelykke
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Ill. Electronic address: c-ober@genetics.uchicago.edu.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
mesh_terms: D000818:Animals; D001249:Asthma / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D004777:Environment; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype
keywords: 17q asthma locus; Asthma; CDHR3; gene-environment interactions; genome-wide association study; rhinovirus