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(Chest. 2006;129:762-770.)
© 2006 American College of Chest Physicians

Influence of ß2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults*

Eric M. Snyder, MD; Kenneth C. Beck, MD; Niki M. Dietz, MD; Michael J. Joyner, MD; Stephen T. Turner, MD and Bruce D. Johnson, PhD

* From the Departments of Internal Medicine (Drs. Snyder, Beck, Turner, and Johnson) and Anesthiology (Drs. Dietz and Joyner), Mayo Clinic and Foundation, Rochester, MN.

Correspondence to: Bruce D. Johnson, PhD, Associate Professor of Medicine, Gonda 5-369, Mayo Clinic and Foundation, 200 First St, SW, Rochester, MN 55905; e-mail: johnson.bruce{at}mayo.edu

Abstract

Background: In humans, ß2-adrenergic receptors (ß2ARs) influence airway tone. There are known functional polymorphisms of the ß2AR, such as substitution of glycine for arginine at codon 16. We sought to determine if this variation in genotype differentially influences airway function during exercise.

Methods: Healthy subjects without asthma who were either homozygous for Arg16 (n = 16; mean age, 29 ± 2 years [± SD]; mean maximum oxygen uptake [VO2], 32 ± 2 mL/kg/min) or the Gly16 allele (n = 26; mean age, 30 ± 1 years; mean maximum VO2, 33 ± 1 mL/kg/min) participated in the study. Baseline testing included spirometry and maximal symptom-limited exercise. On a separate day, an arterial cannula was placed to measure catecholamine levels. Subjects then performed exercise at two work levels (40% and 75% of peak work) for 9 min each and performed spirometry at 3-min intervals for assessment of airway function.

Results: There were no statistically significant differences between groups in maximum VO2 or baseline spirometry (p > 0.05). With both light and heavy exercise, the groups had similar increases in the forced expiratory flow at 50% of vital capacity (FEF50). FEF50 increased by 14 ± 4% and 15 ± 3% in arginine and glycine groups, respectively, by end exercise (p > 0.05). During recovery (5 min and 10 min after), the Gly16 homozygotes demonstrated persistent bronchodilation (10 min after FEF50 = + 7 ± 2% over pre-exercise) while the Arg16 subjects had a rapid return to baseline (10 min after FEF50 = – 3 ± 3%, p = 0.007 between groups). No differences were observed in the catecholamine responses between genotypes, although the increase in epinephrine in the arginine group tended to be higher (p = 0.07).

Conclusions: These data suggest that the Arg16Gly polymorphism of the ß2AR does not influence airway function during short-duration low- and high-intensity exercise. However, during recovery, the Arg16 genotype is associated with a reduced bronchodilation, possibly due to increased catecholamine desensitization.

Key Words: bronchodilation • catecholamines • genetic

The respiratory system adapts to changes in metabolic demand in an attempt to maintain gas exchange homeostasis at minimal cost. Among the many respiratory adaptations that occur during exercise is exercise-induced bronchodilation, the mechanism of which remains controversial.12 Changes in airway tone with exercise, although small, are important, as it allows for a large increase in ventilation without significant increases in airway resistance. Previous authors2 have suggested that changes in airway tone with exercise occur mainly due to vagal withdrawal, while others13 suggest this is primarily catecholamine mediated through the ß2-adrenergic receptor (ß2AR). Although the reported bronchodilation during exercise in healthy subjects can be variable, the result is a beneficial reduction in the flow-resistive work and oxygen cost of breathing.24567

The ß2AR is a G protein-coupled receptor found in airway smooth muscle from the trachea to the alveoli.8 On catecholamine stimulation, the receptor goes through a conformational change that leads to an increase in cyclic adenosine monophosphate, which in turn activates protein kinase A. Protein kinase A transfers the terminal phosphate group of adenosine triphosphate to several target proteins, which leads to muscle relaxation.9 The ß2AR is polymorphic. Specifically, an arginine -> glycine substitution at codon 16 and a glutamine -> glutamate substitution at codon 27 have been described.101112 Significant linkage disequilibrium exists between these sites so that typically when arginine is present at position 16 only glutamine is found at position 27.131415 In vivo, a study16 in humans suggests that the homozygous Arg16Gln27 haplotype may be associated with an agonist-promoted desensitization in the venous circulation. Specifically, Gly16 homozygotes tend to show augmented blood flow when ß-agonists are given in the brachial artery.16

The influence of the polymorphisms of the ß2AR on airway function is controversial, and studies1415171819 have primarily been limited to the asthmatic population. Responses observed in airway smooth muscle may also differ from those observed in blood vessels. Previously, Summerhill et al20 found among Hutterites, that individuals homozygous for the Arg16 allele were found to have normal, although reduced, lung function relative to adults homozygous for the Gly16 allele. These differences were not observed in children, suggesting the Arg16Gly polymorphism may influence the rate of decline in lung function with aging.20

The focus of the present study was to determine if common polymorphisms of the ß2AR differentially influence airway tone during and after short-term exercise in healthy subjects without asthma. We hypothesized that subjects with homozygous Arg16 would have an attenuated bronchodilatory response at exercise intensities that induce catecholamine release (> 50% maximum workload).

Materials and Methods

Subjects
The protocol was reviewed and approved by the Mayo Clinic Institutional Review Board, and all participants signed informed consent before entering the study. Age-, gender-, and activity-matched subjects were recruited from an existing pool of subjects who had previously been genotyped for the ß2AR as a part of a large study13 of the genetic associations with BP. Forty-two individuals who were homozygous for arginine (Arg16, n = 16) or glycine (Gly16, n = 26) at codon 16, and had no exclusion criteria (cardiopulmonary abnormalities, pregnancy, inability to exercise) agreed to participate. All subjects were healthy nonsmokers, without asthma, and were not receiving any medications.

Protocol
Before performing the exercise protocols, subjects underwent baseline pulmonary function testing, an incremental cycle ergometry test to exhaustion, a CBC count (CBC, to rule out anemia), and in women a pregnancy test. The pulmonary function testing included postbronchodilator measures (albuterol) to assess baseline differences between genotypes in airway response to a ß-agonist, and were determined according to current American Thoracic Society recommendations.21 The baseline exercise study served as an initial familiarization session, was used to determine work intensities for subsequent sessions, and acted as a screening study to rule out ischemia and/or abnormal arrhythmias. Following these initial studies, subjects met with the General Clinical Research Center (GCRC) nutritionist and were put on a salt-neutral diet (3,450 mg/d) for 3 days with a 24-h urine collection to confirm sodium intake. A salt-neutral diet was used because previous studies2223 have suggested that the ß2AR may be sodium sensitive. Subjects subsequently returned to the GCRC on two occasions for exercise testing.

The next session consisted of a cycle ergometry test similar to the first visit. However, during this second study, classical gas exchange measures were collected and subjects also were instructed to perform maximal expiratory flow volume (MEFV) maneuvers at rest and over the last 30 s of each work level (every 2 min). Since most subjects were unfamiliar with the MEFV maneuver, this session served primarily as further familiarization with the measurements to be made on the final study day.

On the last visit, subjects exercised for 9 min at 40% and 9 min at 75% of their peak workload achieved during the initial exercise studies while gas exchange measurements were made and MEFV maneuvers were performed. During this session, a catheter was placed in the radial artery for sample collection taken just prior to performing the MEFV maneuvers for subsequent determination of catecholamines. The workloads of 40% and 75% of peak work were chosen in order to assess airway changes at a work intensity at which minimal catecholamine release would occur (< 50% maximum work) vs a work intensity at which substantial catecholamine release would be expected.

Data Collection
Blood Analysis: ß2AR genotyping was polymerase chain reaction (PCR) based according to methods of Bray et al.13 Buffy coat, obtained from whole blood collected on ethylenediamine tetra-acetic acid, was extracted (Gentra Pure DNA isolation kit; Gentra Systems; Minneapolis, MN). Following extraction, DNA was treated with a proteinase K solution in preparation for PCR. The PCR reaction was conducted according to standard methods, using the following primer sequences (eg, for Arg16Gly): (forward) 5'-AGC CAG TGC GCT TAC CTG CCA GAC-3' (at –32) and (reverse) 3'-CA TGG GTA CGC GGC CTG GTG CTG CAG TGC –5', resulting in a PCR product 107 base-pairs (bps) in length. After initial denaturation at 94°C for 4 min, the fragments were amplified by 35 cycles of 1 min at 94°C, 1 min at 61°C, 1 min at 72°C, followed by 5 min at 72°C and 5 min at 98°C. The amplicons were then digested by exposure to 5 U of the restriction enzyme KpnI, followed by electrophoretic separation on 3% aragose gels, staining with ethidium bromide and visualization using ultraviolet light. The Arg16 homozygous genotype is represented by a single 107-bp band; the Arg16/Gly16 group is represented by 25-, 82-, and 107-bp bands; and the Gly16 homozygous group is represented by 82-bp and 260-bp bands.

Cardiopulmonary Assessment During Exercise: Measurements of oxygen uptake (VO2) and the elimination of carbon dioxide were measured continuously during the various exercise tests and stages using a metabolic cart (Medical Graphics; St. Paul, MN) interfaced with a mass spectrometer (Perkin Elmer; Wellesley, MA). This system has been validated against classic "bag" collection techniques, and stability is verified by regular testing at standard exercise intensities by laboratory personnel.24

Catecholamines (epinephrine and norepinephrine) were assessed according to methods developed in the Mayo Clinic GCRC immunochemical core laboratory and the methods of Sealey.25 For our laboratory, intraassay coefficient of variations (CVs) are as follows: norepinephrine, 4.5% and 3.3% at 224 pg/mL and 429 pg/mL; and epinephrine, 12.2% and 3.6% at 13.8 pg/mL and 242 pg/mL, respectively. Interassay CVs are as follows: norepinephrine, 8.2% and 6.3% at 337 pg/mL and 533 pg/mL; and epinephrine, 8.5% and 6.3% at 179 pg/mL and 390 pg/mL, respectively.

At rest, during exercise, and then in the recovery period, subjects performed inspiratory capacity maneuvers followed by a MEFV maneuver. From the MEFV maneuver, maximal expiratory flow after 50% of the vital capacity (VC) [FEF50] has been expired was determined. To determine FEF50, MEFV curves were aligned at total lung capacity (maximal inflation volume) with the reference VC from the best pre-exercise maneuver, so that the data were analyzed at a consistent lung volume (isovolume FEF50). The FEF50 was chosen as the primary index of airway function, since this point along the maximal expiratory curve is in the effort-independent portion, does not require a sustained maximal effort for > 1 s, and because it is more responsive to change after an inhaled ß-agonist than FEV1. FEF50 is also a point along the expiratory flow curve where subjects commonly breathe with heavy exercise. We have previously observed changes in the maximal expiratory flow rates over the mid-to-lower lung volumes combined with mild hyperinflation in patients with asthma during exercise, while no or minimal changes were observed in FEV1.7 In repeat measurements performed in our laboratory on 10 healthy subjects at rest and during exercise, the FEF50 was found to have CVs of 2.6% and 3.6%, respectively.

The MEFV data were obtained on a separate mouthpiece and heated pneumotachograph (Hans Rudolph; Kansas City, MO) measurement system as previously described.726 Pre-exercise MEFV maneuvers were performed until two maneuvers were obtained that resulted in FVC and FEV1 values that differed by < 5%.

Statistical Analysis
The demographic data were examined using independent t tests with an {alpha} = 0.05. We used analysis of variance to examine differences in the primary outcome measure, FEF50 (SPSS; Chicago, IL). An analysis of covariance was also performed between the groups with epinephrine as the covariate and FEF50 as the dependent variable. Prior to beginning the study, and based on previous data from our laboratory on measures of FEF50 at rest and during exercise (and the changes observed with exercise), we estimated that we could detect a difference between genotype groups (homozygous Arg16 vs Gly16) for the percentage change from baseline of 3.5% with n = 16 and n = 26, respectively, for the groups with 85% power.6727

Results

Subject Characteristics
Subject characteristics did not differ significantly between genotype groups (Table 1 ). Baseline pulmonary function did not differ between the groups, although absolute lung volumes and flow rates tended to be slightly higher in the Gly16 subjects relative to the Arg16 subjects. Both groups of subjects demonstrated small but significant increases in FEF50 and the average forced expiratory flow over the middle portion of the vital capacity (FEF25–75) with the inhaled ß-agonist (p < 0.05). No significant differences, however, were observed between groups: FEV1, + 4.0 ± 1.1% vs + 4.0 ± 1.0%; FEF50, + 14.0 ± 5.0% vs + 15.0 ± 2.0%; and FEF25–75, + 18.3 ± 4.2 vs + 16.6 ± 3.0% for the Arg16 and Gly16 groups, respectively.


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  		Table 1.. Subject Characteristics, Baseline Pulmonary Function, and Maximal Exercise Data According to Genotype*

 
Ventilatory Responses During Exercise
Both groups exercised at similar workloads (38 ± 2% vs 36 ± 6% and 75 ± 4% vs 75 ± 6% of peak work for the Arg16 and Gly16 groups, respectively, and percentages of their peak VO2 (Table 2 ) during low- and high-intensity exercise. The Arg16 subjects tended to have a more tachypneic ventilatory response with a lower tidal volume (VT) than the Gly16 subjects, particularly at the higher exercise intensity, even when normalized for VC (p < 0.01), while respiratory rate was faster at rest and throughout exercise (p < 0.01). Inspiratory capacity, expressed as a percentage of pre-exercise FVC, was significantly higher, indicating a lower end-expiratory lung volume in the Gly16 subjects at 40% and 75% of maximal work (69% vs 65% of FVC at both work intensities in the Gly16 vs Arg16 groups, respectively; p < 0.05).


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  		Table 2.. Ventilatory Response to Exercise According to ß2AR Genotype*

 
Catecholamine Response to Exercise
Figure 1 shows the changes in arterial levels of epinephrine and norepinephrine during low- and high-intensity exercise as well as during recovery (expressed as the percentage change from rest). No significant differences were observed between groups, although the Arg16 subjects tended to have a greater increase in epinephrine than the Gly16 subjects (p = 0.07).


Figure 1
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  		Figure 1.. Epinephrine (Epi) and norepinephrine (NorEpi) response to exercise. The dashed lines represent the Arg16 group, while the solid lines represent the Gly16 group (values are mean ± SE). The lines with the black circular bullets (•) represent epinephrine, while the lines with the gray square bullets ({blacksquare}) represent norepinephrine. Both groups had little change in epinephrine and norepinephrine at the lower workload. In contrast, both groups had marked increases in epinephrine and norepinephrine at the higher workload. Although the Arg16 group had higher epinephrine levels at the higher workload (p = 0.07), there were no significant differences between the groups. Max = maximum.

 
Airway Function During Exercise
Small changes were observed in FEF50 with low-intensity exercise in each genotype group (3 to 6%; p = 0.002 from rest). Both groups demonstrated similar increases in bronchodilation during heavy exercise (averaging 14% and 15% for the homozygous Arg16 and Gly16 subjects, respectively, over the last 3 min of exercise; p < 0.001, from rest), and there were no statistically significant differences between the Arg16 and Gly16 groups in the degree of bronchodilation (Fig 2 ). During the recovery period, at 5 min and 10 min after exercise, both groups had a decrease in FEF50, but the FEF50 returned to baseline or below in 12 of 16 Arg16 subjects, while 20 of 26 Gly16 subjects had sustained, mild bronchodilation (p < 0.001). The FEF25–75 showed similar changes during and after exercise, with the Arg16 subjects falling to near baseline values (– 0.72 ± 2.8%), while the Gly16 subjects had a sustained increase (+ 8.0 ± 2.4%) at 10 min after exercise.


Figure 2
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  		Figure 2.. Percent change in FEF50 during exercise and recovery. The dashed line represents the Arg16 group, while the solid line represents the Gly16 group (values are mean ± SE). Both had small increases in FEF50 at the lower workload (p = 0.002, from rest). At the higher workload, both groups had further increases in FEF50 (p < 0.001, from rest); however there were no significant differences between the groups. During recovery, FEF50 in the Arg16 group quickly returned to baseline, while in the Gly16 group FEF50 tended to remain elevated (p < 0.001).

 
Influence of Position 27 of the ß2AR
We performed a post hoc subanalysis of the changes in FEF50 during exercise and recovery based on position 27 of the ß2AR (Table 3 ). All Arg16 subjects were homozygous for glutamine at position 27, creating an Arg16/Gln27 homozygous haplotype. Of the Gly16 homozygotes, 6 homozygotes (23%) were homozygous for glutamine (Gly16/Gln27), 11 homozygotes (42%) were homozygous for glutamate (Gly16/Glu27), and 9 homozygotes (35%) were heterozygous (Gly16Gly/Gln27Glu). While the group numbers were too small for any meaningful statistical analysis, the homozygous Gly16/Gln27 haplotypes tended to have the largest changes in FEF50 with heavy exercise, followed by the Gly16Gly/Gln27Glu group, then the Arg16/Gln27 haplotype, and finally the Gly16/Glu27 haplotype. None of the differences that were observed at 5 min and 10 min of recovery could be explained by position 27.


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  		Table 3.. Percentage Change in FEF50 During Exercise and Recovery According to Positions 16 and 27 of the ß2AR*

 
Discussion

The focus of our study was to examine the influence of variation in the ß2AR gene at codon 16 on the airway responses to exercise in young, healthy adults. We found that the degree of bronchodilation with light- and heavy-intensity exercise was similar between the homozygous Arg16 and Gly16 subjects. However, during the recovery period, the maximal expiratory flow rates in the Arg16 subjects rapidly returned to or fell below baseline values, while the homozygous Gly16 subjects demonstrated a sustained elevation in FEF50 (over pre-exercise values).

Airway Responses to Exercise
A number of previous studies572728 have demonstrated exercise-related bronchodilation in healthy adults. In the present study, we noted a small rise in FEF50 (3 to 6%) during light exercise with a tendency for the Gly16 subjects to have a greater response. This occurred at a time when catecholamine levels were essentially unchanged from baseline. Thus, it is unlikely that the observed changes with light exercise were due to stimulation of the ß2AR unless there are noncatecholamine-mediated pathways that exist, such as a reported interaction between the muscarinic and the ß2ARs.29 The fact that there were only small changes in FEF50 with light exercise suggests that release of vagal tone likely plays little role in the bronchodilation of exercise given this occurred at a time when vagal withdrawal should have been prominent.30

With heavier exercise, we noted a gradual rise in FEF50 for both groups over the 9-min workload, increasing 14% and 15% by the end of exercise for the Arg16 and Gly16 subjects, respectively. Previously, we observed similar, or greater, increases in FEF50 with noticeable variability in the changes in airway tone with exercise among healthy subjects, suggesting that genetic variation may play a role.4627 In addition, the degree of bronchodilation appeared to be intensity dependent. In the present study, the marked increase in catecholamines, paralleling the changes in airway function, suggest this is mediated through the ß2AR, although in the short duration of catecholamine exposure, there was not a clear genotype related difference.

ß2AR, Lung Function, and Genetic Polymorphisms
ß2ARs in the lungs are found to be densely distributed over the airway epithelium and alveolar walls.83132 The ß2AR is a G protein-coupled receptor that has been shown to lead to bronchodilation in response to a ß-agonist.33 Infusion of epinephrine at levels that are similar to those seen during exercise leads to bronchodilation when compared to placebo.28

The coding region of the ß2AR demonstrates multiple sites of polymorphic variation such as positions 16, 27, and 164.14 Positions 16 and 27 have been studied extensively both in vitro and in vivo.1214163435 In vitro, the most impaired polymorphic receptor appears to be due to a threonine to isoleucine change at amino acid 164. However, the heterozygous condition at amino acid 164 occurs in < 5% of the normal population, and the homozygous Ile164 has not been observed in large samples from the general population.15 In the present study, we chose to examine the effects of exercise on airway function in the Arg16Gly polymorphism, since it is commonly found in the population and also appears to be functionally important.12163435 Due to linkage disequilibrium, all homozygous Arg16 subjects in the present study were also homozygous for glutamine at position 27, while position 27 varied (homozygous for glutamine or glutamate, or heterozygous) in the homozygous Gly16 subjects. This is in agreement with previous reports1334363738 regarding the interaction of these polymorphisms.

The most notable difference between genotype groups in the present study was the rapid decline in FEF50 in the Arg16 subjects relative to the sustained elevation in FEF50 in the Gly16 subjects during recovery. This potential genotype effect is consistent with previous studies163435 in the peripheral circulation that have suggested that the Gly16 polymorphism is more resistant to vascular desensitization than the Arg16 polymorphism, and in the airways where long-term use of an inhaled ß-agonist leads to greater desensitization in the Arg16 genotype when compared to Gly16.39 Other studies examining ß2AR desensitization, however, have been contradictory. In particular, in vitro work by Green et al1011 suggested that when the glycine amino acid is present at position 16, there is enhanced down-regulation of the ß2AR.11 Desensitization of G protein-coupled receptors is a time-dependent process that is initiated on binding to an agonist.40 There are several mechanisms proposed for desensitization of the ß2AR, including the uncoupling of receptors (short-term exposure to a ß-agonist) and sequestration of the receptors into the cell that can lead to degradation of the receptor (long-term exposure to a ß-agonist).40

Interestingly, the difference between the Arg16 and Gly16 genotypes in FEF50 occurred during a time when catecholamines were rapidly returning to baseline after the airway ß2ARs had been exposed to catecholamines for 10 to 15 min (exercise plus early cool down). This may suggest that significant in vivo desensitization takes between 9 min and 15 min to occur. Garovic et al35 infused a ß-agonist (isoproterenol) at increasing concentrations and measured changes in forearm blood flow in Arg16 and Gly16 homozygotes. They found that the Arg16 group had smaller increases in forearm blood flow but did not observe a significant difference between the groups until 6 to 12 min of infusion.35

Although a difference in FEF50 between the groups was demonstrated during recovery from exercise, there were no significant differences between the groups in response to a single inhalation of a ß-agonist. All subjects followed a standard protocol, which included prebronchodilator spirometry, inhalation of albuterol, followed by a 10 to 15-min rest prior to repeat spirometry. Albuterol is a long-acting ß2-selective agonist that has been shown to lead to bronchodilation in a manner that is consistent with exercise-related catecholamine stimulation. The lack of difference between the groups with an inhaled ß2-agonist may be due to a slightly shorter time period prior to repeat spirometry (vs exercise), or possibly it is due to different mechanisms of action related to the large endogenous and constant infusion of catecholamines with exercise presumably through the bronchiole circulation vs the effects of a single breath of an inhaled ß-agonist.

Both groups had a similar increase in norepinephrine during exercise; however, the Arg16 subjects tended to have a more marked increase in epinephrine during the heavier workload, although not quite reaching significance (p = 0.07). It is possible that the higher epinephrine levels (the primary agonist for the ß2AR) may enhance the desensitization in the Arg16 subjects independent of a genotype effect. Both groups did exercise at similar percentage of peak work, for similar time periods, and did not differ in regard to body weight (all factors that could influence epinephrine release). Further study would be needed to determine if there may truly be a genotype-related difference in epinephrine release and if differences in circulating catecholamines may have contributed to the observed differences in expiratory flow after exercise between the groups.

Study Limitations
We only investigated the role of a single-nucleotide polymorphism (SNP) on physiologic function. Previous work by Drysdale and colleagues14 sequenced the entire ß2AR in a large population of asthmatics. They subsequently grouped the SNPs according to haplotypes; and while no SNP was associated with response to a ß-agonist, combinations of SNPs grouped according to haplotype pairs did predict ß-agonist responsiveness.14 Thus, it is possible that grouping subjects according to ß2AR haplotype may more accurately predict the airway changes during and after exercise. Other studies164142 have suggested that position 27 may also play a role in modulating receptor function. When we examined the influence of variation at position 27, the homozygous Gly16/Gln27 haplotype tended to have the largest changes in FEF50 during heavy exercise, followed by the Gly16Gly/Gln27Glu combination, the homozygous Arg16/Gln27 group, and finally the homozygous Gly16/Glu27 haplotype, suggesting that Gln at position 27 may be more catecholamine sensitive. However, none of the differences that were observed at 5 min and 10 min of recovery could be explained by position 27. Another limitation of this study was the small sample size in light of the inherent difficulties in identifying subtle changes in airway tone both during and in the recovery phase of exercise in healthy adults and the likely small influence of common polymorphisms of the ß2AR on airway smooth-muscle function.

In conclusion, we found that healthy subjects homozygous for Arg16 or Gly16 of the B2AR had similar bronchodilatory responses during short-duration exercise. However, the airway tone in Arg16 subjects returned to baseline rapidly after exercise, while Gly16 subjects maintained sustained bronchodilation, as measured by FEF50. This suggests that subjects homozygous for the Arg16 polymorphism have enhanced desensitization of the B2AR. This may have implications in the study of exercise-induced bronchospasm and the response to exercise in patients with asthma, in whom changes in airway function are most prominent after exercise.

Acknowledgements

We thank Kathy O’Malley and Angela Tarara for help with data collection, Renee Blumers for help with manuscript preparation, and the study participants for their efforts. We would also like to thank the staff of the GCRC for their assistance throughout this study, and Dr. Robert E. Hyatt for valuable discussions concerning the manuscript.

Footnotes

Abbreviations: ß2AR = ß2 adrenergic receptor; bp = base-pair; CV = coefficient of variation; FEF25–75 = forced expiratory flow at 25 to 75% of vital capacity; FEF50 = forced expiratory flow at 50% of vital capacity; GCRC = General Clinical Research Center; MEFV = maximal expiratory flow volume; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; VC = vital capacity; VO2 = oxygen uptake; VT = tidal volume

This work was supported by National Institutes of Health grants HL71478, HL63328, HL 54464, HL53330, and American Heart Association grant 56051Z.

The Mayo Clinic GCRC is supported by US Public Health Service grant M01-RR00585.

Received for publication June 15, 2004. Accepted for publication August 18, 2005.

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E. M. Snyder, S. T. Turner, and B. D. Johnson
{beta}2-Adrenergic Receptor Genotype and Pulmonary Function in Patients With Heart Failure.
Chest, November 1, 2006; 130(5): 1527 - 1534.
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