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Communications to the Editor |

Airway Hyperresponsiveness and β2-Adrenoceptor Genotypes and Diplotypes at Positions 16 and 27 FREE TO VIEW

Daniel K. C. Lee, MD; Graeme P. Currie, MD, DCH; Kean C. Khoo, MBBCh
Author and Funding Information

Affiliations: Ipswich Hospital, Ipswich, UK,  Aberdeen Royal Infirmary, Aberdeen, UK,  Llandough Hospital, Penarth, UK,  Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

Correspondence to: Daniel K. C. Lee, MD, Department of Respiratory Medicine, Ipswich Hospital, Heath Rd, Ipswich IP4 5PD, UK; e-mail: dkclee@doctors.org.uk



Chest. 2005;127(2):689-691. doi:10.1378/chest.127.2.689
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To the Editor:

Litonjua and colleagues1 (July 2004) examined the association between airway hyperresponsiveness and β2-adrenoceptor polymorphism at positions 16 and 27 in > 500 white men from Boston, MA. However, it is curious that no subgroup analysis was performed to examine the distribution of β2-adrenoceptor genotypes and diplotypes in the asthmatic vs the nonasthmatic population. Although we agree that airway hyperresponsiveness is not synonymous with asthma, it would have been of great interest to have known the genetic distribution especially of the arginine-16 genotype and diplotype in the subgroup of asthmatic and nonasthmatic subjects who were nonsmokers. This is especially important in order to establish the clinical relevance of the authors’ findings, which suggest that β2-adrenoceptor polymorphism was associated with airway hyperresponsiveness particularly among lifelong nonsmokers. Indeed, in such individuals, one would have expected a greater proportion of asthmatic patients to be in possession of the arginine-16 genotype and diplotype compared to their nonasthmatic counterparts.

Nevertheless, the clinical relevance of β2-adrenoceptor polymorphism has been well established in asthma. In particular, patients with the homozygous arginine-16 β2-adrenoceptor genotype have been shown to have worse outcomes of asthma control following regular albuterol use.23 Moreover, the homozygous arginine-16 glutamic acid-27 haplotype has been associated with enhanced β2-adrenoceptor agonist-mediated desensitization in vascular tissue following continuous exposure to isoproterenol.4 Predisposition to bronchoprotective subsensitivity following long-acting β2-agonist use has also been demonstrated with the arginine-16 polymorphism.5 Therefore, although the β2-adrenoceptor polymorphism at positions 16 and 27 is of clinical and therapeutic significance in patients with asthma, its clinical relevance on airway hyperresponsiveness in nonasthmatic persons is unclear.

Litonjua, AA, Silverman, EK, Tantisira, KG, et al (2004) β2-Adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.Chest126,66-74. [CrossRef] [PubMed]
 
Israel, E, Drazen, JM, Liggett, SB, et al The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.Am J Respir Crit Care Med2000;162,75-80. [PubMed]
 
Taylor, DR, Drazen, JM, Herbison, GP, et al Asthma exacerbations during long-term β agonist use: influence of β2adrenoceptor polymorphism.Thorax2000;55,762-767. [CrossRef] [PubMed]
 
Dishy, V, Sofowora, GG, Xie, HG, et al The effect of common polymorphisms of the β2-adrenergic receptor on agonist-mediated vascular desensitization.N Engl J Med2001;345,1030-1035. [CrossRef] [PubMed]
 
Lee, DK, Currie, GP, Hall, IP, et al The arginine-16 β2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol.Br J Clin Pharmacol2004;57,68-75. [PubMed]
 
To the Editor:

We thank Lee and colleagues for their interest in our article1on the association between polymorphisms in the β2-adrenergic receptor gene (ADRB2) and airway hyperresponsiveness among nonsmoking men (July 2004). In their letter, Lee and colleagues propose a subset analysis among the nonsmoking asthmatic patients and control subjects. Since the Normative Aging Study was established to study healthy aging, subjects with chronic conditions, including asthma, were initially excluded from participating.2 Thus, there were few men who acquired asthma during the course of follow-up in the full cohort. Indeed, a review of Tables 1 and 2 in our article shows that there were only 27 asthmatic patients in the current analysis, and there would not be any confidence in the results of that subset analysis due to small numbers in the groups.

There are several reasons why we contend that it is important to study the phenotype of airway hyperresponsiveness instead of asthma. Asthma is a complex disorder characterized by both phenotypic and genotypic heterogeneity.34 Airways hyperresponsiveness is a central feature of asthma, and one of the strategies in the dissection of genetic risks of asthma is to investigate genes that contribute to this intermediate phenotype. The relevance of this strategy is borne out by studies that have shown that increased airways hyperreponsiveness is associated with disease severity among asthmatic patients,5and with increased respiratory symptoms67 and lower levels of lung function78 in general population samples. In addition, it has been shown that airways hyperresponsiveness is prospectively associated with the development of asthma.910 Thus, studying the genetic determinants of this intermediate phenotype gives further insight into the causes and mechanisms of complex disorders, such as asthma.

We disagree with the statement by Lee and colleagues that the clinical relevance of β2-adrenergic receptor polymorphisms has been well established in asthma. As we stated in the introduction of our article, it is now clear that the ADRB2 is not a major gene for asthma. ADRB2 variants may play a role in intermediate or asthma-associated phenotypes, such as response to medications and airways hyperresponsiveness. However, the results have been inconsistent across studies, and it remains unclear which variant or set of variants in or near ADRB2 is clinically important.

References
Litonjua, AA, Silverman, EK, Tantisira, KG, et al β2-Adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.Chest2004;126,66-74. [CrossRef] [PubMed]
 
Bell, B, Rose, CL, Damon, D The Normative Aging Study: an interdisciplinary and longitudinal study of health and aging.Aging Hum Dev1972;3,5-17. [CrossRef]
 
Cookson, WOCM, Palmer, LJ Investigating the asthma phenotype.Clin Exp Allergy1998;28(Suppl 1),88-89. [PubMed]
 
Sandford, AJ, Weir, TD, Paré, PD Phenotypic heterogeneity in asthma and allergy.Clin Exp Allergy1998;28(Suppl 1),2-7. [PubMed]
 
Weiss, ST, Van Natta, ML, Zeiger, RS Relationship between increased airway responsiveness and asthma severity in the childhood asthma management program.Am J Respir Crit Care Med Jul2000;162,50-56
 
Rijcken, B, Schouten, JP, Weiss, ST, et al The relationship of nonspecific bronchial responsiveness to respiratory symptoms in a random population sample.Am Rev Respir Dis1987;136,62-68. [CrossRef] [PubMed]
 
Sparrow, D, O’Connor, G, Colton, T, et al The relationship of nonspecific bronchial responsiveness to the occurrence of respiratory symptoms and decreased levels of pulmonary function: the Normative Aging Study.Am Rev Respir Dis1987;135,1255-1260. [PubMed]
 
Rijcken, B, Schouten, JP, Weiss, ST, et al The relationship between airways hyperresponsiveness to histamine and pulmonary function level in a random population sample.Am Rev Respir Dis1988;137,826-832. [PubMed]
 
Carey, VJ, Weiss, ST, Tager, IB, et al Airways responsiveness, wheeze onset, and recurrent asthma episodes in young adolescents: the East Boston Childhood Respiratory Disease Cohort.Am J Respir Crit Care Med1996;153,356-361. [PubMed]
 
Zhong, NS, Chen, RC, Yang, MO, et al Is asymptomatic bronchial hyperresponsiveness an indication of potential asthma? A two-year follow-up of young students with bronchial hyperresponsiveness.Chest1992;102,1104-1109. [CrossRef] [PubMed]
 

Figures

Tables

References

Litonjua, AA, Silverman, EK, Tantisira, KG, et al (2004) β2-Adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.Chest126,66-74. [CrossRef] [PubMed]
 
Israel, E, Drazen, JM, Liggett, SB, et al The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.Am J Respir Crit Care Med2000;162,75-80. [PubMed]
 
Taylor, DR, Drazen, JM, Herbison, GP, et al Asthma exacerbations during long-term β agonist use: influence of β2adrenoceptor polymorphism.Thorax2000;55,762-767. [CrossRef] [PubMed]
 
Dishy, V, Sofowora, GG, Xie, HG, et al The effect of common polymorphisms of the β2-adrenergic receptor on agonist-mediated vascular desensitization.N Engl J Med2001;345,1030-1035. [CrossRef] [PubMed]
 
Lee, DK, Currie, GP, Hall, IP, et al The arginine-16 β2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol.Br J Clin Pharmacol2004;57,68-75. [PubMed]
 
Litonjua, AA, Silverman, EK, Tantisira, KG, et al β2-Adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.Chest2004;126,66-74. [CrossRef] [PubMed]
 
Bell, B, Rose, CL, Damon, D The Normative Aging Study: an interdisciplinary and longitudinal study of health and aging.Aging Hum Dev1972;3,5-17. [CrossRef]
 
Cookson, WOCM, Palmer, LJ Investigating the asthma phenotype.Clin Exp Allergy1998;28(Suppl 1),88-89. [PubMed]
 
Sandford, AJ, Weir, TD, Paré, PD Phenotypic heterogeneity in asthma and allergy.Clin Exp Allergy1998;28(Suppl 1),2-7. [PubMed]
 
Weiss, ST, Van Natta, ML, Zeiger, RS Relationship between increased airway responsiveness and asthma severity in the childhood asthma management program.Am J Respir Crit Care Med Jul2000;162,50-56
 
Rijcken, B, Schouten, JP, Weiss, ST, et al The relationship of nonspecific bronchial responsiveness to respiratory symptoms in a random population sample.Am Rev Respir Dis1987;136,62-68. [CrossRef] [PubMed]
 
Sparrow, D, O’Connor, G, Colton, T, et al The relationship of nonspecific bronchial responsiveness to the occurrence of respiratory symptoms and decreased levels of pulmonary function: the Normative Aging Study.Am Rev Respir Dis1987;135,1255-1260. [PubMed]
 
Rijcken, B, Schouten, JP, Weiss, ST, et al The relationship between airways hyperresponsiveness to histamine and pulmonary function level in a random population sample.Am Rev Respir Dis1988;137,826-832. [PubMed]
 
Carey, VJ, Weiss, ST, Tager, IB, et al Airways responsiveness, wheeze onset, and recurrent asthma episodes in young adolescents: the East Boston Childhood Respiratory Disease Cohort.Am J Respir Crit Care Med1996;153,356-361. [PubMed]
 
Zhong, NS, Chen, RC, Yang, MO, et al Is asymptomatic bronchial hyperresponsiveness an indication of potential asthma? A two-year follow-up of young students with bronchial hyperresponsiveness.Chest1992;102,1104-1109. [CrossRef] [PubMed]
 
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