The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol

Br J Clin Pharmacol. 2004 Jan;57(1):68-75. doi: 10.1046/j.1365-2125.2003.01955.x.


Aims: The relationship between beta2-adrenoceptor polymorphisms and bronchoprotective response with long-acting beta2-adrenoceptor agonists is unknown.

Methods: We retrospectively analysed data from six placebo-controlled randomized studies in corticosteroid treated asthmatics where formoterol or salmeterol were administered over a 1-2-week period, with prior 1-2 week washout, assessing the primary end point of methacholine PD20 and adenosine monophosphate PC20, following first and last dose, expressed as doubling dose difference from placebo.

Results: There was no significant heterogeneity between the different studies. Patients who had homozygous or heterozygous genotypes containing the arginine-16 polymorphism (Arg16-Arg16 or Arg16-Gly16) had greater bronchoprotective subsensitivity compared with the homozygous glycine-16 genotype (Gly16-Gly16), amounting to a mean doubling dose difference of 1.49 (95% CI 0.50, 2.48), after the last dose. Subsensitivity of response was greater with formoterol than salmeterol after the last dose in all genotypes, especially with the arginine-16 polymorphism, amounting to a doubling dose difference of 3.00 (95% CI 1.01, 4.99) between formoterol and salmeterol.

Conclusions: Our retrospective analysis showed that the arginine-16 polymorphism was associated with subsensitivity of response for bronchoprotection, which was greater for formoterol than salmeterol. A prospective study will be required in order to further evaluate these findings, particularly to assess whether these differences are mirrored by exacerbations.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuterol / analogs & derivatives*
  • Albuterol / therapeutic use*
  • Asthma / drug therapy*
  • Asthma / physiopathology
  • Bronchodilator Agents / therapeutic use*
  • Double-Blind Method
  • Ethanolamines / therapeutic use*
  • Forced Expiratory Volume / physiology
  • Formoterol Fumarate
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Polymorphism, Genetic / genetics*
  • Randomized Controlled Trials as Topic
  • Receptors, Adrenergic, beta-2 / genetics*
  • Retrospective Studies
  • Salmeterol Xinafoate


  • Bronchodilator Agents
  • Ethanolamines
  • Receptors, Adrenergic, beta-2
  • Salmeterol Xinafoate
  • Albuterol
  • Formoterol Fumarate