Saturday, March 5, 2016
Leveraging Gene-Environment Interactions and Endotypes for Asthma Gene Discovery
Asthma is a pressing public health problem in many developed countries. But we don’t really know what causes asthma. In this month’s issue of JACI, Drs. Bønnelykke and Ober talk about the genes and the gene-environment interactions that are thought to underlie susceptibility to developing asthma (J Allergy Clin Immunol 2016; 137(3): 667-679).
So far, there have been about 15 genes strongly linked to asthma, based on large genome-wide association studies (GWAS). But each of these individual gene variants confers only a very modest increase in asthma risk. Clearly, there remains a lot of missing information. Although a significant portion of the risk for asthma may be attributed to environmental exposures, genetic variants may play a stronger role among subgroups of asthmatics who share similar clinical characteristics or similar exposures, as the article discusses.
To tease this apart, genome-wide interaction studies (GWIS) have been conducted to associate specific gene variants to asthma in the presence of specific environmental exposures. Additionally, previous studies have already shown interactions between genes, early life viral wheezing illnesses, and asthma onset in childhood. In particular, genetic variants at the 17q locus are associated with asthma among children with significant rhinovirus infections (common colds) during early childhood, but not among children who do not get very sick with rhinovirus infection. Interestingly, these same variants at the 17q locus are associated with protection from developing asthma among children exposed to farm animals in early life. Similarly, a variant of the CDHR3 gene, which encodes for a receptor for one type of rhinovirus, is associated with risk of severe childhood asthma.
There are several challenges to performing GWIS studies. For example, environmental exposures can be difficult to measure precisely and it is often impossible to dissect effects of a specific exposure from other related factors. An alternative approach is to study gene-environment interactions in cell models where single exposures can be studied in isolation and effects can be directly attributed to the exposure. Drs. Bønnelykke and Ober suggest that future studies using this approach will complement and guide human studies and thereby help understanding the complex mechanisms of asthma.
Regardless, the roots of asthma seem to lurk at the intersections between genetic susceptibility and environmental exposures. As Drs. Bønnelykke and Ober explain, future studies will require targeted, thoughtful research linking particular exposures in combination with genetic variants to asthma risk.