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J Appl Physiol 96: 526-530, 2004; doi:10.1152/japplphysiol.00498.2003
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{beta}2- and {beta}3-Adrenergic receptor polymorphisms and exercise hemodynamics in postmenopausal women

Steve D. McCole,1,2 Alan R. Shuldiner,5,6 Michael D. Brown,1,3 Geoffrey E. Moore,1 Robert E. Ferrell,4 Kenneth R. Wilund,3 Andrea Huberty,7 Larry W. Douglass,7 and James M. Hagberg1,3

1Division of Cardiology, University of Pittsburgh, Pittsburgh 15213; 4Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261; 2Department of Exercise Science and Physical Education, McDaniel College, Westminster 21157; 3Department of Kinesiology and 7Biometrics Program, Department of Animal and Avian Sciences, University of Maryland, College Park 20742; 5Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, and 6Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration, Baltimore, Maryland 21201

Submitted 12 May 2003 ; accepted in final form 22 September 2003


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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We sought to determine whether common genetic variations at the {beta}2 ({beta}2-AR, Gln27Glu) and {beta}3 ({beta}3-AR, Trp64Arg) adrenergic receptor gene loci were associated with cardiovascular (CV) hemodynamics during maximal and submaximal exercise. CV hemodynamics were assessed in 62 healthy postmenopausal women (20 sedentary, 22 physically active, and 20 endurance athletes) during treadmill exercise at 40, 60, 80, and 100% maximal O2 uptake using acetylene rebreathing to quantify cardiac output. The {beta}2-AR genotype and habitual physical activity (PA) levels interacted to significantly associate with arteriovenous O2 difference (a-vDO2) during submaximal exercise (P = 0.05), with the highest submaximal exercise a-vDO2 in sedentary women homozygous for the {beta}2-AR Gln allele and no genotype-dependent differences in submaximal exercise a-vDO2 in physically active and athletic women. The {beta}2-AR genotype also was independently associated with a-vDO2 during submaximal (P = 0.004) and ~100% maximal O2 uptake exercise (P = 0.006), with a 1.2-2 ml/100 ml greater a-vDO2 in the Gln/Gln than in the Glu/Glu genotype women. The {beta}3-AR genotype, independently or interacting with habitual PA levels, was not significantly associated with any CV hemodynamic variables during submaximal or maximal exercise. Thus it appears that the {beta}2-AR genotype, both independently and interacting with habitual PA levels, is significantly associated with a-vDO2 during exercise in postmenopausal women, whereas the {beta}3-AR genotype does not appear to be associated with any maximal or submaximal exercise CV hemodynamic responses in postmenopausal women.

cardiac output; blood pressure; stroke volume; heart rate; genetics

A NUMBER OF COMMON POLYMORPHIC genetic variations, particularly those in the renin-angiotensin system, are related to pathologies within the cardiovascular (CV) system (5, 24). Some recent evidence indicates that common polymorphic genetic variations within the sympathetic nervous system (SNS) may also associate with CV pathologies (10, 15, 25, 26, 28) and with CV physiological function (4, 8). The SNS is critical in regulating the CV hemodynamic responses during stress, especially exercise. However, it is not known whether common genetic variations that may affect SNS activity associate with CV hemodynamics during submaximal or maximal exercise.

We selected the common Gln27Glu {beta}2-adrenergic receptor ({beta}2-AR) variant as one locus of primary interest, because {beta}2-ARs are intimately involved in the regulation of peripheral vascular smooth muscle tone and, therefore, could directly affect total peripheral resistance (TPR) and indirectly affect exercise blood pressure (BP) and stroke volume (SV), cardiac output (), heart rate (HR), and arteriovenous O2 difference (a-vDO2). This variant has been found to associate with altered peripheral blood flow regulation (4). We also selected the Trp64Arg {beta}3-adrenergic receptor ({beta}3-AR) variant for study, because although the {beta}3-AR is thought to be primarily involved in the regulation of metabolic processes (11, 16), {beta}3-ARs are found in the heart, and the Trp64Arg variant has been found to associate with hypertension and BP independent of its metabolic effects (26, 28).

Therefore, our working hypothesis was that common genetic variations at the {beta}2-AR and {beta}3-AR gene loci would associate with CV hemodynamics during submaximal and maximal exercise. Specifically, we hypothesized that women homozygous for the Gln27 {beta}2-AR allele would have higher HR, SV, , systolic and diastolic BP, and TPR and lower a-vDO2 during submaximal and maximal exercise than women with other Gln27Glu {beta}2-AR genotypes. We also specifically hypothesized that women carrying the Arg64 {beta}3-AR allele would have higher HR, SV, , systolic and diastolic BP, and TPR and lower a-vDO2 during submaximal and maximal exercise than women homozygous for the Trp64 {beta}3-AR allele. Because SNS function is markedly affected by endurance exercise training (29, 30), we also hypothesized that these common {beta}2-AR and {beta}3-AR polymorphic variations would interact with habitual physical activity (PA) level to associate with CV hemodynamics during submaximal and maximal exercise. We addressed this hypothesis by studying subjects with markedly different habitual PA levels.


   METHODS
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 ABSTRACT
 METHODS
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Sixty-two healthy postmenopausal Caucasian women were recruited to participate in the study. Women were considered postmenopausal if they had elevated levels of follicle-stimulating and luteinizing hormones and reported a lack of menses for >2 yr. Women were grouped into three PA categories (sedentary, physically active, and endurance athlete) on the basis of their habitual PA history as defined previously (6). Briefly, women were classified as "sedentary" if they were not regularly performing aerobic exercise. "Physically active" women were accumulating >=90 min of aerobic exercise during at least three exercise sessions per week. Women were classified as "athletes" if they were training vigorously for competition in endurance events. Approximately half of the women in each group were on hormone replacement therapy (HRT). The PA and HRT status of all subjects had been constant for >2 yr before the study. The Institutional Review Board of the University of Pittsburgh approved the study, and all subjects provided their written informed consent before they were subjected to testing.

Sedentary and physically active subjects underwent a screening graded maximal exercise test to exclude those with evidence of CV disease (19). Sedentary and physically active women with no evidence of CV disease performed a second graded maximal treadmill exercise test to measure maximal O2 uptake (O2 max) (19). Endurance athletes completed a single graded maximal treadmill exercise test for screening and O2 max measurement. BP, HR, and ECG were monitored before, during, and after each test. O2 uptake (O2) was measured continuously during all exercise tests using a respiratory mass spectrometer (Marquette), mixing chamber (Rayfield), turbine volume meter system (model VMM, Interface Associates), and customized validated metabolic software (19). Exercise continued until the subject reached exhaustion or showed signs or symptoms of CV decompensation. Subjects not reaching standard criteria to determine that a true O2 max was achieved repeated the test until these criteria were exceeded (19). Body composition was determined with dual-energy X-ray absorptiometry (model DPX-L, Lunar, Madison, WI).

was measured by acetylene rebreathing after ~6 min of treadmill exercise at 40, 60, and 80% O2 max and during the last minute of an exercise bout designed to elicit O2 max in ~6 min (19). SV was determined by dividing by HR measured via ECG just before the rebreathing maneuver. O2 was monitored throughout each exercise bout, and a-vDO2 was calculated by dividing O2 by . TPR was calculated as mean arterial pressure (MAP) divided by , with MAP estimated as diastolic BP + 1/3 * (systolic BP - diastolic BP) based on BP measured by auscultation immediately preceding each determination. The independent associations between exercise hemodynamics, habitual PA levels, and HRT have been published previously (18, 19). In these previous studies, HRT was not associated with different CV hemodynamic responses to exercise, and the data from the women on HRT and those not on HRT are pooled in this study.

DNA was isolated from peripheral venous blood samples from all subjects using standard procedures (20). DNA from each subject was typed for the Gln27Glu {beta}2-AR (14) and Trp64Arg {beta}3-AR (27) variants using standard procedures.

For each dependent variable (systolic and diastolic BP, HR, , SV, TPR, and a-vDO2), we conducted a mixed-model repeated-measures factorial ANOVA (SAS online version 8.1, 1999). The three levels of PA and the genotypes at the {beta}2-AR and {beta}3-AR loci form the factorials, and each subject was measured for each dependent variable at 40, 60, 80, and ~100% O2 max, resulting in four repeated measures. Random effects included variation among subjects, covariance among repeated measures, and the residual variation within subjects. Different covariance structures were used to fit the correlation between repeated measures (exercise intensity) within subject, and the best-fitting variance-covariance structure was chosen using the Bayesian information criterion. If the ANOVA model was significant for a genotype or genotype-by-habitual PA level interaction effect, contrasts were conducted for appropriate means comparisons among genotypes using t probabilities to identify significant differences. The Kenward-Roger degrees-of-freedom method was used. Each model and dependent variable also adequately met the assumptions of variance homogeneity and normality. Because not all trials yielded technically valid results, the sample sizes for the different CV hemodynamic variables during exercise vary somewhat; these sample sizes are included in Tables 3 and 4, where these results are presented. P < 0.05 was considered statistically significant. Least squares means ± SE are reported correcting for any unequal replication; the least squares means for submaximal exercise are those averaged across the 40, 60, and 80% O2 max exercise intensities.


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  		Table 3. Exercise CV hemodynamics as a function of {beta}2-AR genotype

 


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{beta}2-AR genotype distribution. As we previously reported (21), {beta}2-AR allele and genotype distributions in this group were similar to previously reported distributions in larger populations (9) (Table 1). However, as we reported previously (21), when stratified by the level of PA, frequency of the {beta}2-AR Glu/Glu genotype was lower than expected in the athletic group. The sedentary and physically active women exhibited genotype distributions similar to those reported previously.


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  		Table 1. {beta}2-AR and {beta}3-AR allele and genotype distributions in study population and general population

 

{beta}2-AR genotype and subject characteristics. There were no significant differences in age, weight, height, or maximum HR among {beta}2-AR genotype groups (Table 2). There were significant differences in O2 max and percent body fat among the {beta}2-AR genotype groups. However, when the lower-than-expected frequency of the {beta}2-AR Glu/Glu genotype in the athletes was considered in the statistical analysis, the differences for O2 max and percent body fat among the {beta}2-AR genotype groups were no longer significant.


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  		Table 2. Subject characteristics, O2max, and maximal HR as a function of {beta}2-AR and {beta}3-AR genotype

 

{beta}2-AR genotype and ~100% O2 max hemodynamics. Tests of the interaction between {beta}2-AR genotype and PA levels were not significant for any of the measured CV hemodynamic variables during ~100% O2 max exercise (Table 3). However, the interaction between {beta}2-AR genotype and PA levels approached statistical significance for diastolic BP (P = 0.07). The {beta}2-AR genotype was independently and significantly associated with a-vDO2 during ~100% O2 max exercise, with the Gln/Gln genotype women having a 2 ml/100 ml greater a-vDO2 than the Glu/Glu genotype women. {beta}2-AR was not independently and significantly associated with any other CV hemodynamic variable during maximal exercise.

{beta}2-AR genotype and submaximal exercise hemodynamics. The interaction between {beta}2-AR genotype and PA levels was significant for a-vDO2 during submaximal exercise, with {beta}2-AR Gln homozygotes having the highest submaximal exercise a-vDO2 among sedentary women (11.9 ± 0.3, 10.3 ± 0.4, and 9.9 ± 0.6 ml/100 ml for {beta}2-AR Gln/Gln, Gln/Glu, and Glu/Glu, respectively) and there being no genotype-dependent differences in submaximal exercise a-vDO2 among physically active (12.5 ± 0.4, 11.9 ± 0.4, and 11.4 ± 0.9 ml/100 ml for {beta}2-AR Gln/Gln, Gln/Glu, and Glu/Glu, respectively) and athletic (11.9 ± 0.4 and 12.1 ± 0.3 ml/100 ml for {beta}2-AR Gln/Gln and Gln/Glu, respectively) women. The {beta}2-AR genotype was also independently and significantly associated with submaximal exercise a-vDO2, with a 1.2 ml/100 ml higher submaximal exercise a-vDO2 in the {beta}2-AR Gln than in the Glu homozygotic women (Table 3).

{beta}3-AR genotype, subject characteristics, and exercise hemodynamics. No women in the present study were homozygous for the variant Arg64 {beta}3-AR allele; thus comparisons could only be made between heterozygotes and those homozygous for the common Trp64 {beta}3-AR allele (Table 1). The distributions of {beta}3-AR alleles and genotypes in the total population and in each of the three PA groups in the present study are similar to those reported in larger population studies (27, 28). The overall distribution also is in Hardy-Weinberg equilibrium.

Age, body weight, height, percent body fat, and maximum HR did not differ between the two {beta}3-AR genotypes (Table 2). O2 max, whether expressed in liters per minute or milliliters per kilogram per minute, was significantly higher in the {beta}3-AR heterozygous than in the {beta}3-AR Trp allele homozygous women. However, because of the lack of Arg alleles in the sedentary women, when habitual PA level was included in the analyses, these genotype-dependent differences in O2 max were no longer significant.

{beta}3-AR genotype and exercise hemodynamics. The interactions between {beta}3-AR genotype and PA levels were not significant for any of the measured CV hemodynamic variables during ~100% O2 max exercise. However, the interaction between {beta}3-AR genotype and PA levels approached the level of statistical significance for a-vDO2 during 100% O2 max exercise (P = 0.06). The {beta}3-AR genotype was not independently associated with any of the maximal exercise CV hemodynamic variables measured in the present study (data not shown). No significant interactions between {beta}3-AR genotype and PA levels affected CV hemodynamics during submaximal exercise. Furthermore, {beta}3-AR genotype did not independently associate with any of the CV hemodynamic measures during submaximal exercise (data not shown).


   DISCUSSION
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 ABSTRACT
 METHODS
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GRANTS
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The present results indicate that a common variant at the {beta}2-AR locus is independently associated with a-vDO2 during maximal and submaximal exercise in postmenopausal women. Furthermore, this variant also interacts with habitual PA levels to significantly associate with a-vDO2 during submaximal exercise. However, a common variant at the {beta}3-AR locus does not appear to associate independently or interactively with habitual PA levels with CV hemodynamic responses to maximal or submaximal exercise in postmenopausal women. We had initially hypothesized that both of these variants would be associated with alterations in a number of CV hemodynamic responses to submaximal and maximal exercise intensities. However, only a-vDO2 was independently and interactively associated with {beta}2-AR genotype. Adding strength to this relation is the fact that a-vDO2 was related to {beta}2-AR genotype in two separate analyses at submaximal and maximal exercise, making it more likely that this is a true positive finding.

A 1997 review by Bouchard et al. (3) indicated that genetic factors play a significant and substantial role in determining CV hemodynamics at rest and during submaximal exercise. Others reported 24-47% heritabilities of a variety of exercise hemodynamic parameters (2). Recently, the HERITAGE study found 40-45% heritabilities of submaximal exercise SV and in ~100 Caucasian two-generation families (1). Landry et al. (13) reported that exercise hemodynamic adaptations with exercise training were more similar in monozygotic than in dizygotic twins. The HERITAGE study also recently found 24-38% heritabilities of submaximal exercise SV and adaptations with endurance exercise training (1).

More recent investigations have assessed the impact of specific common allelic variants within the renin-angiotensin-aldosterone system, most notably the angiotensin-converting enzyme (ACE) insertion/deletion and the M235T angiotensinogen (AGT) variants, on a limited number of CV hemodynamic variables during exercise (12, 22, 23). These previous studies generally assessed genotype-dependent associations with CV hemodynamic responses to the same absolute submaximal exercise work rates among individuals. Such a design does not account for the known and substantial effect of relative exercise intensity on CV hemodynamic responses and may obscure genotype-dependent differences in CV hemodynamic responses to exercise. We previously reported that common variants of ACE and AGT were associated with the responses of several CV variables, in particular HR, during submaximal exercise at the same relative work rate and during maximal exercise in postmenopausal women (7, 17). The design of the present study was similar, inasmuch as we assessed the association between two variants at loci within the SNS and CV hemodynamic responses to exercise at a number of work rates matched for relative exercise intensity across subjects.

{beta}2-AR variants have previously been found by others to relate to BP and the prevalence of hypertension (10, 25). We did not find a similar relation with BP during submaximal or maximal exercise in the postmenopausal women in the present study. SNS function at rest and during submaximal and maximal exercise is markedly affected by endurance exercise training (29, 30). Thus it might be expected that the {beta}2-AR genotype would interact with substantially different habitual PA levels to affect CV hemodynamics during exercise. However, there were no significant interactions during maximal exercise in the present study. The only statistically significant interaction during submaximal exercise affected a-vDO2 (P = 0.05) such that genotype-dependent differences only occurred in the sedentary postmenopausal women, with a higher a-vDO2 in the Gln than the Glu homozygotes.

We had anticipated that the effects of the {beta}2-ARs on vascular smooth muscle would directly affect TPR and, thereby, potentially affect a-vDO2 indirectly. However, we found that the {beta}2-AR genotype was associated with different a-vDO2 responses during submaximal and maximal exercise without significantly affecting TPR. The a-vDO2 was significantly greater in postmenopausal women who were homozygous for the Gln genotype than in those homozygous for the Glu genotype during maximal and submaximal exercise. Our ANOVA analyses assessed the independent effect of {beta}2-AR genotypes while also accounting for the independent effect of different habitual PA levels. Thus the smaller frequency of Glu homozygotes in the women athletes was accounted for when the independent effect of the {beta}2-AR genotype on these exercise hemodynamic responses was assessed. It is possible that the Gln27Glu {beta}2-AR variant may not directly underlie the genotype-dependent differences in exercise hemodynamic responses we observed in these women, inasmuch as some other marker in linkage disequilibrium with the Gln27Glu {beta}2-AR variant may actually be the allelic variant responsible for these different exercise hemodynamic responses.

{beta}3-ARs are primarily involved in adipocyte lipolysis and skeletal muscle thermogenesis (11, 16). However, Tonolo and coworkers (26) recently reported that this allelic variant was associated with hypertension, and we previously found a significant Trp64Arg {beta}3-AR genotype-dependent effect on BP in nondiabetic subjects (28). However, in the present study, we found no evidence that {beta}3-AR allelic variants, either independently or interactively with habitual PA levels, were associated with any of the CV hemodynamic responses during submaximal or maximal exercise.

Our previous studies with a number of statistically significant results have shown that the sample size used in the present study is sufficiently powerful to identify genetic markers with significant associations with CV hemodynamics during submaximal and maximal exercise (6, 7, 17). A number of previous analyses have been performed on these outcome phenotypes as a function of genotype, and it is possible that some of our findings may have been false-positive statistical relations. Also this study was not initially designed to address these genotype-dependent relations, and these analyses were performed in a retrospective fashion. One previous study in this population determined that women with the ACE II genotype had a 6.3 ml·kg-1·min-1 higher O2 max than women with the ACE DD genotype and that this difference was associated with genotype-dependent differences in a-vDO2 at maximal exercise (6). We also reported that these ACE variants are associated with many CV hemodynamic responses to submaximal exercise (7). In addition, we reported a number of significant associations between CV hemodynamic responses during submaximal and maximal exercise and the AGT polymorphism (17). Therefore, the relative lack of significant associations found with the {beta}2-AR genotype, except for a-vDO2, and the {beta}3-AR genotype in the present study suggests that they may not be strong candidates for future investigations attempting to identify the genetic markers underlying CV hemodynamic responses during exercise.

In conclusion, the a-vDO2 response to submaximal and maximal exercise in postmenopausal women was associated with the {beta}2-AR genotype, such that a-vDO2 was greater in women with the Gln/Gln genotype than in those homozygous for the Glu allelic variant. Variants at the {beta}3-AR locus, however, are not associated with changes in the CV hemodynamic response to exercise in these women.


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This research was supported by the grants from the American Association of Retired Persons-Andrus Foundation and the Pennsylvania Affiliate of the American Heart Association (J. M. Hagberg) and National Institutes of Health Grants AG-00268 (K. R. Wilund), HL-39107, HL-45778, and DK-46204 (R. E. Ferrell), and DK-02673 (A. R. Shuldiner). This research also was supported by University of Pittsburgh General Clinical Research Center NIH/NCRR/GCRC Grant 5MO1 RR-00056.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. M. Hagberg, Dept. of Kinesiology, Univ. of Maryland, College Park, MD 20742-2611 (E-mail: hagberg{at}umd.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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