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Asthma Steroid Pharmacogenetics

A Study Strategy to Identify Replicated Treatment Responses

Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston; and Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Scott T. Weiss, M.D., M.S., Director, Respiratory, Genetic, and Environmental Epidemiology, Channing Laboratory, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: restw{at}channing.harvard.edu

Asthma treatment with inhaled steroids demonstrates significant between-person variability. Genetic variation could contribute to this response to inhaled glucocorticosteroids. Difficulties in performing genetic association studies are well known. We designed a test and validation strategy to assess steroid pathway candidate genes. One hundred thirty-one single nucleotide polymorphisms in 14 candidate genes in the steroid pathway were genotyped in an 8-week clinical trial of 470 adults with moderate to severe asthma. We then validated our findings in a second population of individuals with childhood asthma in a 4-year clinical trial of inhaled corticosteroids and a third population of adults with asthma. One gene, corticotrophin-releasing hormone receptor 1 (CRHR1, NM_004382), demonstrated multiple single nucleotide polymorphism associations within each of the three populations. The approach of a test and multiple replication populations is a valuable strategy in asthma pharmacogenetics, which can insure valid association findings.

Key Words: association studies • asthma • drug treatment • pharmacogenetics • steroids

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