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(Chest. 2006;130:449-454.)
© 2006 American College of Chest Physicians

Association Between Nonspecific Airway Hyperresponsiveness and Arg16Gly ß2-Adrenergic Receptor Gene Polymorphism in Asymptomatic Healthy Japanese Subjects*

Yoshinobu Fukui, MD; Nobuyuki Hizawa, MD; Daisuke Takahashi, MD; Yukiko Maeda, MD; Eisei Jinushi, MD; Satoshi Konno, MD and Masaharu Nishimura, MD

* From the First Department of Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to: Nobuyuki Hizawa, MD, First Department of Medicine, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan; e-mail: nhizawa{at}med.hokudai.ac.jp

Abstract

Background: Nonspecific airway hyperresponsiveness (AHR), a cardinal feature of asthma, is thought to result from several genetic and environmental factors. Asymptomatic AHR in nonasthmatic healthy subjects might be a risk factor for the development of asthma. Genetic variations in codons 16 and 27 of the human ß2-adrenergic receptor (ß2-AR) alter receptor function in vitro and are associated with various asthma-related phenotypes, including asthma severity and AHR. To date, however, few reports have examined the impact of ß2-AR gene polymorphism on AHR in asymptomatic healthy subjects.

Objective: To determine whether polymorphism of the ß2-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects.

Design and participants: A cohort of 120 asymptomatic healthy subjects was analyzed using a stepwise linear regression model. Nonspecific airway responsiveness was measured using a continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. Genotyping to identify polymorphisms at codons 16 and 27 was conducted using an assay combining kinetic real-time quantitative polymerase chain reaction with allele-specific amplification.

Results: The Gly16Gly genotype was associated with lower Dmin values. The log Dmin value of asymptomatic healthy subjects carrying the Arg16 allele (Arg16/Arg or Arg16/Gly, n = 90) was 1.09 ± 0.56 (mean ± SD), while those homozygous for the Gly16 allele (n = 30) yielded a log Dmin value of 0.85 ± 0.56 (p < 0.05).

Conclusion: This study indicates that a specific ß2-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.

Key Words: airway hyperresponsiveness • asymptomatic healthy subject • ß2-adrenergic receptor • polymorphism

Nonspecific airway hyperresponsiveness (AHR) is thought to be determined by several genetic and environmental factors, and is an important feature of asthma.1 Asymptomatic AHR in nonasthmatics might be a risk factor for the development of asthma.23 A number of reports456789101112 describe factors associated with AHR, including increased levels of total serum IgE and the presence of specific IgE antibodies toward mites, house dust, cats, pollen, and mold. Increased levels of exposure to the house dust mite (HDM) allergen are also associated with AHR.1314 Furthermore, AHR is associated with female gender and smoking in randomly selected adults.12

Postma and coworkers11 reported that a gene governing AHR is located at chromosome 5q31-q33, where the ß2-adrenergic receptor (ß2-AR) gene is located. Due to its involvement in regulation of airway tone, the ß2-AR gene is thought to play a role in bronchial hyperresponsiveness. Several polymorphisms of the ß2-AR gene exist. Specifically, amino acid substitutions at positions 16, 27, and 164 are known to alter receptor function in vitro.1516 Three mutated receptors with substitutions involving Arg16->Gly, Gln27->Glu, or both, markedly altered the degree of agonist-induced down-regulation of receptor expression. After 24-h exposure to 10 mmol/L isoproterenol, there was a 26% reduction in wild-type ß2-AR density. In contrast, a 41% reduction in the receptor density of a mutated ß2-AR containing an Arg16->Gly substitution was observed. However, no down-regulation of a mutated receptor containing a Gln27->Glu substitution was observed. Mutated receptors containing both Arg16->Gly and Gln27->Glu substitutions demonstrated greater agonist-induced down-regulation of receptor density than the wild-type ß2-AR (39%).15

Several studies implicate functional polymorphisms in the development of asthma and asthma-related phenomena, such as AHR. Asthmatic subjects with the Gly16 allele have increased AHR to methacholine, compared to those homozygous for Arg16.17 Asthmatic subjects homozygous for Glu27 have less airway responsiveness than asthmatics homozygous for Gln27.18 To date, although asymptomatic AHR may be associated with increased risk for asthma developing, few reports have examined the genetic contribution of ß2-AR gene polymorphisms on AHR in asymptomatic healthy subjects. Furthermore, the clinical relevance of AHR in nonasthmatic subjects remains unclear. Here, we investigated whether ß2-AR gene polymorphisms might influence nonspecific AHR in asymptomatic healthy Japanese subjects.

Materials and Methods

Study Subjects
One hundred twenty asymptomatic healthy subjects (87 men and 33 women; median age, 24 years; range, 18 to 35 years) were recruited for this study (Table 1 ). The subjects were medical students from Hokkaido University and were living in Sapporo, Japan. All subjects gave written informed consent for enrollment in this study and all associated procedures. All participants underwent structured interviews and completed questionnaires regarding history of allergic or respiratory disease, as well as any family history of asthma. None had ever experienced wheezing, shortness of breath, or any other respiratory disease. None of the participants reported recent respiratory infections. We examined peripheral blood eosinophil counts and specific IgE antibodies to 14 inhaled antigens, including Dermatophagoides farinae, grass pollens, animal dander, and molds. Spirometry was performed (Autospiro AS-300; Minato; Osaka, Japan). In addition, dust samples were collected from the beds of 91 participants using a dust sampler and a vacuum cleaner, after which the samples were stored at – 20°C. Levels of Der p 1 and Der f 1, major allergens from Dermatophagoides pteronyssinus and D farinae, were measured in the dust samples using a two-site monoclonal antibody enzyme-linked immunosorbent assay.19


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  		Table 1. Patient Characteristics*

 
Measurement of Nonspecific Airway Responsiveness
Nonspecific airway responsiveness, as judged by the degree of methacholine-induced bronchoconstriction, was measured by continuous methacholine inhalation with simultaneous measurement of respiratory resistance (Astograph; Chest; Tokyo, Japan).2021 After recording the baseline respiratory resistance, increasing doses of methacholine were inhaled, beginning with the lowest concentration, at 1-min intervals. We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. One unit of Dmin represents a 1-min inhalation of 1 mg/mL of methacholine using this method.22 Log Dmin values as an index of AHR were used because previous studies have shown that AHR assessed by Dmin is well correlated with the degree of airway inflammation including exhaled nitric oxide concentration23 and eosinophil count in sputum22 in patients with asthma.

DNA Genotyping
Genomic DNA was extracted from blood leukocytes using an extraction kit (Sepagene; Wako; Tokyo, Japan). We identified 46A->G and 79C->G exon polymorphisms using an assay combining kinetic real-time quantitative polymerase chain reaction (PCR) with allele-specific amplification,24 in which primers were designed (Primer Express software; PE Applied Biosystems; Foster City, CA) to specifically amplify either wild-type or mutant alleles in separate PCR reactions. The PCR products were detected with an ABI Prism 7700 Sequence Detection System (PE Applied Biosystems) using the double-stranded DNA-specific fluorescent dye (SYBR Green I; Qiagen; Valencia, CA). The following primers were used: 46A forward primer, 5'-GCC TTC TTG CTG GCA CCC AAA A-3', 46G forward primer, 5'-GCC TTC TTG CTG GCA CCC AAA G-3', 46 reverse primer, 5'-TCA CCC ACA CCT CGT CCC T-3', 79C forward primer, 5'-ACC ACG ACG TCA CGC AGC-3', 79G forward primer, 5'-ACC ACG ACG TCA CGC AGG-3', and 79 reverse primer, 5'-GAG AGA CAT GAC GAT GCC CAT.

Statistical Analysis
We used a stepwise linear regression model to determine which variables are most useful in predicting log Dmin values. We tested two models using 91 subjects and 120 subjects, respectively. We examined the following independent variables in model 1: age; gender; the presence of allergic rhinitis; family history of asthma; smoking status (never, past, or present); body mass index; FEV1/FVC; peripheral blood eosinophil count; total serum IgE level; specific IgE antibodies against 14 commonly inhaled antigens; concentration of mite antigen in bedding; presence of the Arg16 allele; and presence of the Glu27 allele. The same variables, with the exception of concentration of mite antigen in bedding, were examined in model 2. Owing to the small sample size, the results for homozygous ArgArg and heterozygous ArgGly genotypes at codon 16 were combined for analysis. We set the F-to-remove value as 2.99, and the F-to-enter value as 3.00 in both models. The possibility of a statistical association between ADRB haplotypes and Dmin levels was also examined using software (Haplo.score; Mayo Foundation for Medical Education and Research; Rochester, MN) to calculate simulation p values for each haplotype (1,000 simulations were performed).25

Results

In this study, 74.2% of subjects (n = 89) had specific IgE antibodies to at least 1 of 14 inhaled antigens, including D farinae, grass pollens, animal dander, and molds (Table 1). Seventy-seven subjects (64.2%) had specific IgE to D farinae. Twenty-nine subjects (24.2%) had allergic rhinitis. Thirteen subjects (10.8%) had a family history of asthma. Fifty-seven of 91 subjects (62.6%) had concentrations of mite antigens (Der p 1 and Der f 1) > 2 µg/g of dust in their bedding, which is reportedly associated with an increased risk of specific sensitization.26

A normal distribution of log Dmin values was observed among 120 asymptomatic subjects (mean value ± SD for log Dmin, 1.03 ± 0.58; Fig 1 ). In Figure 1, we also show the distribution of Dmin values of a group of patients with mild persistent asthma (n = 105; mean log Dmin, – 0.17 ± 0.77, using the same method) as a reference.27 The genotypic and allelic frequencies of various ß2-AR gene polymorphisms among asymptomatic Japanese subjects are shown in Table 2 . The allelic frequency of the Glu27 polymorphism of the ß2-AR gene is less prevalent among Japanese than white populations. Only 7.5% of subjects in the present study carried the Glu27 polymorphism. The frequency of the Arg16 allele was 53.8%, which is similar in frequency to that observed in the white population. The prevalence of Arg16Gly and Glu27Gln polymorphism did not significantly deviate from Hardy-Weinberg equilibrium in the population examined.


Figure 1
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  		Figure 1. Distribution of log Dmin values among patients with mild asthma and asymptomatic healthy subjects. A normal distribution of log Dmin values was observed in both 105 patients with asthma and 120 asymptomatic healthy subjects, with a significant overlap between the two groups.

 

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  		Table 2. Genotypic and Allelic Frequencies of the ß2AR Gene in 91 Japanese Subjects*

 
In model 1, presence of the Arg16 allele (F = 5.351), number of peripheral blood eosinophils (F = 3.229), smoking status (F = 3.095), and age (F = 3.039) were entered into the model to determine log Dmin values by stepwise linear regression analysis (R2 = 0.135) [Table 3 ]. In model 2, presence of the Arg16 allele (F = 4.702), smoking status (F = 3.012), and body mass index (F = 5.002) were entered in the model (R2 = 0.092; Table 3). The results suggest that the Arg16 allele has a protective effect against AHR. The other factors examined in the present study, including atopy, were removed in each model.


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  		Table 3. Results of Stepwise Linear Regression Analysis

 
When the influence of haplotype on Dmin values was examined in 120 subjects, the Arg46/Gln79 haplotype demonstrated the greatest haplotype-specific score (1.64 with a haplotype frequency of 0.51), although it did not reach statistical significance (p = 0.080; a positive haplotype-specific score is associated with higher levels of Dmin), which is compatible with the results of a single nucleotide polymorphism analysis.

Discussion

Several studies have examined possible relationships between ß2-AR polymorphisms and AHR, a cardinal feature of asthma. Although some of the results are conflicting, it is clear that the ß2-AR gene determines the degree of airway responsiveness in a number of different populations.111718282930 In the present study, we investigated whether polymorphism at codon 16 might influence airway responsiveness among asymptomatic healthy individuals, and found an association between presence of the Arg16 allele and reduced nonspecific airway responsiveness, as assessed by methacholine-induced bronchoconstriction. This finding underscores the importance of the ß2-AR in regulation of airway responsiveness in asymptomatic healthy subjects. AHR is associated with the development of asthma in prospective studies.231 An alternative theory is that AHR may more accurately identify subjects having at least partial phenotypic expression of asthma even when these subjects did not have an overt phenotypic expression of asthma. Thus, studying the genetic determinants of asymptomatic AHR might provide further insight into the etiology and mechanism by which asthma occurs.

In vitro functional studies1516 indicate that down-regulation of ß2-ARs occurs in individuals expressing Gly16 in response to circulating catecholamines or exogenously administered ß2-agonists. The Arg16 ß2-AR, which demonstrates resistance to down-regulation, might therefore be expressed at greater levels than the Gly16 ß2-AR within airways. Accordingly, individuals carrying the Gly16Gly genotype might be more sensitive to stimuli resulting in bronchoconstriction, and therefore have more reactive airways than individuals carrying the Arg16 allele. The present findings agree with a comprehensive metaanalysis32 of 28 previously published genetic studies evaluating the role of Arg16Gly and Gln27Glu polymorphisms that found a strong association between the Gly16 allele and nocturnal asthma and asthma severity.

Alterations in function due to ß2-AR polymorphisms might result from a combination of polymorphisms, rather than a single polymorphism. Drysdale and coworkers33 identified 12 haplotypes involving 20 single nucleotide polymorphisms of the ß2-AR gene among white, African American, and Asian subjects. Of these haplotypes, only four common (> 5%) haplotypes were identified in Asian subjects. The detection of Arg16Gly and Gln27Glu identify three haplotypes among these four common haplotypes, and it does not allow us to further dissect the role of specific haplotypes on AHR in asymptomatic subjects. The most important polymorphisms, however, appear to be nonsynonymous polymorphisms at loci 16, 27 and 164, as well as a polymorphism involving amino acid 19 of the 5' leader cistron of the ß2-AR, which is also known to influence levels of ß2-AR expression in cells. Of note, both the Glu27 and Cys19 alleles, which are in complete linkage equilibrium, are very rare among Japanese people. In addition, the Ile164 allele has not been identified in the Japanese population. Thus, we believe that the observed association between Arg16Gly polymorphism and AHR in asymptomatic subjects in the present study reflects the functional consequences of this polymorphism on ß2-AR down-regulation. However, we cannot exclude the possibility that other polymorphisms or complex haplotypes within the promoter and coding regions of the ß2-AR gene or adjacent genes might contribute to the present results. Unidentified susceptibility alleles within or near the ADRB2 gene may also be responsible for increased AHR. Alternatively, complex interactions among different ADRB2 haplotypes may provide an overall risk factor for increased levels of Dmin. Furthermore, since altering ß-adrenergic receptor expression might affect the function of cholinergic receptors controlling airway contractility,34 there remains a possibility that functional alterations in other receptors, such as cholinergic receptors, might explain the significant association observed between the Arg16 allele and AHR to methacholine in the present study.

Four genetic studies of AHR, including the present study, report contradictory results. In an Italian population,28 the Gly16/Gln27 haplotype is associated with AHR, while the same haplotype is significantly underrepresented among German29 and American white30 populations with increased AHR. These and other studies suggest that the effects of Arg16Gly polymorphism are influenced by several other genetic and environmental factors, such as ethnic background,33 smoking status,30 and gender.35 Significant differences in the prevalence of atopy were reported among the Italian and German studies.2829 Furthermore, 40.7% of subjects in the Italian study28 had detectable IgE against HDM, while only 12.5% of subjects in the German study29 had IgE against HDM. The population we examined also had a high frequency of D farinae allergy (64.2%). Given the association between specific IgE responses to HDM and AHR,14 sensitization to HDM might modify the effects of ß2-AR polymorphisms. Due to the limited number of subjects examined in the present study, we were unable to examine the effects of ß2-AR polymorphisms by stratification according to smoking status, gender, or atopy on the development of AHR.

In conclusion, the present study indicates that nonspecific AHR or the degree of methacholine-induced bronchoconstriction is associated with a specific ß2-AR genotype in asymptomatic healthy subjects. Specifically, we observed that individuals who are homozygous for the Gly16 allele are more responsive to methacholine than subjects who carry the Arg16 allele. Our findings are preliminary but suggest that ß2-AR polymorphisms contribute to altered airway responsiveness in asymptomatic individuals, as well as patients with asthma.

Acknowledgements

We thank all the subjects of this study for their participation. We also thank Yoshiko Obata and Kotomi Hosono for technical assistance. We also thank Ken Sawazaki at the Pharmaceutical Research Laboratory, Hitachi Chemical Co., Ltd., for measuring specific IgE antibody levels (multiple radioallergosorbent test).

Footnotes

Abbreviations: AHR = airway hyperresponsiveness; ß2-AR = ß2-adrenergic receptor; Dmin = cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance started to decrease; HDM = house dust mite; PCR = polymerase chain reaction

This study was funded in part by Grant-in-Aid for Scientific Research 13670585 from the Japan Society for the Promotion of Science.

No author has any conflict of interest with respect to this article.

Received for publication September 2, 2005. Accepted for publication January 20, 2006.

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