Role of interactions in pharmacogenetic studies: leukotrienes in asthma

Researchers have identified thousands of loci involved in complex traits and drug response. However, in most cases they only explain a small proportion of the heritability of the trait. Among different strategies conducted to identify this 'missing heritability', here we illustrate the importance of complex gene-environment interactions using findings regarding the role of leukotrienes on the bronchodilator response to albuterol in Latino asthmatics. Patients managing their asthma with leukotriene-modifying medication presented higher increases in the bronchodilator response to albuterol. Moreover, interactions between genes responsible for leukotriene production were associated with a decreased risk of asthma. Combining genetic and pharmacologic effects, leukotriene-modifying users carrying certain combinations of alleles presented higher improvements in lung function after bronchodilator administration. Genes and drugs act at different orders of interaction (from individual effects to gene-gene-drug-drug interactions) and population-specific effects have to be considered. These results may be extrapolated to other complex phenotypes.