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Published ahead of print on December 1, 2005, doi:10.1164/rccm.200509-1519OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 5, March 2006, 519-526

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Submitted on September 28, 2005
Accepted on November 30, 2005

{beta}-adrenergic Receptor Polymorphisms and Response to Salmeterol

Michael E Wechsler1, Erik Lehman2, Stephen C Lazarus3, Robert F Lemanske, Jr.4, Homer A Boushey3, Aaron Deykin1, John V Fahy3, Christine A Sorkness4, Vernon M Chinchilli2, Timothy J Craig2, Emily DiMango5, Monica Kraft6, Frank Leone7, Richard J Martin8, Stephen P Peters9, Stanley J Szefler8, Wenlei Liu2, and Elliot Israel1*

1 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, 2 Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA, 3 Department of Medicine, University of California at San Francisco, San Francisco, CA, USA, 4 Department of Medicine and Pediatrics, University of Wisconsin, Madison, WI, USA, 5 Department of Medicine, Harlem Lung Center and Columbia University, New York, NY, USA, 6 Department of Medicine, Duke University Medical Center, Durham, NC, USA, 7 Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA, 8 Department of Medicine and Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA, 9 Wake Forest University Health Sciences Center, Winston-Salem, NC, USA

* To whom correspondence should be addressed. E-mail: eisrael{at}partners.org.

Rationale: Several studies suggest that asthmatics homozygous for the arginine allele at the 16th position of the {beta}2-adrenergic receptor may not benefit from short-acting {beta}-agonists. Objectives: We investigated whether such genotype-specific effects occur when patients are treated with long-acting {beta}-agonists and whether such effects are modified by concurrent inhaled corticosteroid(ICS) use. Methods: We compared salmeterol response in asthmatics homozygous for arginine at B16(B16Arg/Arg) to those homozygous for glycine at B16(B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS. Results: In both trials, B16Arg/Arg subjects did not benefit compared to B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared to placebo, the addition of salmeterol was associated with a 51.4 L/min lower AM peak expiratory flow(PEF)(p=0.005) in B16Arg/Arg subjects(salmeterol n=12,placebo n=5) subjects as compared to B16Gly/Gly subjects (salmeterol n=13, placebo n=13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently(n=8) had a lower AM PEF (36.8L/min difference, p=0.048) than B16Gly/Gly subjects(n=22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42L, p=0.003), increased symptom scores(0.2 units, p=0.034) and increased albuterol rescue use(0.95 puffs/day, p=0.004) compared with B16Gly/Gly subjects. Conclusions: Relative to B16Gly/Gly asthmatics, B16Arg/Arg asthmatics may have an impaired therapeutic response to salmeterol, in either the absence or presence of concurrent ICS. Investigation of alternate treatment strategies may benefit this group.
Key words: Asthma, pharmacogenetics, beta-adrenergic receptor, beta-agonists, salmeterol




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