Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma.
OBJECTIVE
Corticotropin-releasing hormone receptor (CRHR)-2 participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short-acting beta2-agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma.


METHODS
We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic patients recruited as part of the Childhood Asthma Management Program. Replication was conducted in two Caucasian adult asthma cohorts--a cohort of 427 participants enrolled in a completed clinical trial conducted by Sepracor Inc. (Massachusetts, USA) and a cohort of 152 participants enrolled in the Clinical Trial of Low-Dose Theophylline and Montelukast conducted by the American Lung Association Asthma Clinical Research Centers.


RESULTS
Five variants were significantly associated with acute bronchodilator response in at least one cohort (P<or=0.05). Variant rs7793837 was associated in Childhood Asthma Management Program and Low-Dose Theophylline and Montelukast (P=0.05 and 0.03, respectively) and haplotype blocks residing at the 5' end of CRHR2 were associated with response in all three cohorts.


CONCLUSIONS
We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. Although no single variant was significantly associated in all three cohorts, the findings that variants at the 5' end of CRHR2 are associated in each of three cohorts strongly suggest that the causative variants reside in this region and its genetic effect, although present, is likely to be weak.
Poon
Audrey H
AH
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Tantisira
Kelan G
KG
Litonjua
Augusto A
AA
Lazarus
Ross
R
Xu
Jingsong
J
Lasky-Su
Jessica
J
Lima
John J
JJ
Irvin
Charles G
CG
Hanrahan
John P
JP
Lange
Christoph
C
Weiss
Scott T
ST
D000420:Albuterol / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D005787:Gene Frequency; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010919:Placebos; D020641:Polymorphism, Single Nucleotide; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D012119:Respiration / Q000187:drug effects* / Q000235:genetics; D013806:Theophylline / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; C101531:CRF receptor type 2; D010919:Placebos; D018019:Receptors, Corticotropin-Releasing Hormone; D013806:Theophylline; D000420:Albuterol