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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1184-1187
Copyright © 2003 by The Endocrine Society

{alpha}2B-Adrenergic Receptor Deletion Polymorphism Associates with Autonomic Nervous System Activity in Young Healthy Japanese

Naoko Suzuki, Tetsuro Matsunaga, Kae Nagasumi, Tsubasa Yamamura, Nobuyuki Shihara, Toshio Moritani, Hidetoshi Ue, Mitsuo Fukushima, Akiko Tamon, Yutaka Seino, Kinsuke Tsuda and Koichiro Yasuda

Laboratories of Metabolism (N.Su., T.Ma., K.N., T.Y., N.Sh., A.T., K.T.) and Applied Physiology (T.Mo., H.U.), Kyoto University Graduate School of Human and Environmental Studies; Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine (M.F., Y.S., K.Y.); and Laboratory of Metabolism, Kyoto University Faculty of Integrated Human Studies (K.T., K.Y.), Kyoto 606-8501, Japan

Address all correspondence and requests for reprints to: Koichiro Yasuda, M.D., Laboratory of Metabolism, Kyoto University Faculty of Integrated Human Studies, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: yasuda{at}tom.life.h.kyoto-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Several polymorphisms of genes involved in autonomic nervous system (ANS) function have been reported to affect metabolic regulation. We have investigated the association of an {alpha}2B-adrenergic receptor ({alpha}2BAR) three-amino acid deletion polymorphism with ANS activity in young healthy subjects by means of electrocardiogram R-R interval power spectral analysis. Three hundred eighty-one young healthy Japanese males (mean ± SE, 20.6 ± 0.1 yr) were studied. One hundred sixty-eight (44.1%) were homozygotes of Long allele (Long/Long), 162 (42.5%) were heterozygotes (Long/Short), and 51 (13.4%) were homozygotes of Short allele (Short/Short). The allele frequency of Short allele was 0.35. No significant differences were observed in any of the characteristics investigated: body mass index, plasma glucose, plasma insulin, or family history of diabetes and obesity. In R-R spectral analysis of heart rate variability, carriers of Short/Short had significantly greater low frequency and very low frequency than Long/Long, as well as a higher sympathetic nervous system index. These findings suggest that the {alpha}2BAR deletion polymorphism might result in metabolic disorder by altering ANS function.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADRENERGIC RECEPTORS ARE principal components of the autonomic nervous system (ANS), mediating physiological responses to catecholamines. At least nine adrenergic receptors have been identified on the basis of their affinity for different pharmacological agents and divided into {alpha} and ß subtypes. A polymorphism of the ß3-adrenergic receptor (ß3AR) gene has been shown to be associated with diabetes and obesity (1, 2, 3). It also has been reported that a polymorphism of ß2AR is associated with a 7-fold higher relative risk for obesity (4). Recently, a polymorphism of the {alpha}2BAR gene with three glutamic acids deleted from a glutamic acid repeat element (Glux12, amino acids 297–309) in the putative third intracellular loop of the receptor protein was identified (5, 6), and obese patients with the mutation in both alleles were found to have a lower basal metabolic rate (BMR) (5). Moreover, a significant interactive effect of the ß3AR and {alpha}2BAR gene polymorphisms on fat mass was observed (7).

ANS activity is an important factor in metabolic regulation. Particularly, sympathetic nervous system (SNS) activity has been shown to contribute to the control of BMR (8). Bray (9) has proposed that a relative or absolute suppression in the activity of the thermogenic component of SNS is a primary factor in obesity. In previous studies we investigated association of the ß3AR gene polymorphism with ANS activity (10, 11). ANS activity was assessed by power spectral analysis of heart rate variability (HRV), a noninvasive and sensitive method of evaluating ANS activity by measuring instantaneous beat to beat variations in R-R interval length (10, 11, 12, 13, 14, 15). In general, the high frequencies of HRV (>0.15 Hz; HI) are associated solely with parasympathetic nervous system (PNS) activity, and the low frequencies of HRV (<0.15 Hz; LO) are associated with both SNS and PNS activities (12, 15). We previously reported that the very low frequencies of HRV (<0.035 Hz; VLO) especially reflect thermoregulatory control of SNS activity (16).

In this study we determined the prevalence of the {alpha}2BAR deletion polymorphism in young healthy Japanese males and investigated the association of the polymorphism with ANS activity by electrocardiogram (ECG) R-R interval power spectral analysis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Three hundred eighty-one young healthy males (mean ± SE, 20.6 ± 0.1 yr) were examined after written informed consent was obtained. All subjects were Japanese and were determined by interview not to be taking any medications. Weight, height, blood glucose, and insulin were measured. Family history was investigated by interview, and relatives within the third degree who were diabetic or were significantly obese [body mass index (BMI), >30] were identified. We randomly chose 93 of the subjects for analysis of ANS activity by ECG R-R interval power spectral analysis. We also measured blood pressure, total cholesterol, and triglycerides.

The study protocol was reviewed by the appropriate institutional review committee of Kyoto University School of Medicine, and the investigation was performed in accordance with the guidelines expressed in the Declaration of Helsinki.

Genotyping

Genomic DNA was extracted from whole blood (DNA Extractor WB Kit, Wako, Osaka, Japan). Genomic DNA samples were amplified with the following primers (Nisshinbo, Tokyo, Japan): 5'-AGGGTGTTTGTGGGGCATCTCC-3' and 5'-CAAGCTGAGGCCGGAGACACTG-3' for genotyping of the three glutamic acid deletion polymorphisms. PCR amplification was conducted in a 20-µl volume containing 50 ng genomic DNA, 5 pmol of each primer, 10 mmol/liter Tris-HCl (pH 8.8), 50 mmol/liter KCl, 1.5 mmol/liter MgCl and Triton X-100, 0.25 U DNA polymerase (Stratagene, Austin, TX), and 200 µmol/liter deoxy-NTP. The conditions of PCR were denaturation at 94 C for 5 min, followed by 35 cycles of denaturation at 94 C for 30 sec, annealing at 60 C for 30 sec, and extension at 72 C for 30 sec with a final extension at 72 C for 5 min. The product size was 112 bp for the normal long allele and 103 bp for the mutant short allele. PCR products were subjected to electrophoresis through a 4% NuSieve agarose gel (BMA, Rockland, ME).

R-R interval power spectral analysis

We randomly chose 93 subjects for analysis of ANS activity by ECG R-R interval power spectral analysis. ANS activity was examined during supine rest and postural change to standing in the morning (0900–1100 h) after overnight fast. Subjects were at supine rest for 10 min, and then stood up by the bedside at standing rest for another 10 min at 25 C. The respiratory rate was controlled at 0.25 Hz by an electric metronome to avoid interference of the parasympathetic component with the low frequency component.

Our R-R interval power spectral analysis procedures have been fully described previously (10, 11, 16). Briefly, ECG R-R interval data obtained from the CM5 lead was digitized at 1000 Hz, and the derived R-R interval time series then was aligned in 2 Hz sequence for power spectral analysis. The direct current component and linear trend then were completely eliminated by digital filtering for band-pass between 0.007 and 0.5 Hz. After passing through the Hamming-type data window, power spectral analysis by means of a fast Fourier transform was performed on the consecutive 480-sec time series of R-R interval data obtained during the tests. We analyzed VLO (0.007–0.035 Hz), LO (0.035–0.15 Hz), HI (0.15–0.5 Hz), and total power (0.007–0.5 Hz; TOTAL) by integrating the spectrum for the respective band width. TOTAL reflects overall ANS activity. LO arises from combined SNS and PNS functions, and HI largely arises from PNS activity (12, 13, 14, 15). VLO is closely associated with thermoregulatory control of SNS activity (16). The ratio of (VLO+LO)/HI reflects SNS activity (SNS index), and the HI/TOTAL ratio reflects PNS activity (PNS index) (17, 18).

Measurement of plasma glucose, insulin, and lipids

Plasma obtained by centrifugation was used for measurement of glucose and immunoreactive insulin. Plasma glucose was measured by the glucose-oxidase method (19). Immunoreactive insulin was determined by RIA using the polyethylene glycol method (20). Total cholesterol and triglycerides were measured by Cholesterol C-test Wako and Triglyceride G-test Wako (Wako Pure Chemical Industries Ltd., Osaka, Japan).

Statistical analysis

Significant differences were evaluated by {chi}2 test or ANOVA, where appropriate. All data were expressed as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Prevalence of the polymorphism

The genotype distribution was 168 (44.1%), 162 (42.5%), and 51 (13.4%) for Long/Long, Long/Short, and Short/Short, respectively. The allele frequency was 0.35.

Clinical characteristics

Clinical characteristics of subjects according to genotype of {alpha}2BAR are shown in Table 1Go. No significant differences were observed in any investigated characteristics. There also are no significant differences in any of the clinical characteristics in the subjects of ECG R-R interval power spectral analysis (Table 2Go).


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  		Table 1. Clinical characteristics of subjects, according to genotype of the {alpha}2BAR

 

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  		Table 2. Clinical characteristics of subjects of R-R interval power spectral analysis

 
R-R interval data analysis in young subjects

Figure 1Go shows a typical power spectrum, with different frequency components associated with ANS activities. Group data for R-R interval power spectral parameters are shown in Fig. 2Go. At supine rest, both VLO and LO of Short/Short were significantly higher than those of Long/Long or Long/Short (VLO, 771.2 ± 118.4 vs. 406.2 ± 61.0 and 444.8 ± 59.1 msec2; LO, 1078.5 ± 182.6 vs. 636.4 ± 104.5 and 591.9 ± 95.1 msec2; P < 0.05, Short/Short vs. Long/Long and Long/Short, respectively; Fig. 2Go, B and C). The SNS index of Short/Short was significantly higher and the PNS index of Short/Short was significantly lower than those of Long/Long (SNS index, 2.80 ± 0.31 vs. 1.62 ± 0.23; PNS index, 0.29 ± 0.02 vs. 0.45 ± 0.03; P < 0.05; Fig. 2Go, E and F). At standing, no significant differences among the groups were observed in any of the power spectral parameters tested.



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  		Figure 1. A typical set of computer-aided ECG R-R interval power spectral analysis results: raw R-R interval (A) and the corresponding spectrum (B), from which various ANS activity components are derived.

 


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  		Figure 2. ANS activity by R-R interval power spectral analysis. R-R interval power spectra were integrated for three band widths: VLO (0.007–0.035 Hz), LO (0.035–0.15 Hz), and HI (0.15–0.5 Hz). A, TOTAL at supine rest separated by {alpha}2BAR genotype; B, VLO; C, LO; D, HI; E, SNS index, the ratio of (VLO + LO)/HI that reflects SNS activity; F, PNS index, the ratio of HI/TOTAL that reflects PNS activity. L/L, Long/Long; L/S, Long/Short; S/S, Short/Short. Values are mean ± SE. *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We show in this study that a three-glutamic acid deletion polymorphism of {alpha}2BAR is common in the Japanese population. The frequency of the short allele was 0.35, almost the same as that reported previously in American Caucasian women (0.33) (7) and somewhat lower than that in a study of Finnish Caucasians (0.45, 0.43) (5, 21). We found by R-R power spectral analysis that VLO and LO of Short/Short were higher than those of Long/Long. In addition, Short/Short had a higher SNS index and a lower PNS index than Long/Long. These results show clearly that Short/Short has increased SNS activity.

ANS activity is closely involved in metabolic regulation, modulating glucose and fat metabolism through both direct neural and hormonal effects (22). A previous study demonstrated that both PNS and SNS activities decreased as the percentage of body fat increased (23). In addition, an association between genetic background and ANS activity has been reported. Modified autonomic balance has been detected in young offspring of patients with noninsulin-dependent diabetes mellitus, in whom the noninsulin-dependent diabetes mellitus phenotype had not yet been expressed (24, 25). We have already found that polymorphisms of ß3AR and uncoupling protein 1 genes, which are considered to be candidate genes of obesity, affect ANS activity in young healthy subjects (10, 11). Thus, the altered ANS activity associated with the Short/Short variant in this study may well be causative of metabolic disorder.

There were no significant differences in clinical features in any of the groups, although Short/Short had higher VLO, implying greater thermoregulatory control of SNS activity. Previous studies found subjects with Short/Short to have a lower BMR (or resting metabolic rate) than Long/Long (5), and subjects with both short allele and Trp64Arg of the ß3AR gene variant to have higher fat mass and percent body fat than subjects with only Trp64Arg of the ß3AR gene variant (7). Sivenius et al. (21) reported that Short/Short subjects had a greater increase in body weight than subjects with other genotypes among nondiabetic subjects during a 5-yr follow-up study. Because reduced SNS activity should lower BMR and be a risk for body weight gain (8), our results seem inconsistent with previous reports. We did not measure BMR directly, so we cannot determine how the higher SNS activity affects BMR in our subjects. However, as BMI and other clinical parameters are similar among the groups, it is likely that the Short/Short subjects have the same BMR as the other groups in this study. With higher SNS activity and unchanged BMR, Short/Short subjects might well have up-regulated ANS activity in compensation for lower BMR, possibly due to receptor dysfunction, that would not manifest at the young age of our subjects. The subjects of this study were young and in good health with almost ideal BMI (age, 20.6 ± 0.1 yr; BMI, 21.6 ± 0.1 kg/m2), whereas the subjects in previous reports were middle-aged (mean age, >45 yr) or obese (mean BMI, >30 kg/m2). Absolute heart rate variability becomes lower with age (26, 27, 28), and low frequency especially reflects the aging process (28). As ANS activity lessens with aging and compensative SNS action diminishes, the BMR of Short/Short subjects should decrease, and the clinical features, such as increased fat mass or body weight, only then would appear. We intend to perform a follow-up study to clarify the influence of this polymorphism.

In conclusion, although details of the mechanism remain to be determined, the {alpha}2BAR deletion polymorphism clearly affects ANS activity in youth. These findings also suggest that the {alpha}2BAR polymorphism is a genetic marker of the metabolic disorder.


   Acknowledgments
 
We thank Ms. Nobuko Hamano for technical advice.


   Footnotes
 
This work was supported by Health Science Research Grants for Research on Human Genome, Tissue Engineering, and Food Biotechnology Chouju Kagaku Sougou from the Ministry of Health, Labor, and Welfare, Japan; a grant from the Smoking Research Foundation; a grant from the Japan Diabetes Foundation; and a grant from the Suzuken Memorial Foundation.

Abbreviations: ANS, Autonomic nervous system; {alpha}2BAR, {alpha}2B-adrenergic receptor; BMI, body mass index; BMR, basal metabolic rate; ECG, electrocardiogram; HI, high frequency; HRV, heart rate variability; LO, low frequency; PNS, parasympathetic nervous system; SNS, sympathetic nervous system; TOTAL, total power; VLO, very low frequency.

Received July 30, 2002.

Accepted November 20, 2002.


   References
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 Introduction
 Subjects and Methods
 Results
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