Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses.
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.
Weiss
Scott T
ST
Respiratory, Genetic, and Environmental Epidemiology, Channing Laboratory, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. restw@channing.harvard.edu
Lake
Stephen L
SL
Silverman
Eric S
ES
Silverman
Edwin K
EK
Richter
Brent
B
Drazen
Jeffrey M
JM
Tantisira
Kelan G
KG
D000280:Administration, Inhalation; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000235:genetics*; D000328:Adult; D000368:Aged; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005446:Fluocinolone Acetonide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D005446:Fluocinolone Acetonide; C007734:flunisolide