Role of Interactions in Pharmacogenetic Studies: Leukotrienes in Asthma

Abstract

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.

KEYWORDS::

• albuterol
• asthma
• bronchodilator drug response
• drug–drug interaction
• ethnic differences
• gene–gene interaction
• leukotriene modifier
• leukotrienes

Financial & competing interests disclosure

M Via was supported by the Beatriu de Pinós Program (2009 BP-B 00274). H Tcheurekdjian was funded by the Glaser Pediatric Research Network. EG Burchard was supported by the NIH (HL078885, AI077439 and HL088133), the Flight Attendant Medical Research Institute (FAMRI), American Asthma Foundation and the Sandler Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

M Via was supported by the Beatriu de Pinós Program (2009 BP-B 00274). H Tcheurekdjian was funded by the Glaser Pediatric Research Network. EG Burchard was supported by the NIH (HL078885, AI077439 and HL088133), the Flight Attendant Medical Research Institute (FAMRI), American Asthma Foundation and the Sandler Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.