Polymorphism at codon 16 of the beta2-adrenoceptor (beta2-AR) affects the responsiveness to salmeterol in asthmatics. Data concerning formoterol are more controversial in the literature. The aim of this study was to verify whether homozygous for arginine-16 (ArgArg16) and homozygous for glycine-16 (GlyGly16) genotypes differently influence the long-term responsiveness to formoterol. Twenty-nine patients with mild-to-moderate asthma, in stable clinical conditions, underwent genotyping at codon 16 of the beta2-AR by RFLP-PCR assay. The effects of a 4-week monotherapy with formoterol (12？μg BID) were tested on the peak expiratory flow (PEF) variability and the forced expiratory volume in 1？sec (FEV1) slope of the dose-response curve to salbutamol. Variability in PEF significantly increased during the 4-week treatment period in 14 patients with GlyGly16, but not in 15 patients with ArgArg16 and ArgGly16 . The FEV1 slope of the dose-response curve to salbutamol decreased after the 4-week treatment period in GlyGly16, but not in pooled ArgArg16 and ArgGly16 patients. This study provides preliminary evidence that tolerance to formoterol develops more frequently in asthmatics with GlyGly16 genotype. If confirmed in a larger population, this finding might be useful in choosing the bronchodilator therapy on the basis of genetic polymorphism of the beta2-AR. 1. Introduction Genetic factors, mainly the polymorphism at codons 16 and 27 of the beta2-adrenoceptor (beta2-AR) on chromosome 5q31, are known to modulate the bronchodilatory effects of beta2-agonists [1, 2]. In vitro studies performed on peripheral lymphocytes have shown that asthmatics homozygous for glycine-16 (GlyGly16) are more prone to beta2-agonist-induced downregulation than either homozygous for arginine-16 (ArgArg16) or heterozygous (ArgGly16) [3]. Consistent with in vitro findings are the effects of the acute exposure of asthmatics to short-acting beta2-agonists (SABAs) [4, 5]. However, chronic exposure to SABAs or to the long-acting beta2-agonist (LABA) salmeterol resulted in greater desensitisation among ArgArg16 asthmatics [2, 6–9] and these patients are also exposed to an increased risk of exacerbations [10]. A study carried out in children with severe asthma exacerbation hospitalized in intensive care unit showed that patients with genotype GlyGly16 had a more rapid and intense response to therapy with inhaled salbutamol compared with patients with other genotypes [11]. Furthermore, GlyGly16 genotype protected from increase in responsiveness to methacholine during regular treatment with the
References
[1]
S. B. Liggett, “Beta2-adrenergic receptor pharmacogenetics,” American Journal of Respiratory and Critical Care Medicine, vol. 161, pp. S197–S201, 2000.
[2]
L. P. Chung, G. Waterer, and P. J. Thompson, “Pharmacogenetics of β2 adrenergic receptor gene polymorphisms, long-acting β-agonists and asthma,” Clinical and Experimental Allergy, vol. 41, no. 3, pp. 312–326, 2011.
[3]
J. Oostendorp, D. S. Postma, H. Volders, et al., “Differential desensitisation of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 3, pp. 322–328, 2005.
[4]
F. D. Martinez, P. E. Graves, M. Baldini, S. Solomon, and R. Erickson, “Association between genetic polymorphisms of the β2-adrenoceptor and response to albuterol in children with and without a history of wheezing,” Journal of Clinical Investigation, vol. 100, no. 12, pp. 3184–3188, 1997.
[5]
J. J. Lima, D. B. Thomason, M. H. N. Mohamed, L. V. Eberle, T. H. Self, and J. A. Johnson, “Impact of genetic polymorphisms of the β2-adrenergic receptor on albuterol bronchodilator pharmacodynamics,” Clinical Pharmacology and Therapeutics, vol. 65, no. 5, pp. 519–525, 1999.
[6]
D. R. Taylor, J. M. Drazen, G. P. Herbison, C. N. Yandava, R. J. Hancox, and G. I. Town, “Asthma exacerbations during long term β agonist use: influence of β2 adrenoceptor polymorphism,” Thorax, vol. 55, no. 9, pp. 762–767, 2000.
[7]
E. Israel, J. M. Drazen, S. B. Liggett, et al., “The effect of polymorphisms of the beta2-adrenergic receptor on the response to regular use of albuterol in asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 1, pp. 75–80, 2000.
[8]
E. Israel, V. M. Chinchilli, J. G. Ford et al., “Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial,” The Lancet, vol. 364, no. 9444, pp. 1505–1512, 2004.
[9]
M. E. Wechsler, E. Lehman, S. C. Lazarus, et al., “Beta-adrenergic receptor polymorhysms and response to salmeterol,” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 5, pp. 519–526, 2006.
[10]
K. Basu, C. N. A. Palmer, R. Tavendale, B. J. Lipworth, and S. Mukhopadhyay, “Adrenergic β2-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol,” Journal of Allergy and Clinical Immunology, vol. 124, no. 6, pp. 1188–1194, 2009.
[11]
C. L. Carroll, P. Stoltz, C. M. Schramm, and A. R. Zucker, “β2-adrenergic receptor polymorphisms affect response to treatment in children with severe asthma exacerbations,” Chest, vol. 135, no. 5, pp. 1186–1192, 2009.
[12]
R. J. Hancox, M. R. Sears, and D. R. Taylor, “Polymorphysm of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma,” European Respiratory Journal, vol. 11, no. 3, pp. 589–593, 1998.
[13]
S. Tan, I. P. Hall, J. Dewar, E. Dow, and B. Lipworth, “Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics,” The Lancet, vol. 350, no. 9083, pp. 995–999, 1997.
[14]
I. Aziz, I. P. Hall, L. C. McFarlane, and B. J. Lipworth, “β2-Adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma,” Journal of Allergy and Clinical Immunology, vol. 101, no. 3, pp. 337–341, 1998.
[15]
S. H. Kim, Y. M. Ye, G. Y. Hur et al., “Effect of β2-adrenergic receptor polymorphism in asthma control of patients receiving combination treatment,” Yonsei Medical Journal, vol. 50, no. 2, pp. 182–188, 2009.
[16]
E. R. Bleecker, D. S. Postma, R. M. Lawrance, D. A. Meyers, H. J. Ambrose, and M. Goldman, “Effect of ADRB2 polymorphisms on response to longacting β2-agonist therapy: a pharmacogenetic analysis of two randomised studies,” The Lancet, vol. 370, no. 9605, pp. 2118–2125, 2007.
[17]
J. C. Kips and R. A. Pauwels, “Long-acting inhaled β2-agonist therapy in asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 6, pp. 923–932, 2001.
[18]
GINA, Global Initiative for Asthma, Global strategy for asthma management and prevention, 2008, http://ginasthma.org.
[19]
American Thoracic Society, “Standardization of spirometry: 1994 update,” American Journal of Respiratory and Critical Care Medicine, vol. 152, no. 3, pp. 1107–1136, 1995.
[20]
G. Ryan, M. B. Dolovich, and R. S. Roberts, “Standardization of inhalation provocation tests: two techniques of aerosol generation and inhalation compared,” American Review of Respiratory Disease, vol. 123, no. 2, pp. 195–199, 1981.
[21]
M. E. Wechsler, S. J. Kunselman, V. M. Chinchilli et al., “Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial,” The Lancet, vol. 374, no. 9703, pp. 1754–1764, 2009.
[22]
E. R. Bleecker, H. S. Nelson, M. Kraft et al., “β2-receptor polymorphisms in patients receiving salmeterol with or without fluticasone propionate,” American Journal of Respiratory and Critical Care Medicine, vol. 181, no. 7, pp. 676–687, 2010.
[23]
E. R. Bleecker, S. W. Yancey, L. A. Baitinger et al., “Salmeterol response is not affected by β2-adrenergic receptor genotype in subjects with persistent asthma,” Journal of Allergy and Clinical Immunology, vol. 118, no. 4, pp. 809–816, 2006.
[24]
B. J. Lipworth, O. J. Dempsey, and I. Aziz, “Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 β2-adrenoceptor polymorphism,” Chest, vol. 118, no. 2, pp. 321–328, 2000.
[25]
D. K. C. Lee, C. M. Jackson, C. E. Bates, and B. J. Lipworth, “Cross tolerance to salbutamol occurs independently of β2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol,” Thorax, vol. 59, no. 8, pp. 662–667, 2004.
[26]
E. R. Bleecker, D. A. Meyers, W. C. Bailey, et al., “ADRB2 polymorphisms and budesonide/formoterol responses in COPD,” Chest, vol. 142, no. 2, pp. 320–328, 2012.
[27]
A. Ullman and N. Svedmyr, “Salmeterol, a new long acting inhaled β2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients,” Thorax, vol. 43, no. 9, pp. 674–678, 1988.
[28]
M. Palmqvist, G. Persson, L. Lazer, J. Rosenborg, P. Larsson, and J. L？tvall, “Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency,” European Respiratory Journal, vol. 10, no. 11, pp. 2484–2489, 1997.
[29]
M. G. H. Scott, C. Swan, T. M. Jobson, S. Rees, and I. P. Hall, “Effects of a range of β2 adrenoceptor agonists on changes in intracellular cyclic AMP and on cyclic AMP driven gene expression in cultured human airway smooth muscle cells,” British Journal of Pharmacology, vol. 128, no. 3, pp. 721–729, 1999.
[30]
N. . Larocca, D. Moreno, J. V. Garmendia, et al., “Beta 2 adrenergic receptor polymorphisms, at codons 16 and 27, and bronchodilator responses in adult Venezuelan asthmatic patients,” Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic, 2012.
[31]
M. Y. Lee, S. N. Cheng, S. J. Chen, H. L. Huang, C. C. Wang, and H. C. Fan, “Polymorphisms of the β2-adrenergic receptor correlated to nocturnal asthma and the response of terbutaline nebulizer,” Pediatrics and Neonatology, vol. 52, no. 1, pp. 18–23, 2011.
[32]
C. L. Carroll, K. A. Sala, A. R. Zucker, and C. M. Schramm, “Beta2-adrenergic receptor haplotype linked to intubation and mechanical ventilation in children with asthma,” Journal of Asthma, vol. 49, no. 6, pp. 563–568, 2012.
[33]
S. B. Liggett, “Genetic variability of the β2 adrenergic receptor and asthma exacerbations,” Thorax, vol. 61, no. 11, pp. 925–927, 2006.
[34]
G. A. Hawkins, K. Tantisira, D. A. Meyers, et al., “Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study,” American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 10, pp. 1101–1119, 2006.
[35]
C. N. A. Palmer, B. J. Lipworth, S. Lee, T. Ismail, D. F. Macgregor, and S. Mukhopadhyay, “Arginine-16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol,” Thorax, vol. 61, no. 11, pp. 940–944, 2006.
[36]
I. P. Hall, J. D. Blakey, K. A. Al Balushi et al., “β2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study,” The Lancet, vol. 368, no. 9537, pp. 771–779, 2006.
[37]
A. M. Wilson, R. D. Gray, I. P. Hall, and B. J. Lipworth, “The effect of β2-adrenoceptor haplotypes on bronchial hyper-responsiveness in patients with asthma,” Allergy, vol. 61, no. 2, pp. 254–259, 2006.
[38]
M. E. Wechsler and E. Israel, “How pharmacogenomics will play a role in the management of asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 1, pp. 12–18, 2005.
