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-Adrenergic Receptor Polymorphisms and Response to Salmeterol

Brigham and Women's Hospital; Harvard Medical School, Boston, Massachusetts; Pennsylvania State University College of Medicine, Hershey; Thomas Jefferson University, Philadelphia, Pennsylvania; University of California at San Francisco, San Francisco, California; University of Wisconsin, Madison, Wisconsin; Harlem Lung Center; Columbia University, New York, New York; Duke University Medical Center, Durham; Wake Forest University Health Sciences Center, Winston-Salem, North Carolina; and National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Elliot Israel, M.D., Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115. E-mail: eisrael{at}partners.org

Rationale: Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the ₂-adrenergic receptor may not benefit from short-acting -agonists.

Objectives: We investigated whether such genotype-specific effects occur when patients are treated with long-acting -agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use.

Methods: We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with 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 with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with 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 A.M. PEF (36.8 L/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 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects.

Conclusions: Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group.

Key Words: asthma • -adrenergic receptor • -agonists • pharmacogenetics • salmeterol

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