Human Molecular Genetics Advance Access originally published online on May 5, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 13 1353-1359
DOI: 10.1093/hmg/ddh149
Human Molecular Genetics, Vol. 13, No. 13 © Oxford University Press 2004; all rights reserved
Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids
1Channing Laboratory and 2Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, 3Western Australian Institute for Medical Research, Center for Medical Research, University of Western Australia, Perth 6000, Australia, 4Pulmonary Division, University of Cincinnati, Cincinnati, OH 45867, USA, 5Department of Pediatrics and Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA, 6Eli and Edythe L. Broad Institute, Cambridge, MA 02141, USA, 7Departments of Genetics and Medicine, Massachusetts General Hospital and Harvard Medical School, MA, USA and 8Whitehead Institute Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02141, USA
Received March 5, 2004; Accepted April 19, 2004
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.
* To whom correspondence should be addressed at: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 6175252278; Fax: +1 6175250958; Email: scott.weiss{at}channing.harvard.edu
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