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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2441-2444
Copyright © 1998 by The Endocrine Society

Original Studies

Meta-Analysis of the Association of Trp64Arg Polymorphism of ß3-Adrenergic Receptor Gene with Body Mass Index1

Tomomi Fujisawa, Hiroshi Ikegami, Yoshihiko Kawaguchi and Toshio Ogihara

Department of Geriatric Medicine, Osaka University Medical School, Osaka, Japan

Address all correspondence and requests for reprints to: Hiroshi Ikegami, M.D., Ph.D., Department of Geriatric Medicine, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565, Japan. E-mail: ikegami{at}geriat.med.osaka-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A possible pathogenic polymorphism in the ß3-adrenergic receptor gene (Trp64Arg) has been reported to be associated with increased body weight, clinical features of insulin resistance, and early development of type 2 diabetes mellitus in several populations. However, such findings have not been consistent among studies, making the hypothesis that this genetic marker is associated with clinical features controversial. To assess the effect of the genotypes on body mass index (BMI), we performed a meta-analysis of the data from the literature using an extension of ANOVA for continuous measures. In a total of 48 subgroups containing subjects with (n = 2447) and without (n = 6789) the Trp64Arg variant, the summary weighted mean difference in BMI was 0.30 (95% confidence interval, 0.13–0.47) kg/m2, indicating that variant carriers exhibited higher BMI (on the average, 0.30 kg/m2 higher) than normal homozygous subjects. In this case, there was no significant evidence against homogeneity of the effect (P = 0.36). This is the first meta-analysis assessing quantitative phenotypes in relation to a genetic polymorphism, and the results support the hypothesis that the Trp64Arg polymorphism is associated with BMI across diverse population groups, suggesting that the ß3-adrenergic receptor gene locus plays a role in genetic predisposition to increased body weight in a universal manner.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SEVERAL lines of evidence from twin and family studies have strongly suggested that genetic factors are involved in an increase in body weight (1, 2). To elucidate genetic factors responsible for obesity, several candidate genes have been investigated, but little is known about the genetic basis of obesity in general populations (3).

The ß3-adrenergic receptor is predominantly expressed in adipose tissue and regulates lipid metabolism and thermogenesis. Therefore, an impairment of ß3-adrenergic receptor function may lead to obesity through its effect on energy expenditure of fat tissue (4), allowing us to accept the ß3-adrenergic receptor gene (ADRB3) as a candidate gene for obesity. Indeed, a missense mutation in codon 64 of ADRB3, leading to the replacement of tryptophan by arginine (Trp64Arg) in the receptor protein, has been reported to be associated with increased body weight, early development of type 2 diabetes mellitus, and clinical features of insulin resistance in several populations. However, as discussed recently (5, 6, 7, 8), such findings have not been consistent among studies, raising a question about the significance of a possible relation between the Trp64Arg polymorphism and these clinical features. Such a controversy prompted us to carry out a meta-analysis of the association of genotype with body mass index (BMI).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Identification of studies

As this polymorphism was reported recently (August 1995) (9, 10, 11), most of the studies published in the field were known to us. In addition, to identify studies, a search was performed on MEDLINE and PubMed using the following key words: ADRB3, adrenergic receptor gene, or Trp64Arg (January 10, 1998). In the analysis, only studies showing mean BMI values (and SD or SEM) according to genotype were included, and only data from unrelated individuals were analyzed. When BMI according to the genotype was reported for more than one subpopulation (for example, subjects with type 2 diabetes mellitus and control subjects) in one study, each subpopulation was considered separately.

Statistical methods

To assess the difference in quantitative variables according to genotype, we adopted an extension of ANOVA in a fixed effect model for continuous measures followed by assessment of the heterogeneity of the difference (12), which has usually been used to estimate the effect size in meta-analyses. A dominant model was used for assessing the difference; homozygotes and heterozygotes were grouped together. For calculation of the common variance between two genotype groups, each variance divided by the corresponding number of subjects was added and taken as the estimated variance, because every variable in a different genotype group is theoretically independent of every other. The 95% confidence interval (CI) was also calculated.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In a total of 31 studies with sufficient information that have been published to date, 48 groups containing 2447 Trp64Arg carriers and 6789 normal homozygotes (9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) were available. There was no statistical evidence of lack of homogeneity of the difference (Q value = 49.7 with 47 df; P = 0.36). The summary weighted mean difference in BMI (Trp64Arg carrier vs. noncarrier) of the pooled data was 0.30 (95% CI, 0.13–0.47) kg/m2; Fig. 1Go), indicating that individuals positive for the Arg allele may have an average increase in BMI of 0.30 kg/m2 compared with that in normal homozygous subjects.



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  		Figure 1. Estimates of differences in BMI between the two groups according to Trp64Arg polymorphism of ADRB3. Values more than zero imply an increase in BMI associated with the Arg allele. The 95% CIs are expressed by bars (for each group) and diamonds (for all studies combined). The broken vertical line represents the weighted mean difference in BMI for the total pooled data. The reference number is in brackets.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our current analysis, using data from more than 9000 individuals, demonstrated a significant association of the Trp64Arg polymorphism with BMI. In addition, the association among the diverse population groups exhibited a relatively similar strength despite the different genetic (including distribution of ADRB3 genotypes) and environmental backgrounds. Therefore, the ADRB3 locus has been shown, for the first time to our knowledge, to be a genetic factor associated with body weight in a universal manner.

The development of obesity is suggested to be at least in part genetically determined (1, 2). Little is known, however, about the genetic factors responsible for body weight increase in general populations. Despite the suggestive role of the Trp64Arg polymorphism in the genetic predisposition to obesity (the Arg allele was associated with a lower metabolic rate) (9, 14, 28), this variant itself has not been associated with severe obesity (11, 14, 21, 25), nor has it been demonstrated to be more prevalent in relation to higher BMI in each study group, except for two subgroups that consisted of individuals without specific disease (13, 20). These observations may reflect a relatively modest effect of the polymorphism on BMI that is masked under pathological states such as severe obesity or type 2 diabetes mellitus. Although the effect is relatively modest, the universal effect makes this polymorphism an important factor that contributes to body weight increase and predisposes a large number of people to common, multifactorial diseases, such as diabetes mellitus and insulin resistance syndrome.

In addition, it should be noted that this study represents the first application of meta-analysis to assess a difference in quantitative phenotypes according to a genetic polymorphism. This statistical method seems to be a powerful strategy for identifying genetic factors contributing to complex traits such as obesity, type 2 diabetes mellitus, hypertension, and hyperlipidemia, in which the particular phenotypes are of a quantitative rather than a qualitative nature (e.g. BMI and blood glucose level). In addition, if there is some association of one genetic marker with the phenotypes, its contribution may be so small as to be easily masked by other genetic and environmental factors due to the nature of multifactorial diseases. From these points of view, a quantitative meta-analysis such as that employed in the current study appears to be a powerful strategy, because 1) it potentially investigates a large number of individuals with diverse backgrounds; 2) in the case of significant association, it also can estimate whether the association is common among the different population groups or, alternatively, shows heterogeneity depending on the background; and 3) it can estimate the strength of the effect on the phenotypes. Thus, our quantitative meta-analysis demonstrated a potential application of this statistical procedure (12) for elucidating genetic factors in common diseases.

The Trp64Arg polymorphism has been reported to be associated with early development of type 2 diabetes mellitus (9, 10, 15, 19). It is likely that the Arg64-associated phenotypic alteration might play a role as a promotive factor in an individual genetically predisposed to type 2 diabetes, resulting in acceleration of the development of diabetes mellitus. We performed a similar calculation using the age at onset of type 2 diabetes mellitus as a target variable. A summary mean difference in age at onset of type 2 diabetes (n = 2532; 14 subgroups) (9, 10, 15, 16, 19, 22, 24, 25, 30, 34, 37, 39) was -1.9 yr (95% CI, -2.8 to -1.0); patients with the variant showed an earlier onset of disease (-1.9 yr) than those without it. In this model, however, the homogeneity of the effect was reduced, although there was no statistically significant evidence (P = 0.11). Therefore, the effect, if one exists, of the genotype on the acceleration of development of type 2 diabetes mellitus may differ depending on some other factors. To address this issue, association between the genotypes and the age at onset should be investigated with other factors, such as racial difference or sex, accounted for.

It is likely that biases toward rejecting negative studies exist in the peer review/editorial process. As a result, this meta-analysis may be somewhat biased, and it is possible that the estimated difference in BMI (0.30 kg/m2) may be, to some extent, overestimated.

In summary, our present meta-analysis demonstrated two important findings. First, the Trp64Arg polymorphism was associated with BMI across the population groups, suggesting that the ADRB3 locus plays a universal role in the genetic predisposition to body weight increase. Second, quantitative meta-analysis, such as that employed in this study, is potentially applicable for elucidating genetic factors in complex traits.


   Footnotes
 
1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture; a Grant for Diabetes Research from the Ministry of Health and Welfare; a grant from the Sandoz Foundation for Gerontological Research; and a grant from the Kato Memorial Trust for Nambyo Research. Back

Received January 30, 1998.

Revised March 23, 1998.

Accepted March 30, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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