Original Article

International Journal of Obesity (2008) 32, 1240–1249; doi:10.1038/ijo.2008.90; published online 24 June 2008

The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals

N Kurokawa1,2,3,5, E H Young1,4,5, Y Oka2, H Satoh3, N J Wareham1, M S Sandhu1,4 and R J F Loos1

  1. 1MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
  2. 2Division of Molecular Metabolism and Diabetes, Graduate School of Medicine, Tohoku University, Sendai, Japan
  3. 3Environmental Health Sciences, Graduate School of Medicine, Tohoku University, Sendai, Japan
  4. 4Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK

Correspondence: Dr RJF Loos, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge CB2 0QQ, UK. E-mail: ruth.loos@mrc-epid.cam.ac.uk

5These two authors contributed equally to this work.

Received 5 January 2008; Revised 30 April 2008; Accepted 4 May 2008; Published online 24 June 2008.

Top

Abstract

Background:

 

The β-3 adrenergic receptor gene (ADRB3) is part of the adrenergic system, which is known to play a key role in energy metabolism. The association between the Trp64Arg variant in the ADRB3 and body mass index (BMI) has been widely examined, but previous studies have been small and results have been inconsistent.

Methods:

 

We assessed the association between the ADRB3 Trp64Arg variant and BMI in a large UK population-based cohort of 4854 middle-aged men and women. We also performed a meta-analysis of 97 studies, involving 44833 individuals, to place our findings in context.

Results:

 

Although we found no significant difference in BMI (0.20kg/m2, P=0.40) between the Trp64Trp homozygotes and Arg64 allele carriers in our UK population-based cohort, the meta-analysis showed significant association between the Arg64Trp variant and BMI, with Arg64-allele carriers having a 0.24kg/m2 (P=0.0002) higher BMI compared with noncarriers. However, we also found substantial heterogeneity among the studies (P=2.2 × 10−14). The difference in East Asians (0.31kg/m2, P=0.001) was 3.9 times larger than that in Europeans in whom no significant association was observed (0.08kg/m2, P=0.36). This was consistent with the chronological cumulative decrease in the effect size, which decreased steadily in Europeans and reached nonsignificance after 11 studies in 1996. In East Asians, the cumulative effect size decreased after the first reports, but reached a steady state at a significant effect size of 0.24kg/m2 in 2000. Although the funnel plot indicated no apparent publication bias, smaller studies tended to report greater differences in BMI, compared with larger studies.

Conclusions:

 

Collectively, these data suggest that the Trp64Arg ADRB3 genetic variant might be associated with BMI in East Asians, but not Europeans. More generally, our study shows the importance of meta-analyses in the field of genetic association studies for common traits. Each genetic variant makes only a small contribution to variation in BMI, and large sample sizes are needed to reliably assess and interpret gene–phenotype associations.

Keywords:

β-3 adrenergic receptor, gene, polymorphism, meta-analysis

Top

Introduction

The adrenergic system plays a key role in regulating energy balance through the stimulation of both thermogenesis and lipid mobilization in adipose tissue. Polymorphisms in the adrenergic receptor genes (ADRs) have been extensively studied for association with obesity-related phenotypes.1 The ADRB3 Trp64Arg polymorphism, a missense mutation in the first transmembrane domain of the β3-adrenergic receptor, has been the subject of considerable attention since it was first reported in 1995 when the New England Journal of Medicine published three studies2, 3, 4 that showed weak but significant associations between the Trp64Arg variant and the onset of type 2 diabetes, insulin resistance and weight gain in the Pima Indian,2 French3 and Finnish populations.4 Three subsequent meta-analyses on the association between the Trp64Arg polymorphism and body mass index (BMI) were published with inconsistent conclusions.5, 6, 7 In the first meta-analysis, Allison et al.5 pooled data from 23 studies published before June 1997 including a total of 7399 individuals of different ethnicities. No significant association was found, and the absence of effect heterogeneity suggested that the results were not affected by ethnicity or diabetes status.5 Fujisawa et al.6 reported on a second meta-analysis including eight additional studies published before January 1998 (a total of 31 studies and 9236 individuals). In contrast to the previous meta-analysis, Fujisawa et al.,6 observed a small but significant effect of the Trp64Arg polymorphism on BMI, with a higher BMI for the Arg64-carriers compared to those individuals who were Trp64Trp homozygotes (mean difference=0.30kg/m2, 95% confidence interval (CI): 0.13–0.47). As in the previous meta-analysis, there was no evidence for effect heterogeneity by ethnicity. A third meta-analysis, restricted to studies of Japanese populations only (n=6582 individuals), reported a small but significant mean difference in BMI of 0.26kg/m2 (P<0.01), indicating that the presence of the Arg64 allele was associated with increased BMI.7

Since the publication of the original meta-analyses, further studies have been conducted, and to date over 100 studies have reported on the relationship between the ADRB3 Trp64Arg polymorphism and BMI. Collectively, observational studies have reported conflicting associations and, importantly, the relevance of this variant to BMI remains uncertain.

We therefore assessed the association between the ADRB3 Trp64Arg polymorphism and BMI in a large population-based cohort of 4854 middle-aged men and women of European descent. To help clarify the association between this variant and BMI, we also did an updated systematic review and meta-analysis, including data on 97 studies with 44833 individuals.

Top

Participants and methods

Study population

The study population is an ethnically homogeneous European population from the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC). EPIC-Norfolk is an ongoing prospective cohort study of chronic diseases comprising approximately 25000 Norfolk residents aged 45–75 who were recruited from general practice registers between 1993 and 1997 for a first health examination.8 From January 1998, the cohort was invited for a second health examination and 15786 people had attended by October 2000.

The study population of 5000 individuals was randomly selected from the 15786 people who had attended both health examinations. Participants were free of disease (cancer, coronary heart disease and diabetes) at baseline, and had height and weight measured during both clinical assessments. Only baseline data were included in the current analyses. BMI was calculated as weight (kg)/height2 (m2). BMI and genotype data were available for 4854 participants. Details of recruitment, anthropometric measurements, health examinations and questionnaires following standardized protocols have been reported previously.8

Ethical permission was granted by the Norwich Local Research Ethics Committee, and all participants gave informed consent.

Genotyping

DNA was extracted from whole blood/EDTA samples (Whatman Biosciences, Ely, UK). A custom TaqMan (Applied Biosystems, Warrington, UK) assay was used for the ADRB3 SNP (rs4994) using the forward sequence primer 5′-GCAACCTGCTGGTCATCGT-3′ and the reverse sequence primer 5′-GTTGGTCATGGTCTGGAGTCT-3′. The following MGB probes were used for allelic discrimination: VIC-5′-CATCGCCTGGACTC-3′ and FAM-5′-ATCGCCCGGACTC-3′. Genotyping was performed on 10ng of PEP-amplified DNA arrayed in 384-well PCR plates. The PCR reaction contained 80 × assay mix and 2 × TaqMan Universal PCR Master Mix, No AmpErase UNG in a total volume of 5μl. The PCR cycling conditions on an MJ Research TETRAD PTC-225 DNA Engine were as follows: 1 cycle at 95°C for 10min and then 45 cycles of 15s at 92°C and 1min at 60°C. Samples were placed at −20°C before allele calling on the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems). The genotyping success rate exceeded 97% and genotype frequencies were in Hardy–Weinberg equilibrium (P>0.05). The allele frequency was 0.075, consistent with findings in several other studies of European populations (Table 1).


Statistical analysis

We tested for Hardy–Weinberg equilibrium using a likelihood ratio test. On the basis of previous reports and comparability, we used a dominant genetic model for the primary analysis, comparing common homozygotes (Trp64Trp) with carriers of the Arg64-allele (Trp64Arg or Arg64Arg). In a secondary analysis, we used an additive model. STATA version 9.2 was used for all analyses (Stata Corp, Texas, USA). Power calculations were performed using Quanto v1.1.1 (http://hydra.usc.edu/gxe).

Systematic review

Population-based case–control and cohort studies of adult participants published before May 2007, in which the ADRB3 gene Trp64Arg polymorphism had been related to BMI, were identified by electronic searches of PubMed, scanning of relevant reference lists, and by correspondence with authors of studies. We used the following key words: ADRB, ADRB3, ADR, and Trp64Arg.

We only included studies in which mean BMI and standard deviation or standard error by genotype were available. When information was reported for more than one sub-population within a study (for example, obese versus nonobese; type 2 diabetes versus no diabetes), each sub-population was considered separately. Where intervention studies were identified, we used pre-intervention baseline data. If studies included samples that had been reported before, we verified with the authors to avoid including duplicate data. Studies were excluded if no response was received from the authors.

Some studies had been included in an earlier meta-analysis by Allison et al.5 Of these studies, where the data we required did not appear in the original publication, we used the results presented in Allison's meta-analysis.

Meta-analysis

To calculate a pooled estimate of the relation between genotype and BMI, we used fixed (metan) and random (metan, random) effects models. Heterogeneity among studies was assessed using the Q and I2 statistics. Information was collected on pre-specified study-level covariates to explore possible sources of heterogeneity (metareg): ethnicity, diabetes status, study size, BMI category (<25.0, 25.0–29.9, greater than or equal to30.0) and study design (population based on selected individuals). Ethnic group was defined as European, East Asian or other, as reported genotype frequencies vary substantially between these populations. Cumulative meta-analysis (metacum) was used to describe the chronological change over time. Funnel plots and the Egger test (metabias, graph(begg)) were used to assess evidence of possible publication bias.

Top

Results

In our study of British Europeans, full BMI and genotype data were available for 4854 participants. We found no significant association between the ADRB3 Trp64Arg polymorphism and BMI (Table 1). Our study had sufficient power (>80%) to detect differences of up to 0.5kg/m2 under a dominant model (Trp64Trp versus Arg64-carriers) at a 5% significance level. However, to detect smaller differences similar to those reported in previous meta-analyses,5, 6, 7 that is, between 0.19kg/m2 and 0.3kg/m2, we would need between 12500 and 28000 individuals. Therefore, we combined all available data in a meta-analysis.

We identified 97 studies,2, 3, 4, 9, 10, 11, 12, 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, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 including this study, that met the inclusion criteria for the meta-analysis. The total sample included 44833 individuals: 34773 (77.6%) Trp64Trp homozygotes and 10060 (22.4%) Arg64-allele carriers. On the basis of categories of ethnicity, diabetes status, study size, BMI and study design, we distinguished 172 subgroups.

Using a random effects model, we found a significant association between the Arg64Trp variant and BMI, with Arg64-allele carriers having a 0.24kg/m2 (95% CI 0.12–0.37; P=0.0002) higher BMI compared to Trp64Trp homozygotes (Figure 1). This absolute difference is equivalent to a standardized difference of 0.061 (95% CI 0.038–0.084; P=1.99 × 10−7) according to Cohen's d. We also found evidence for heterogeneity among the 172 subgroups (Q=349.85 (171 df), P=2.2 × 10−14; I2=51.1%). A funnel plot showed a symmetrical distribution, suggesting that there was no apparent publication bias (Begg's test P=0.051; Egger's test P=0.14) (Supplementary Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Difference in mean body mass index (BMI) and their 95% CI between the ADRB3 Arg64-allele carriers and Trp64Trp homozygotes across the 172 subgroups of 97 studies, including 44833 individuals. The size of the square reflects the statistical weight of the study in the overall pooled analysis.

Full figure and legend (180K)

To examine possible sources of heterogeneity, we analysed the data stratified by pre-specified study-level covariates: ethnicity, diabetes status, study size, BMI category and study design (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Difference in mean body mass index (BMI) and their 95% CI between the ADRB3 Arg64-allele carriers and Trp64Trp homozygotes across the 172 subgroups of 97 studies, stratified by ethnicity, diabetes status, study size, BMI category and study design. The size of the square reflects the statistical weight of the subgroup in the overall pooled analysis.

Full figure and legend (54K)

The difference in mean BMI between Trp64Trp and Arg64-allele carriers in East Asians (0.31kg/m2, 95% CI 0.13–0.48, P=0.001) was greater than that in European populations in whom no significant association was observed (0.08kg/m2, 95% CI −0.09 to 0.24, P=0.36). Although there was no statistically significant heterogeneity between East Asians and Europeans (P=0.22), the difference in minor allele frequency (18% in East Asians and 7.5% in Europeans) and in mean BMI warrants population stratification. The cumulative decrease in effect size over time reflects the difference between European and East Asian populations (Supplementary Figure 2). One year after the initial studies,3, 4 which reported large differences between Arg64–allele carriers and Trp64Trp homozygotes, the cumulative effect size decreased steadily in Europeans and reached nonsignificance after 11 studies in 1996.21 In East Asian populations, the cumulative effect size decreased after the first reports, but reached a steady state at a significant effect size of 0.24kg/m2 in 2000.53

In addition to ethnicity, when we considered other study-level covariates, we found that there was a tendency for smaller studies (n<100) to report larger differences (mean difference: 0.40kg/m2 95% CI 0.07–0.73, P=0.017) when compared with bigger studies (n>500) (0.11kg/m2, 95% CI −0.02 to 0.23, P=0.095). When stratified by study design and BMI categories, studies of non-selected populations were found to show smaller differences (0.10kg/m2, 95% CI 0.00–0.21, P=0.051) than those based on selected populations (0.37kg/m2, 95% CI 0.15–0.59, P=0.001), and studies in obese individuals reported more pronounced differences (1.03kg/m2, 95% CI 0.13–1.92, P=0.024) than studies in normal weight individuals (0.13kg/m2, 95% CI 0.01–0.25, P=0.029). Compared with nondiabetes controls, studies of type 2 diabetes showed smaller differences in BMI by genotype. These trends suggest that the overall estimate may be biased and an overestimation of any true association, although none of the study-level covariables materially explained the heterogeneity among studies.

Top

Discussion

In this paper, we have reported on the largest individual population-based study including 4854 individuals of European descent, showing no significant association between the ADRB3 Trp64Arg variant and BMI. Despite the large sample size, our study only had sufficient power (80%) to detect significant (α=0.05) differences of 0.50kg/m2 and larger. If the observed difference of 0.20kg/m2 BMI between Trp64Trp homozygotes and Arg64-carriers were true (α=0.05), we would need to study a population of at least 28000 individuals to have comparable power. Therefore, we combined all available studies in a meta-analysis.

The meta-analysis, including 44833 individuals of 97 studies, found a small but statistically significant difference in mean BMI by ADRB3 Trp64Arg genotype. The ADRB3 Arg64-allele carriers had a 0.24kg/m2 higher BMI than the Trp64Trp homozygotes. The difference was more pronounced (0.31kg/m2) and significant in East Asian populations. Among Europeans, there was no significant difference (0.08kg/m2). These observations are consistent with the first meta-analysis by Allison et al.,5 which included a total of 7399 individuals, one-fifth of the number included here. They found an overall nonsignificant BMI difference of 0.19kg/m2, with a larger difference in Japanese (0.24kg/m2, P=0.07) than in Europeans (0.17kg/m2, P=0.43). A meta-analysis published in 2001 pooling data from Japanese populations only (27 studies, n=6582) observed a similar effect size (0.26kg/m2, 95% CI: 0.18–0.42, P<0.01) to the one found by us in East Asians.7

The nearly fourfold difference in effect size and difference in Arg64-allele frequency suggest that the Trp64Arg polymorphism might be more important in East Asians than in Caucasians. A difference of 0.31kg/m2, as observed in East Asians, equals a difference of 790g to 1kg in absolute weight for a person with a height of 1.60–1.80m, respectively. With an Arg64-allele frequency of ~18%, 32.7% of the East Asian populations carry this variant and are thus at risk of a slightly higher BMI. In contrast, only 14.5% of Europeans carry the Arg64-allele (MAF ~7.5%), and the observed effect size (0.08kg/m2) equals a difference of only 200–260g for a person of 1.60–1.80m height. However, this assumes that the association in Caucasians is ‘true’, which would require a sample size of 165000 individuals (power=80%) to prove at a significance level of 5%. Ethnic heterogeneity was also reported in a recent meta-analysis of 12805 individuals that examined the association between the Trp64Arg variant and measures of insulin resistance.102 The Arg64-allele was associated with increased fasting insulin levels in Asians, but not Caucasians.102 These population differences are suggestive of an evolutionary divergence that might reflect a history of negative selection against the ADRB3 risk allele in Caucasians.

The functional effect of the Trp64Arg polymorphism on the expression and activity of the ADBR3 gene remains unclear. In vitro experiments in rodent and human cell lines showed that stimulation of cell lines with the Arg64-variant had a reduced ability to stimulate adenyl cyclase, activity compared with cell lines stimulated with the Trp variant.103, 104 Lipolysis in human adipocytes was lower in cells with the Arg64-variant compared with cells with the Trp variant.105 However, others did not observe any in vitro functional effects.12, 106 Thus, the functional properties of this variant remain uncertain. It is possible that the ADRB3 Trp64Arg variant is not the causal variant but it is in complete or nearly complete linkage disequilibrium with a yet unidentified variant that has functional relevance. A difference in linkage disequilibrium structure between Asians and Caucasians could explain why the Trp64Arg variant showed a significant association in Asians, but not Caucasians.

The chronological cumulative effect size, which is the combined effect size of all studies published up to a particular year, indicates that one could have made these observations 12 years ago. Supplementary Figure 2 suggests that the initial publications that reported large effect sizes prompted many to investigate the ADRB3 Trp64Arg-BMI association in their populations. However, most studies that followed could not replicate the initial results such that the cumulative effect size came down quickly and reached nonsignificance for Europeans in 1996, after 11 publications. Nevertheless, many more studies were published and are indeed still being published. Similarly, for East Asians the cumulative effect size came down quickly, but reached a significant steady state in 2000 at a cumulative BMI difference of ~0.24kg/m2.

While these previous reports indicate that there may be ethnic-specific differences in the magnitude of the association between this variant and BMI, our data and updated meta-analysis on 44833 individuals show that the association between Trp64Arg genotype and BMI was statistically significant in East Asians but not in Europeans, although the difference between these two groups did not attain statistical significance. Nevertheless, we observed a difference in the cumulative plots for Europeans and East Asians. Collectively, these ethnic differences could be interpreted in a number of ways. First, the lack of association among Caucasians could be true, or it might simply be a reflection of the rarity of the minor allele in these populations, thus making it difficult to detect a true difference without using even larger studies. Second, the association we observed in East Asians may likewise be true; or, given that the cumulative effect size did not move to a null, it is possible to speculate that the association is open to bias from a perpetuation of multiple small studies or from selective reporting. This reinforces the need for fewer larger-scale studies to reliably confirm or refute gene–disease associations. Third, if the associations we observed in both populations were true, this would reflect real differences in disease risk.

Publication bias is a common problem in meta-analyses and generally leads to an overestimation of the effect size. However, the symmetrical funnel plot (Supplementary Figure 1) indicates that the average difference in mean BMI does not systematically increase with its standard error and, thus, there is no apparent publication bias. This is consistent with previous meta-analyses on the Trp64Arg variant. Although none of our study-level covariables importantly explained study heterogeneity, we found trends that were suggestive of bias in the overall summary estimate of the association between this genetic variant and BMI. Specifically, larger studies, studies on unselected populations, and those based on populations with lower BMIs tended on average to report smaller associations.

Our study clearly shows the importance of meta-analyses in the field of genetic association studies for common traits. Each genetic variant makes only a small contribution to variation in BMI, and large sample sizes are needed to prove that the associations are significant. However, if too large sample sizes are needed, because of small effect size or rare variants, one needs to question the clinical relevance of the variant. We also show that the observations we made in this paper could have been made earlier if meta-analyses had been carried out in 2000. Studies published over the last 7 years did not change the effect size or significance of the association.

Top

References

  1. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B et al. The human obesity gene map: the 2005 update. Obesity 2006; 14: 529–644. | Article | PubMed | ISI |
  2. Walston J, Silver K, Bogardus C, Knowler WC, Celi FS, Austin S et al. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. N Engl J Med 1995; 333: 343–347. | Article | PubMed | ISI | ChemPort |
  3. Clement K, Vaisse C, Manning BS, Basdevant A, Guy-Grand B, Ruiz J et al. Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 1995; 333: 352–354. | Article | PubMed | ISI | ChemPort |
  4. Widen E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 1995; 333: 348–351. | Article | PubMed | ISI | ChemPort |
  5. Allison DB, Heo M, Faith MS, Pietrobelli A. Meta-analysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with body mass index. Int J Obes Relat Metab Disord 1998; 22: 559–566. | Article | PubMed | ChemPort |
  6. Fujisawa T, Ikegami H, Kawaguchi Y, Ogihara T. Meta-analysis of the association of Trp64Arg polymorphism of beta3-adrenergic receptor gene with body mass index. J Clin Endocrinol Metab 1998; 83: 2441–2444. | Article | PubMed | ISI | ChemPort |
  7. Kurokawa N, Nakai K, Kameo S, Liu Z-M, Satoh H. Association of BMI with the beta3-adrenergic receptor gene polymorphism in Japanese: meta-analysis. Obesity Res 2001; 9: 741–745. | Article | ChemPort |
  8. Day N, Oakes S, Luben R, Khaw KT, Bingham S, Welch A et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br J Cancer 1999; 80: 95–103. | PubMed | ISI |
  9. Kadowaki H, Yasuda K, Iwamoto K, Otabe S, Shimokawa K, Silver K et al. A mutation in the beta 3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects. Biochem Biophys Res Commun 1995; 215: 555–560. | Article | PubMed | ISI | ChemPort |
  10. Yoshida T, Sakane N, Umekawa T, Sakai M, Takahashi T, Kondo M. Mutation of beta 3-adrenergic-receptor gene and response to treatment of obesity. Lancet 1995; 346: 1433–1434. | Article | PubMed | ChemPort |
  11. Awata T, Katayama S. Genetic variation in the beta3-adrenergic receptor in Japanese NIDDM patients. Diabetes Care 1996; 19: 271–272. | PubMed | ChemPort |
  12. Li LS, Lonnqvist F, Luthman H, Arner P. Phenotypic characterization of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene in normal weight and obese subjects. Diabetologia 1996; 39: 857–860. | Article | PubMed | ISI | ChemPort |
  13. Urhammer SA, Clausen JO, Hansen T, Pedersen O. Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene. Diabetes 1996; 45: 1115–1120. | Article | PubMed | ISI | ChemPort |
  14. Sakane N, Yoshida T, Yoshioka K, Umekawa T, Takakura Y, Kogure A et al. Genetic variation in the beta 3-adrenergic receptor in Japanese NIDDM patients. Diabetes Care 1996; 19: 1034–1035. | PubMed | ChemPort |
  15. Kurabayashi T, Carey DG, Morrison NA. The beta 3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women. Effects on weight, BMI, abdominal fat, blood pressure, and reproductive history in an elderly Australian population. Diabetes 1996; 45: 1358–1363. | Article | PubMed | ISI | ChemPort |
  16. Silver K, Walston J, Wang Y, Dowse G, Zimmet P, Shuldiner AR. Molecular scanning for mutations in the beta 3-adrenergic receptor gene in Nauruans with obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81: 4155–4158. | Article | PubMed | ChemPort |
  17. Gagnon J, Mauriege P, Roy S, Sjostrom D, Chagnon YC, Dionne FT et al. The Trp64Arg mutation of the beta3 adrenergic receptor gene has no effect on obesity phenotypes in the quebec family study and Swedish obese subjects cohorts. J Clin Invest 1996; 98: 2086–2093. | Article | PubMed | ISI | ChemPort |
  18. Zhang Y, Wat N, Stratton IM, Warren-Perry MG, Orho M, Groop L et al. UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. UK Prospective Diabetes Study. Diabetologia 1996; 39: 1505–1511. | Article | PubMed | ChemPort |
  19. Fumeron F, Durack-Bown I, Betoulle D, Cassard-Doulcier AM, Tuzet S, Bouillaud F et al. Polymorphisms of uncoupling protein (UCP) and beta 3 adrenoreceptor genes in obese people submitted to a low calorie diet. Int J Obes Relat Metab Disord 1996; 20: 1051–1054. | PubMed | ChemPort |
  20. Oksanen L, Mustajoki P, Kaprio J, Kainulainen K, Janne O, Peltonen L et al. Polymorphism of the beta 3-adrenergic receptor gene in morbid obesity. Int J Obes Relat Metab Disord 1996; 20: 1055–1061. | PubMed | ChemPort |
  21. Elbein SC, Hoffman M, Barrett K, Wegner K, Miles C, Bachman K et al. Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair. J Clin Endocrinol Metab 1996; 81: 4422–4427. | Article | PubMed | ChemPort |
  22. Sakane N, Yoshida T, Umekawa T, Kondo M, Sakai Y, Takahashi T. Beta 3-adrenergic-receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome. Diabetologia 1997; 40: 200–204. | Article | PubMed | ChemPort |
  23. Ueda K, Tanizawa Y, Oota Y, Inoue H, Kizuki N, Tsukuda K et al. Prevalence of the Trp64Arg missense mutation of the beta3-adrenergic receptor gene in Japanese subjects. Metabolism 1997; 46: 199–202. | Article | PubMed | ISI | ChemPort |
  24. Higashi K, Ishikawa T, Ito T, Yonemura A, Shige H, Nakamura H. Association of a genetic variation in the beta 3-adrenergic receptor gene with coronary heart disease among Japanese. Biochem Biophys Res Commun 1997; 232: 728–730. | Article | PubMed | ChemPort |
  25. Nagase T, Aoki A, Yamamoto M, Yasuda H, Kado S, Nishikawa M et al. Lack of association between the Trp64 Arg mutation in the beta 3-adrenergic receptor gene and obesity in Japanese men: a longitudinal analysis. J Clin Endocrinol Metab 1997; 82: 1284–1287. | Article | PubMed | ChemPort |
  26. Yuan X, Yamada K, Koyama K, Ichikawa F, Ishiyama S, Koyanagi A et al. Beta 3-adrenergic receptor gene polymorphism is not a major genetic determinant of obesity and diabetes in Japanese general population. Diabetes Res Clin Pract 1997; 37: 1–7. | Article | PubMed | ChemPort |
  27. Jeyasingam CL, Bryson JM, Caterson ID, Yue DK, Donnelly R. Expression of the beta 3-adrenoceptor gene polymorphism (Trp64Arg) in obese diabetic and non-diabetic subjects. Clin Exp Pharmacol Physiol 1997; 24: 733–735. | Article | PubMed | ChemPort |
  28. Moriarty M, Wing RR, Kuller LH, Ferrell RE. Trp64Arg substitution in the beta 3-adrenergic receptor does not relate to body weight in healthy, premenopausal women. Int J Obes Relat Metab Disord 1997; 21: 826–829. | Article | PubMed | ChemPort |
  29. Arii K, Suehiro T, Yamamoto M, Ito H, Ikeda Y, Nakauchi Y et al. Trp64Arg mutation of beta 3-adrenergic receptor and insulin sensitivity in subjects with glucose intolerance. Intern Med 1997; 36: 603–606. | Article | PubMed | ChemPort |
  30. Silver K, Mitchell BD, Walston J, Sorkin JD, Stern MP, Roth J et al. TRP64ARG beta 3-adrenergic receptor and obesity in Mexican Americans. Hum Genet 1997; 101: 306–311. | Article | PubMed | ChemPort |
  31. Biery AJ, Ebbesson SO, Shuldiner AR, Boyer BB. The beta(3)-adrenergic receptor TRP64ARG polymorphism and obesity in Alaskan Eskimos. Int J Obes Relat Metab Disord 1997; 21: 1176–1179. | Article | PubMed | ChemPort |
  32. O'Dell SD, Bolla MK, Miller GJ, Cooper JA, Humphries SE, Day IN. W64R mutation in beta-3-adrenergic receptor gene and weight in a large population sample. Int J Obes Relat Metab Disord 1998; 22: 377–379. | Article | PubMed | ChemPort |
  33. McFarlane-Anderson N, Bennett F, Wilks R, Howell S, Newsome C, Cruickshank K et al. The Trp64Arg mutation of the beta3-adrenergic receptor is associated with hyperglycemia and current body mass index in Jamaican women. Metabolism 1998; 47: 617–621. | Article | PubMed | ChemPort |
  34. Sun L, Ishibashi S, Osuga J, Harada K, Ohashi K, Gotoda T et al. Clinical features associated with the homozygous Trp64Arg mutation of the beta3-adrenergic receptor: no evidence for its association with obesity in Japanese. Arterioscler Thromb Vasc Biol 1998; 18: 941–946. | PubMed | ChemPort |
  35. Shima Y, Tsukada T, Nakanishi K, Ohta H. Association of the Trp64Arg mutation of the beta3-adrenergic receptor with fatty liver and mild glucose intolerance in Japanese subjects. Clin Chim Acta 1998; 274: 167–176. | Article | PubMed | ChemPort |
  36. Janssen JA, Koper JW, Stolk RP, Englaro P, Uitterlinden AG, Huang Q et al. Lack of associations between serum leptin, a polymorphism in the gene for the beta 3-adrenergic receptor and glucose tolerance in the Dutch population. Clin Endocrinol (Oxf) 1998; 49: 229–234. | Article | PubMed | ChemPort |
  37. Buettner R, Schaffler A, Arndt H, Rogler G, Nusser J, Zietz B et al. The Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is not associated with obesity or type 2 diabetes mellitus in a large population-based Caucasian cohort. J Clin Endocrinol Metab 1998; 83: 2892–2897. | Article | PubMed | ChemPort |
  38. Xiang K, Jia W, Lu H, Zheng T, Lu J, Tang J et al. Effects of Trp64Arg mutation in the beta 3-adrenergic receptor gene on body fat, plasma glucose level, lipid profile, insulin secretion and action in Chinese [article in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 1998; 15: 337–340. | PubMed | ChemPort |
  39. Vendrell J, Gutierrez C, Broch M, Fernandez-Real JM, Aguilar C, Richart C. Beta 3-adrenoreceptor gene polymorphism and leptin. Lack of relationship in type 2 diabetic patients. Clin Endocrinol (Oxf) 1998; 49: 679–683. | Article | PubMed | ChemPort |
  40. Sakane N, Yoshida T, Yoshioka K, Nakamura Y, Umekawa T, Kogure A et al. Trp64Arg mutation of beta3-adrenoceptor gene is associated with diabetic nephropathy in Type II diabetes mellitus. Diabetologia 1998; 41: 1533–1534. | Article | PubMed | ChemPort |
  41. Hayashi H, Nagasaka S, Ishikawa S, Kawakami A, Rokkaku K, Nakamura T et al. Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene to multiple risk factors in Japanese men with hyperuricemia. Endocr J 1998; 45: 779–784. | Article | PubMed | ChemPort |
  42. Fogelholm M, Valve R, Kukkonen-Harjula K, Nenonen A, Hakkarainen V, Laakso M et al. Additive effects of the mutations in the beta3-adrenergic receptor and uncoupling protein-1 genes on weight loss and weight maintenance in Finnish women. J Clin Endocrinol Metab 1998; 83: 4246–4250. | Article | PubMed | ChemPort |
  43. Shiwaku K, Gao TQ, Isobe A, Fukushima T, Yamane Y. A Trp 64 Arg mutation in the beta3-adrenergic receptor gene is not associated with moderate overweight in Japanese workers. Metabolism 1998; 47: 1528–1530. | Article | PubMed | ISI | ChemPort |
  44. Hoffstedt J, Poirier O, Thorne A, Lonnqvist F, Herrmann SM, Cambien F et al. Polymorphism of the human beta3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. Diabetes 1999; 48: 203–205. | Article | PubMed | ISI | ChemPort |
  45. Tonolo G, Melis MG, Secchi G, Atzeni MM, Angius MF, Carboni A et al. Association of Trp64Arg beta 3-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population. J Hypertens 1999; 17: 33–38. | Article | PubMed | ISI | ChemPort |
  46. Ghosh S, Langefeld CD, Ally D, Watanabe RM, Hauser ER, Magnuson VL et al. The W64R variant of the beta3-adrenergic receptor is not associated with type II diabetes or obesity in a large Finnish sample. Diabetologia 1999; 42: 238–244. | Article | PubMed | ChemPort |
  47. Yanagisawa K, Iwasaki N, Sanaka M, Minei S, Kanamori M, Omori Y et al. Polymorphism of the beta3-adrenergic receptor gene and weight gain in pregnant diabetic women. Diabetes Res Clin Pract 1999; 44: 41–47. | Article | PubMed | ChemPort |
  48. Festa A, Krugluger W, Shnawa N, Hopmeier P, Haffner SM, Schernthaner G. Trp64Arg polymorphism of the beta3-adrenergic receptor gene in pregnancy: association with mild gestational diabetes mellitus. J Clin Endocrinol Metab 1999; 84: 1695–1699. | Article | PubMed | ChemPort |
  49. Hayakawa T, Nagai Y, Taniguchi M, Yamashita H, Takamura T, Abe T et al. Phenotypic characterization of the beta3-adrenergic receptor mutation and the uncoupling protein 1 polymorphism in Japanese men. Metabolism 1999; 48: 636–640. | Article | PubMed | ChemPort |
  50. Sheu WH, Lee WJ, Yao YE, Jeng CY, Young MM, Chen YT. Lack of association between genetic variation in the beta3-adrenergic receptor gene and insulin resistance in patients with coronary heart disease. Metabolism 1999; 48: 651–654. | Article | PubMed | ChemPort |
  51. Lin SY, Sheu WH, Lee WJ, Song YM, Chen YT. Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is associated with increased plasma leptin levels in obese Chinese women. Zhonghua Yi Xue Za Zhi (Taipei) 1999; 62: 569–576. | PubMed | ChemPort |
  52. Benecke H, Topak H, von zur Muhlen A, Schuppert F. A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors. Exp Clin Endocrinol Diabetes 2000; 108: 86–92. | Article | PubMed | ChemPort |
  53. Sun L, Yoko I, Shun I. Investigation and comparison of the beta3-adrenergic receptor gene Trp64Arg mutation in the Chinese and Japanese [article in Chinese]. Zhonghua Yi Xue Za Zhi 2000; 80: 107–110. | PubMed | ChemPort |
  54. Thomas GN, Tomlinson B, Chan JC, Young RP, Critchley JA. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab Disord 2000; 24: 545–551. | Article | PubMed | ChemPort |
  55. Pamies-Andreu E, Garcia-Lozano R, Palmero-Palmero C, Garcia-Morillo S, Alonso-Arcas A, Stiefel P et al. Genetic variation in the beta-3-adrenergic receptor in essential hypertension. Life Sci 2000; 67: 391–397. | Article | PubMed | ChemPort |
  56. Alevizaki M, Thalassinou L, Grigorakis SI, Philippou G, Lili K, Souvatzoglou A et al. Study of the Trp64Arg polymorphism of the beta3-adrenergic receptor in Greek women with gestational diabetes. Diabetes Care 2000; 23: 1079–1083. | Article | PubMed | ChemPort |
  57. Ringel J, Kreutz R, Distler A, Sharma AM. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus. Am J Hypertens 2000; 13: 1027–1031. | Article | PubMed | ChemPort |
  58. Evans D, Minouchehr S, Hagemann G, Mann WA, Wendt D, Wolf A et al. Frequency of and interaction between polymorphisms in the beta3-adrenergic receptor and in uncoupling proteins 1 and 2 and obesity in Germans. Int J Obes Relat Metab Disord 2000; 24: 1239–1245. | Article | PubMed | ChemPort |
  59. Manraj M, Francke S, Hebe A, US R, Froguel P. Genetic and environmental nature of the insulin resistance syndrome in Indo-Mauritian subjects with premature coronary heart disease: contribution of beta3-adrenoreceptor gene polymorphism and beta blockers on triglyceride and HDL concentrations. Diabetologia 2001; 44: 115–122. | Article | PubMed | ChemPort |
  60. Lowe Jr WL, Rotimi CN, Luke A, Guo X, Zhu X, Comuzzie AG et al. The beta 3-adrenergic receptor gene and obesity in a population sample of African Americans. Int J Obes Relat Metab Disord 2001; 25: 54–60. | Article | PubMed | ChemPort |
  61. Oeveren van-Dybicz AM, Vonkeman HE, Bon MA, van den Bergh FA, Vermes I. Beta 3-adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population. Diabetes Obes Metab 2001; 3: 47–51. | Article | PubMed | ChemPort |
  62. Strazzullo P, Iacone R, Siani A, Cappuccio FP, Russo O, Barba G et al. Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pressure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens 2001; 19: 399–406. | Article | PubMed | ISI | ChemPort |
  63. Yamauchi T, Kuno T, Takada H, Mishima K, Nagura Y, Takahashi S et al. The impact of Trp64Arg mutation in the beta3-adrenergic receptor gene on haemodialysis patients. Nephrol Dial Transplant 2001; 16: 641–642. | Article | PubMed | ChemPort |
  64. Huang XE, Hamajima N, Saito T, Matsuo K, Mizutani M, Iwata H et al. Possible association of beta2- and beta3-adrenergic receptor gene polymorphisms with susceptibility to breast cancer. Breast Cancer Res 2001; 3: 264–269. | Article | PubMed | ChemPort |
  65. Carlsson M, Orho-Melander M, Hedenbro J, Groop LC. Common variants in the beta2-(Gln27Glu) and beta3-(Trp64Arg)--adrenoceptor genes are associated with elevated serum NEFA concentrations and type II diabetes. Diabetologia 2001; 44: 629–636. | Article | PubMed | ISI | ChemPort |
  66. Shihara N, Yasuda K, Moritani T, Ue H, Uno M, Adachi T et al. Synergistic effect of polymorphisms of uncoupling protein 1 and beta3-adrenergic receptor genes on autonomic nervous system activity. Int J Obes Relat Metab Disord 2001; 25: 761–766. | Article | PubMed | ChemPort |
  67. Oizumi T, Daimon M, Saitoh T, Kameda W, Yamaguchi H, Ohnuma H et al. Genotype Arg/Arg, but not Trp/Arg, of the Trp64Arg polymorphism of the beta(3)-adrenergic receptor is associated with type 2 diabetes and obesity in a large Japanese sample. Diabetes Care 2001; 24: 1579–1583. | Article | PubMed | ChemPort |
  68. Chen Y, Xu Y, Zhou L. Association of beta 3-adrenergic receptor gene with obesity in patients with type 2 diabetes mellitus [article in Chinese]. Zhonghua Yu Fang Yi Xue Za Zhi 2001; 35: 333–335. | PubMed | ChemPort |
  69. Kawamura T, Egusa G, Fujikawa R, Okubo M. Beta(3)-adrenergic receptor gene variant is associated with upper body obesity only in obese Japanese–American men but not in women. Diabetes Res Clin Pract 2001; 54: 49–55. | Article | PubMed | ChemPort |
  70. Corella D, Guillen M, Portoles O, Sorli JV, Alonso V, Folch J et al. Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation. J Intern Med 2001; 250: 348–360. | Article | PubMed | ISI | ChemPort |
  71. Ishii T, Hirose H, Kawai T, Hayashi K, Maruyama H, Saito I et al. Effects of intestinal fatty acid-binding protein gene Ala54Thr polymorphism and beta3-adrenergic receptor gene Trp64Arg polymorphism on insulin resistance and fasting plasma glucose in young to older Japanese men. Metabolism 2001; 50: 1301–1307. | Article | PubMed | ChemPort |
  72. Santos JL, Perez-Bravo F, Martinez JA, Montalvo D, Albala C, Carrasco E. No evidence for an association between genetic polymorphisms of beta(2)- and beta(3)-adrenergic receptor genes with body mass index in Aymara natives from Chile. Nutrition 2002; 18: 255–258. | Article | PubMed | ChemPort |
  73. Zhu L, Liu K, Wang R, Hou J. Investigation and comparison of the beta(3)-adrenergic receptor gene Trp64Arg mutation in simple obesity and metabolic syndrome [article in Chinese]. Zhonghua Nei Ke Za Zhi 2002; 41: 224–228. | PubMed | ChemPort |
  74. Okumura K, Matsui H, Ogawa Y, Takahashi R, Matsubara K, Imai H et al. The polymorphism of the beta3-adrenergic receptor gene is associated with reduced low-density lipoprotein particle size. Metabolism 2003; 52: 356–361. | Article | PubMed | ISI | ChemPort |
  75. Walston J, Andersen RE, Seibert M, Hilfiker H, Beamer B, Blumenthal J et al. Arg64 beta3-adrenoceptor variant and the components of energy expenditure. Obes Res 2003; 11: 509–511. | Article | PubMed | ChemPort |
  76. Frederiksen L, Brodbaek K, Fenger M, Madsbad S, Urhammer SA, Jorgensen T et al. No interactions between polymorphisms in the beta3-adrenergic receptor gene and the PPAR-gamma gene on the risk of the insulin resistance syndrome in the Danish MONICA cohort. Diabetologia 2003; 46: 729–731. | PubMed | ChemPort |
  77. Matsushita H, Kurabayashi T, Tomita M, Kato N, Tanaka K. Effects of uncoupling protein 1 and beta3-adrenergic receptor gene polymorphisms on body size and serum lipid concentrations in Japanese women. Maturitas 2003; 45: 39–45. | Article | PubMed | ISI | ChemPort |
  78. Shiwaku K, Nogi A, Anuurad E, Kitajima K, Enkhmaa B, Shimono K et al. Difficulty in losing weight by behavioral intervention for women with Trp64Arg polymorphism of the beta3-adrenergic receptor gene. Int J Obes Relat Metab Disord 2003; 27: 1028–1036. | Article | PubMed | ChemPort |
  79. Aoyama M, Shidoji Y, Saimei M, Tsunawake N, Ichinose M. Phenotypic linkage between single-nucleotide polymorphisms of beta3-adrenergic receptor gene and NADH dehydrogenase subunit-2 gene, with special reference to eating behavior. Biochem Biophys Res Commun 2003; 309: 261–265. | Article | PubMed | ChemPort |
  80. Matsushita Y, Yokoyama T, Yoshiike N, Matsumura Y, Date C, Kawahara K et al. The Trp(64)Arg polymorphism of the beta(3)-adrenergic receptor gene is not associated with body weight or body mass index in Japanese: a longitudinal analysis. J Clin Endocrinol Metab 2003; 88: 5914–5920. | Article | PubMed | ChemPort |
  81. Karasaki Y, Kashiwazaki H. Polymorphism of Trp64Arg in beta3-adrenergic receptor gene among Bolivian people in rural areas at high and low altitudes. Ann Clin Biochem 2004; 41: 57–60. | Article | PubMed | ChemPort |
  82. Malina AN, Laivuori HM, Agatisa PK, Collura LA, Crombleholme WR, Sims CJ et al. The Trp64Arg polymorphism of the beta3-adrenergic receptor is not increased in women with preeclampsia. Am J Obstet Gynecol 2004; 190: 779–783. | Article | PubMed | ChemPort |
  83. Kim OY, Cho EY, Park HY, Jang Y, Lee JH. Additive effect of the mutations in the beta3-adrenoceptor gene and UCP3 gene promoter on body fat distribution and glycemic control after weight reduction in overweight subjects with CAD or metabolic syndrome. Int J Obes Relat Metab Disord 2004; 28: 434–441. | Article | PubMed | ChemPort |
  84. Nozaki Y, Saibara T, Nemoto Y, Ono M, Akisawa N, Iwasaki S et al. Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis. Alcohol Clin Exp Res 2004; 28: 106S–110S. | PubMed | ChemPort |
  85. Tsai PJ, Ho SC, Tsai LP, Lee YH, Hsu SP, Yang SP et al. Lack of relationship between beta3-adrenergic receptor gene polymorphism and gestational diabetes mellitus in a Taiwanese population. Metabolism 2004; 53: 1136–1139. | Article | PubMed | ChemPort |
  86. Ramis JM, Gonzalez-Sanchez JL, Proenza AM, Martinez-Larrad MT, Fernandez-Perez C, Palou A et al. The Arg64 allele of the beta 3-adrenoceptor gene but not the -3826G allele of the uncoupling protein 1 gene is associated with increased leptin levels in the Spanish population. Metabolism 2004; 53: 1411–1416. | Article | PubMed | ChemPort |
  87. Zhang C, Williams M, Edwards K, Austin M. Trp(64)Arg polymorphism of the beta3-adrenergic receptor gene, pre-pregnancy obesity and risk of pre-eclampsia. J Matern Fetal Neonatal Med 2005; 17: 19–28. | Article | PubMed | ISI | ChemPort |
  88. Perez-Bravo F, Echiburu B, Maliqueo M, Santos JL, Sir-Petermann T. Tryptophan 64 right arrow arginine polymorphism of beta-3-adrenergic receptor in Chilean women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2005; 62: 126–131. | Article | PubMed | ChemPort |
  89. Nagano T, Matsuda Y, Tanioka T, Yoshioka T, Hiroi T, Yoshikawa K et al. No association of the Trp 64 Arg mutation of the beta3-adrenergic receptor gene with obesity, type 2 diabetes mellitus, hyperlipidemia, and hypertension in Japanese patients with schizophrenia. J Med Invest 2005; 52: 57–64. | Article | PubMed |
  90. Zhang LQ, Yao WZ, He QY, Wang YZ, Ren B, Lin YP. Polymorphisms in the beta2 and beta3 adrenergic receptor genes in obstructive sleep apnea/hypopnea syndrome [article in Chinese]. Zhonghua Nei Ke Za Zhi 2005; 44: 333–336. | PubMed | ChemPort |
  91. Terra SG, McGorray SP, Wu R, McNamara DM, Cavallari LH, Walker JR et al. Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study. Int J Obes (Lond) 2005; 29: 746–754. | Article | PubMed | ChemPort |
  92. Miyaki K, Sutani S, Kikuchi H, Takei I, Murata M, Watanabe K et al. Increased risk of obesity resulting from the interaction between high energy intake and the Trp64Arg polymorphism of the beta3-adrenergic receptor gene in healthy Japanese men. J Epidemiol 2005; 15: 203–210. | Article | PubMed |
  93. Mattevi VS, Zembrzuski VM, Hutz MH. Impact of variation in ADRB2, ADRB3, and GNB3 genes on body mass index and waist circumference in a Brazilian population. Am J Hum Biol 2006; 18: 182–186. | Article | PubMed |
  94. Wang CY, Nguyen ND, Morrison NA, Eisman JA, Center JR, Nguyen TV. Beta3-adrenergic receptor gene, body mass index, bone mineral density and fracture risk in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES). BMC Med Genet 2006; 7: 57. | Article | PubMed | ChemPort |
  95. Kim K, Lee S, Lim K, Cheun W, Ahn N, Shin Y et al. Comparison of body fat distribution and blood lipid profiles according to Trp64Arg polymorphism for the beta 3-adrenergic receptor gene in Korean middle-aged women. J Nutr Sci Vitaminol (Tokyo) 2006; 52: 281–286. | Article | PubMed | ChemPort |
  96. Yuan M, Ohishi M, Ito N, Sugimoto K, Takagi T, Terai M et al. Genetic influences of beta-adrenoceptor polymorphisms on arterial functional changes and cardiac remodeling in hypertensive patients. Hypertens Res 2006; 29: 875–881. | Article | PubMed | ChemPort |
  97. Tamaki S, Nakamura Y, Tabara Y, Okamura T, Kita Y, Kadowaki T et al. Relationship between metabolic syndrome and Trp64arg polymorphism of the beta-adrenergic receptor gene in a general sample: the Shigaraki study. Hypertens Res 2006; 29: 891–896. | Article | PubMed | ChemPort |
  98. Fallucca F, Dalfra MG, Sciullo E, Masin M, Buongiorno AM, Napoli A et al. Polymorphisms of insulin receptor substrate 1 and beta3-adrenergic receptor genes in gestational diabetes and normal pregnancy. Metabolism 2006; 55: 1451–1456. | Article | PubMed | ChemPort |
  99. Kawaguchi H, Masuo K, Katsuya T, Sugimoto K, Rakugi H, Ogihara T et al. beta2- and beta3-Adrenoceptor polymorphisms relate to subsequent weight gain and blood pressure elevation in obese normotensive individuals. Hypertens Res 2006; 29: 951–959. | Article | PubMed | ChemPort |
  100. Mergen H, Karaaslan C, Mergen M, Deniz Ozsoy E, Ozata M. LEPR, ADBR3, IRS-1 and 5-HTT genes polymorphisms do not associate with obesity. Endocr J 2007; 54: 89–94. | Article | PubMed | ChemPort |
  101. Ueno T, Takahashi Y, Matsumoto T, Tsunemi A, Watanabe H, Tahira K et al. Postprandial plasma lipid levels are influenced by the interaction of functional polymorphisms in the microsome triglyceride transfer protein and beta3 adrenergic receptor genes. Med Sci Monit 2007; 13: BR112–BR118. | PubMed | ChemPort |
  102. Zhan S, Ho SC. Meta-analysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with insulin resistance. Obesity Res 2005; 13: 1709–1719. | Article | ChemPort |
  103. Pietri-Rouxel F, Manning BS, Gros J, Strosberg AD. The biochemical effect of the naturally occurring Trp64 right arrow Arg mutation on human beta3-adrenoceptor activity. Eur J Biochem 1997; 247: 1174–1179. | Article | PubMed | ChemPort |
  104. Kimura K, Sasaki N, Asano A, Mizukami J, Kayahashi S, Kawada T et al. Mutated human beta3-adrenergic receptor (Trp64Arg) lowers the response to beta3-adrenergic agonists in transfected 3T3-L1 preadipocytes. Horm Metab Res 2000; 32: 91–96. | PubMed | ChemPort |
  105. Umekawa T, Yoshida T, Sakane N, Kogure A, Kondo M, Honjyo H. Trp64Arg mutation of beta3-adrenoceptor gene deteriorates lipolysis induced by beta3-adrenoceptor agonist in human omental adipocytes. Diabetes 1999; 48: 117–120. | Article | PubMed | ChemPort |
  106. Candelore MR, Deng L, Tota LM, Kelly LJ, Cascieri MA, Strader CD. Pharmacological characterization of a recently described human beta 3- adrenergic receptor mutant. Endocrinology 1996; 137: 2638–2641. | Article | PubMed | ISI | ChemPort |
Top

Acknowledgements

We gratefully acknowledge the support of the corresponding authors for providing us additional information to conduct the necessary analyses: Professor K Tsuda, Laboratory of Metabolism, Graduate School of Human and Environmental Studies, Kyoto University, Japan; Dr N Sakane, Department of Preventive Medicine, Clinical Research Institute for Endocrine and Metabolic Disease, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan; Dr FS Celi, Clinical Endocrinology Branch, NIDDK, NIH, USA. NK is supported by a Grant-in-Aid for JSPS Fellows (15.6974) and the Daiwa Anglo-Japanese Foundation.

Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo)

Extra navigation

.

natureevents

ADVERTISEMENT