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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1623-1627
Copyright © 1999 by The Endocrine Society

Original Studies

The Association between Trp64Arg Polymorphism of the ß3-Adrenergic Receptor and Autonomic Nervous System Activity1

Nobuyuki Shihara, Koichiro Yasuda, Toshio Moritani, Hidetoshi Ue, Tetsuya Adachi, Hisako Tanaka, Kinsuke Tsuda and Yutaka Seino

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

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


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The ß3-adrenergic receptor plays a significant role in the control of lipolysis and thermogenesis in brown adipose tissue through autonomic nervous system (ANS) activity. As the Trp64Arg polymorphism of the ß3-adrenergic receptor gene might affect ANS activity, we investigated the association of the polymorphism with ANS activity. The prevalence of the polymorphism was determined in 204 subjects. Ten normal homozygous, 10 heterozygous, and 1 variant homozygous subjects were examined for ANS activity during supine rest and standing by electrocardiogram R-R interval power spectral analysis. Subjects with the variant did not differ from subjects without the variant in body mass index, plasma glucose, plasma insulin, or family history of diabetes or obesity. The total power of heterozygotes at supine rest was lower than that of normal subjects (1124.6 ± 191.6 vs. 3029.8 ± 758.8 ms2; mean ± SE). With a postural change to standing, the parasympathetic and sympathetic nervous system activity indexes of heterozygotes showed a higher response than those of normal subjects (parasympathetic nervous system index, 0.10 ± 0.02 vs. 0.17 ± 0.02; sympathetic nervous system index, 10.55 ± 1.47 vs. 6.26 ± 1.09), and the difference in total power disappeared. These findings show that subjects with the variant, even the heterozygotes, had lower resting ANS activity than normal subjects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ACTIVITY of the autonomic nervous system (ANS) has been considered one of the important factors in metabolic regulation. The resting metabolic rate is regulated by the sympathetic nervous system (SNS) (1, 2) through the modulation of lipolysis and thermogenesis in brown adipose tissue (3, 4). Bray (5) has proposed that obesity is associated with a relative or absolute suppression of the activity of the thermogenic component of the SNS.

Recently, power spectral analysis of heart rate variability has attracted much interest as a noninvasive and very sensitive method to evaluate ANS activity (6, 7, 8, 9). It generates two major frequency components of heart rate variability, i.e. the high respiration-linked component (HI) and the low frequency component (LO), which can provide quantitative markers of parasympathetic nervous system (PNS) and SNS activities, respectively, and of their dynamic balance (6, 7, 8). For example, HI could be abolished upon vagal blockade by pharmacological drugs (e.g. glycopyrrolate or atropine), whereas the amplitude of LO was reduced (6, 7, 8). On the other hand, under conditions of ß-sympathetic blockade alone, the LO was reduced to some extent, but could not be totally abolished (6, 7, 8, 9). Combined vagal blockade and ß-sympathetic blockade abolished all heart rate fluctuations, leading to a metronome-like heartbeat (6). Akselrod et al. (7) also provided some evidence that the low frequency component of the R-R frequency spectrum was jointly mediated by PNS and SNS and appeared to compensate for blood pressure fluctuations at this frequency. These studies together with the earlier work thus suggest the possibility that the low and high frequency components of the R-R spectrum provide markers of the PNS-SNS balance that modulates heart rate variability. This measurement has been widely applied in various pathological conditions as well as physiological states; in diabetes, for example, it can be used for the early diagnosis of autonomic neuropathy (10).

The ß3-adrenergic receptor (ß3AR) plays a significant role in the control of lipolysis and thermogenesis in brown adipose tissue through ANS activity (11, 12, 13). A gene coding for human ß3AR was characterized in 1989 (14). A missense variant that replaced tryptophan with arginine at position 64 (Trp64Arg) was reported in 1995 from the study in Pima Indians (15). Since then, many studies in several populations suggest that the polymorphism was not uncommon.

It was reported that among Pima Indians, homozygotes for Trp64Arg had an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM) and tended to have lower metabolic rates (15). In Finns, the variant was associated with abdominal obesity and resistance to insulin (16). Another study of Finns, however, reported Trp64Arg not to be associated with NIDDM or features of the insulin resistance syndrome (17). Similarly, in Japanese, both positive and negative results on the influence of the polymorphism have been reported (18, 19, 20, 21, 22, 23, 24, 25), but the reports that the variant had an influence in Japanese were obtained mainly from homozygotes, and there has been little recognition of the influence of heterozygotes, so the effects of Trp64Arg are not yet well defined.

As it is possible that the ß3AR polymorphism affects the entire ANS activity in which ß3AR functions, in this study we determined the prevalence of the polymorphism in a large number of subjects and then investigated the association of the ß3AR 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

Two hundred and four male volunteers were studied after giving informed consent. All subjects were Japanese and were determined by interview not to be taking any medications. The mean age of the subjects was 20.1 ± 1.2 (±SD) yr. Blood sampling was carried out between 0900–1000 h after an overnight fast. At the same time, height and weight were measured, and family history was investigated by interview, including whether a subject had any relatives within the third degree who were or had been diagnosed as diabetic or were significantly obese [body mass index (BMI), >30].

Measurements of plasma glucose and insulin

Plasma obtained by centrifugation was used for measurements of glucose and immunoreactive insulin. Plasma glucose was measured by the glucose oxidase method (26). Immunoreactive insulin was determined by RIA using the polyethylene glycol method (27).

Determination of Trp64Arg polymorphism in the ß3AR gene

Genomic DNA was extracted from peripheral blood cells using a DNA Extractor WB Kit (Wako, Japan). PCR was carried out using 50 ng genomic DNA with the primers (sense, 5'-CGCCCAATACCGCCAACAC-3'; antisense, 5'-CCACCAGG AGTCCCATCACC-3') under conditions described previously (22).

The PCR products (210 bp) were digested with 60 U MvaI in a 200-µL volume and separated on a 3% agarose gel. Digestion of the normal sequence yields fragments of 99, 62, 30, 12, and 7 bp in length, whereas the Trp64Arg variant eliminates one of the MvaI sites, yielding a novel 161-bp product.

R-R interval power spectral analysis

Twenty-one subjects screened for the Trp64Arg polymorphism [10 normal homozygous (Trp/Trp), 10 heterozygous (Trp/Arg), and 1 variant homozygous (Arg/Arg)] were investigated for ANS activity by R-R interval power spectral analysis. Trp/Trp and Trp/Arg subjects were randomly chosen from the subjects without family history in each group. Only 1 Arg/Arg subject was found in this study; no statistical analysis could be made, and his ANS activity data are used only as a case report.

We investigated ANS activity during supine rest and postural change to standing in the morning (0900–1100 h) after an overnight fast. Subjects were at supine rest for 5 min and then stood up by the bedside for standing rest for another 5 min. The respiratory rate was controlled at 0.25 Hz by an electric metronome to avoid the parasympathetic component interfering with the low frequency component.

ECG R-R interval data obtained from the CM5 lead were digitized at 1000 Hz, and the derived R-R interval time series was then aligned in 2-Hz sequence for power spectral analysis. The DC component and linear trend were completely eliminated by digital filtering for bandpass between 0.03–0.5 Hz. After passing through the Hamming-type data window, power spectral analysis by means of a fast Fourier transform was performed on consecutive 240-s time series of R-R interval data obtained during the tests. We analyzed low frequency (0.03–0.15 Hz; LO), high frequency (0.15–0.4 Hz; HI), and total power (0.03–0.4 Hz; TOTAL) by integrating the spectrum for the respective band width. Figure 1Go shows examples of raw R-R interval data (top) and the corresponding spectra (bottom). In this spectrum, the black area shows the LO, and the white area shows the HI. TOTAL reflects overall autonomic nervous system activity. LO arises from combined SNS and PNS functions; HI is from PNS activity only. The ratio of LO/HI (SNS index) reflects SNS activity, and the ratio of HI/TOTAL (PNS index) reflects PNS activity (28, 29).



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

 
Statistical analysis

Significant differences were evaluated by Student’s t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Trp64Arg polymorphism of the ß3AR gene

One (0.5%) of the subjects was homozygous for the variant (Arg/Arg), and 49 (24.0%) were heterozygous (Trp/Arg) and 154 (75.5%) were homozygous for the normal (Trp/Trp) allele. The frequency of the Trp64Arg allele was 0.13.

Clinical characteristics

Table 1Go shows clinical characteristics of the subjects according to genotype. Subjects with Trp/Arg did not differ from subjects without the variant (P > 0.05) in any investigated characteristic: BMI (22.2 ± 3.4 vs. 21.7 ± 2.7 kg/m2; Trp/Arg vs. Trp/Trp; mean ± SD), plasma glucose (5.3 ± 0.6 vs. 5.1 ± 0.4 mmol/L), insulin (49.2 ± 9.6 vs. 47.4 ± 6.0 pmol/L), or family history of diabetes or obesity (26.5 vs. 24.0%). In the subjects of ECG R-R interval power spectral analysis, no significant difference in any of the clinical characteristics was observed between the Trp/Trp and Trp/Arg groups (see Table 1Go).


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  		Table 1. Clinical characteristics of subjects, according to genotype of the ß3-AR

 
Autonomic activities of subjects with and without the Trp64Arg polymorphism

Figure 2Go represents a typical set of raw R-R intervals and the corresponding power spectral data obtained from subjects with Trp/Trp (Fig. 2AGo), Trp/Arg (Fig. 2BGo), and Arg/Arg (Fig. 2CGo), respectively, during supine rest. Note that the mean heart rate was subtracted from the original R-R interval data; thus, only the R-R variability could be directly compared in this figure. It can readily be seen that R-R variability in subjects with both Trp/Arg and Arg/Arg was markedly reduced compared with that in the individual with Trp/Trp. The corresponding R-R interval power spectra also demonstrate vast differences in both LO and HI among the subjects.



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  		Figure 2. Examples of raw R-R interval data (left) and the corresponding spectra (right) from representative subjects at supine rest. A, Trp/Trp; B, Trp/Arg; C, Arg/Arg.

 
Table 2Go and Fig. 3Go show the group data on the autonomic activities analyzed by R-R interval power spectral analysis. The TOTAL of Trp/Arg at supine rest was significantly lower than that of Trp/Trp (1124.6 ± 191.6 vs. 3029.8 ± 758.8 ms2; mean ± SE; P = 0.039). With the postural change to standing, the SNS index and PNS index of Trp/Arg showed higher responses than those of Trp/Trp [SNS index, 10.55 ± 1.47 vs. 6.26 ± 1.09 (P = 0.047); PNS index, 0.10 ± 0.02 vs. 0.17 ± 0.02 (P = 0.020)]. All variables showed significant differences (P < 0.05) between the supine and standing conditions, except TOTAL of Trp/Arg.


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  		Table 2. ECG R-R interval power spectral analysis results

 


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  		Figure 3. ANS activity during postural change analyzed by R-R interval power spectral analysis. R-R interval power spectra were integrated for two band widths, LO (0.03–0.15 Hz) and HI (0.15–0.4 Hz), and for TOTAL (0.03–0.4 Hz). A, TOTAL reflects overall ANS activity. LO arises from combined SNS and PNS function; HI arises from PNS activity only. B, The ratio of LO/HI (SNS index) reflects SNS activity; C, the ratio of HI/TOTAL (PNS index) reflects PNS activity. Values are the mean ± SE. *, P < 0.05, Trp/Trp vs. Trp/Arg.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we investigated the relationship between the Trp64Arg polymorphism of ß3AR and ANS activity by ECG R-R interval power spectral analysis. The allele frequency of Trp64Arg was 0.13. This value is slightly lower than that reported in previous studies of Japanese (18, 19, 20, 21, 22, 23, 24, 25), but higher than that in Caucasians (17, 30). The polymorphism is not associated with the clinical features of abnormality. In ANS activity, the TOTAL of Trp/Arg at supine rest was lower than that of Trp/Trp, and no difference in PNS or SNS index was observed. In addition, the one subject with Arg/Arg (n = 1) had lower TOTAL than mean Trp/Arg (n = 10), but no statistical analysis could be performed (853.5 vs. 1124.6 ± 191.6 ms2). With the postural change to standing, the difference in TOTAL disappeared, and a higher response was observed in both PNS and SNS activities of Trp/Arg than in those of Trp/Trp.

The oscillation of R-R interval reflects the ANS activity, the coefficient of variation score of which has been used for evaluation of ANS activity. TOTAL can also be an indicator of overall ANS activity. Diabetic neuropathy patients have significantly lower TOTAL (31). Our results indicate that the ANS activity of the Trp/Arg group was relatively low at rest as a whole, keeping the PNS-SNS balance. However, with standing, no such difference was found. In diabetic neuropathy patients, TOTAL was always lower than normal for any given physiological perturbation, and the responsiveness of both PNS and SNS activities thus remained nearly constant at a very low level (31). On the other hand, the carrier of Trp/Arg had a higher response in PNS and SNS activities to postural perturbation. This suggests that the low resting ANS activity was caused not by an organic defect of the nervous system, but by the imbalance of whole body ANS activity that was induced by the variant of ß3AR.

Of the biochemical effects of the Trp64Arg variant on ß3AR, the maximal adenylyl cyclase activity of the cell lines, hamster CHO-K1 and human HEK293, expressing variant ß3AR is lower than normal for various agonists (32). It is suggested that the variant ß3AR may be coupled less efficiently to the Gs protein than the normal ß3AR. In addition to lipolysis and thermogenesis in adipocytes, ß3AR modulates neural bronchomotor control, inducing relaxation of airway smooth muscle (33) and producing sustained peripheral vasodilation that is predominant in skin and fat (34, 35). Decreased effects of SNS activity caused by the variant ß3AR may be balanced not with up-regulation of SNS activity but by down-regulation of PNS activity, resulting in decreased TOTAL of Trp/Arg. On the other hand, the higher response of the PNS and SNS with standing may be the result of a compensatory action for the low basal activity.

In this study there were no significant differences in the clinical features in any of the groups we tested. Therefore, Trp64Arg alone does not seem to be a determining factor in obesity or NIDDM. The subjects of the previous studies showing adverse effects of Trp64Arg variant were mostly diabetic patients or obese individuals, and all were of middle age. However, the subjects of this study were young and in good health at the time of experiments, and their BMIs were almost ideal. There is a report that TOTAL declines with age (36). When the influence of aging is added to the effect of the variant of ß3AR, the defect in ANS activity may only then become obvious. The Trp64Arg variant has also been shown to be related to a low basal metabolic rate (BMR) in both Caucasian and Japanese subjects (26, 37) and possibly also in Pima Indians (15). The dysfunction of ANS may affect BMR, and low BMR is one of the risk factors for weight gain (1). The subjects of these studies were also in middle age and obese, so the complex risk factors, including the variant of ß3AR, may have become apparent.

In conclusion, the Trp64Arg variant, even heterozygous, decreased resting ANS activity, whereas the clinical characteristics did not differ between the groups with and without the variant. However, it is likely that the certain effects of the low ANS activity caused by the variant will become more obvious with aging or alteration of living environmental factors. We intend to continue a follow-up study to clarify the influence of Trp64Arg with aging. As R-R interval power spectral analysis is a very sensitive method for measuring ANS activity, as demonstrated by previous studies as well as the present experiment, it may be a useful tool to detect early neuronally mediated abnormal metabolic states.


   Acknowledgments
 
We thank Ms. Kyoko Hishida and Mr. Susumu Oka for technical assistance.


   Footnotes
 
1 This work was supported by Grants-in-Aids for Scientific Research from the Ministry of Education, Science, Sports, and Culture (09470219, 09877194, and 10770569); Health Sciences Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare, Japan; and a grant for Research for the Future Program from the Japan Society for the Promotion of Science (JSPS RFTF97I00201). Back

Received November 4, 1998.

Revised February 3, 1999.

Accepted February 11, 1999.


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 Introduction
 Subjects and Methods
 Results
 Discussion
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