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Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses
Scott T Weiss1, Stephen L Lake, Eric S Silverman
1Respiratory, Genetic, and Environmental Epidemiology, Channing Laboratory, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. restw@channing.harvard.edu
Abstract:
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.
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