Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately,
therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled
corticosteroids are the most commonly used
asthma controller
therapy. However, asthmatic response to
corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled
corticosteroid therapy in
asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the
biologic actions of
corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled
corticosteroids as the primary
therapy in at least one treatment arm. Variation in one gene,
corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to
therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to
corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of
adrenocorticotropic hormone, which regulates endogenous
cortisol levels, CRHR1 plays a pivotal, pleiotropic role in
steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to
corticosteroids, provide a rationale for predicting therapeutic response in
asthma and other
corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.