Regulatory haplotypes in ARG1 are associated with altered bronchodilator response.
BACKGROUND
β₂-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with β₂-agonist bronchodilator response (BDR).


OBJECTIVE
To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro.


METHODS
We resequenced ARG1 in 96 individuals and identified three common, 5' haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression.


RESULTS
BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03-1.71) and 2.18 (95% confidence interval, 1.34-2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3.


CONCLUSIONS
The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to β(2)-agonists for optimal asthma management. Clinical trial registered with www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840).
Duan
Qing Ling
QL
Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. reqdu@channing.harvard.edu
Gaume
Brigitte R
BR
Hawkins
Gregory A
GA
Himes
Blanca E
BE
Bleecker
Eugene R
ER
Klanderman
Barbara
B
Irvin
Charles G
CG
Peters
Stephen P
SP
Meyers
Deborah A
DA
Hanrahan
John P
JP
Lima
John J
JJ
Litonjua
Augusto A
AA
Tantisira
Kelan G
KG
Liggett
Stephen B
SB
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000420:Albuterol / Q000494:pharmacology*; D001119:Arginase / Q000187:drug effects / Q000235:genetics*; D001249:Asthma / Q000188:drug therapy / Q000235:genetics*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002648:Child; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
D001993:Bronchodilator Agents; D001119:Arginase; D000420:Albuterol