Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases

Abstract

Objective:

To determine if a missense change at codon 64 of ADRB3 (Trp64Arg), a candidate obesity gene, is associated with obesity and levels of subcutaneous or visceral fat in African-American breast cancer cases. Several observational studies have found that women, who are overweight or obese at the time of diagnosis, as well as those who gain weight after diagnosis, are at greater risk for breast cancer recurrence and death than non-overweight women.

Design:

Prospective cohort of breast cancer cases.

Subjects:

219 African-American breast cancer patients participating in the Los Angeles component of the Health, Eating, Activity and Lifestyle Study.

Measures:

ADRB3 Trp64Arg genotype, measures of weight including body mass index (BMI), weight gain (weight 5 years before diagnosis compared with weight at 30 months after diagnosis), obesity (BMI30 kg/m2), waist/hip circumference and visceral or subcutaneous fat were determined by magnetic resonance imaging.

Results:

African-American women who were homozygous for the ADRB3 wild-type allele had significantly higher mean visceral fat levels than women who carried the variant (P=0.04), and were significantly more likely to be obese (odd ratios (OR)=2.1, 95% confidence interval (CI)=1.1–4.2). The association with obesity was most pronounced among women who were premenopausal (OR=4.8, 95% CI=1.3–18), who received chemotherapy for their breast cancer (OR=6.1, 95% CI=1.8–20), or who were not physically active (OR=3.9, 95% CI=1.5–9.7).

Conclusion:

The wild-type allele of the ADRB3 missense change was associated with measures of obesity in our sample of African-American women. The association was modified by menopausal status, history of chemotherapy and modest levels of physical activity. These results will need to be confirmed in an independent sample.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. American Cancer Society. Detailed Guide: Breast Cancer. What are the Key Statistics for Breast Cancer?. Atlanta, GA, 2005. www.cancer.org.

  2. Chlebowski RT, Aiello E, McTiernan A . Weight loss in breast cancer patient management. J Clin Oncol 2002; 20: 1128–1143.

    Article  Google Scholar 

  3. Demark-Wahnefried W, Rimer BK, Winer EP . Weight gain in women diagnosed with breast cancer. J Am Diet Assoc 1997; 97: 519–526, 529; quiz 527–528.

    Article  CAS  Google Scholar 

  4. Daling JR, Malone KE, Doody DR, Johnson LG, Gralow JR, Porter PL . Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma. Cancer 2001; 92: 720–729.

    Article  CAS  Google Scholar 

  5. Newman SC, Lees AW, Jenkins HJ . The effect of body mass index and oestrogen receptor level on survival of breast cancer patients. Int J Epidemiol 1997; 26: 484–490.

    Article  CAS  Google Scholar 

  6. Goodwin P, Esplen MJ, Butler K, Winocur J, Pritchard K, Brazel S et al. Multidisciplinary weight management in locoregional breast cancer: results of a phase II study. Breast Cancer Res Treat 1998; 48: 53–64.

    Article  CAS  Google Scholar 

  7. Weiderpass E, Braaten T, Magnusson C, Kumle M, Vainio H, Lund E et al. A prospective study of body size in different periods of life and risk of premenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 2004; 13: 1121–1127.

    PubMed  Google Scholar 

  8. Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95: 1218–1226.

    Article  CAS  Google Scholar 

  9. Bouchard C, Perusse L . Genetics of obesity. Annu Rev Nutr 1993; 13: 337–354.

    Article  CAS  Google Scholar 

  10. Maes HH, Neale MC, Eaves LJ . Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997; 27: 325–351.

    Article  CAS  Google Scholar 

  11. Emorine L, Blin N, Strosberg AD . The human beta 3-adrenoceptor: the search for a physiological function. Trends Pharmacol Sci 1994; 15: 3–7.

    Article  CAS  Google Scholar 

  12. 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  CAS  Google Scholar 

  13. 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  CAS  Google Scholar 

  14. Mitchell BD, Blangero J, Comuzzie AG, Almasy LA, Shuldiner AR, Silver K et al. A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. J Clin Invest 1998; 101: 584–587.

    Article  CAS  Google Scholar 

  15. 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  CAS  Google Scholar 

  16. McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R et al. Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 2003; 21: 1961–1966.

    Article  CAS  Google Scholar 

  17. Irwin ML, Crumley D, McTiernan A, Bernstein L, Baumgartner R, Gilliland FD et al. Physical activity levels before and after a diagnosis of breast carcinoma: the health, eating, activity, and lifestyle (HEAL) study. Cancer 2003; 97: 1746–1757.

    Article  Google Scholar 

  18. Irwin ML, McTiernan A, Bernstein L, Gilliland FD, Baumgartner R, Baumgartner K et al. Physical activity levels among breast cancer survivors. Med Sci Sports Exerc 2004; 36: 1484–1491.

    PubMed  PubMed Central  Google Scholar 

  19. McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R et al. Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 2003; 21: 1961–1966.

    Article  CAS  Google Scholar 

  20. Kriska A . Modifiable activity questionnaire. Med Sci Sports Exerc 1997; 29: S73–S78.

    Google Scholar 

  21. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 2000; 32 (Suppl 9): S498–S504.

    Article  CAS  Google Scholar 

  22. Ogden CL, Flegal KM, Carroll MD, Johnson CL . Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002; 288: 1728–1732.

    Article  Google Scholar 

  23. Livak KJ . Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999; 14: 143–149.

    Article  CAS  Google Scholar 

  24. 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  CAS  Google Scholar 

  25. 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  CAS  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. 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  CAS  Google Scholar 

  28. 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 Relat Metab Disord 2005; 29: 746–754.

    Article  CAS  Google Scholar 

  29. 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  CAS  Google Scholar 

  30. Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko C et al. Molecular characterization of the human beta 3-adrenergic receptor. Science 1989; 245: 1118–1121.

    Article  CAS  Google Scholar 

  31. Arner P, Hoffstedt J . Adrenoceptor genes in human obesity. J Intern Med 1999; 245: 667–672.

    Article  CAS  Google Scholar 

  32. 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  CAS  Google Scholar 

  33. Pietri-Rouxel F, St John Manning B, Gros J, Strosberg AD . The biochemical effect of the naturally occurring Trp64 → Arg mutation on human beta3-adrenoceptor activity. Eur J Biochem 1997; 247: 1174–1179.

    Article  CAS  Google Scholar 

  34. 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  CAS  Google Scholar 

  35. Heasman KZ, Sutherland HJ, Campbell JA, Elhakim T, Boyd NF . Weight gain during adjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 1985; 5: 195–200.

    Article  CAS  Google Scholar 

  36. 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  CAS  Google Scholar 

  37. Lonnqvist F, Thome A, Nilsell K, Hoffstedt J, Arner P . A pathogenic role of visceral fat beta 3-adrenoceptors in obesity. J Clin Invest 1995; 95: 1109–1116.

    Article  CAS  Google Scholar 

  38. Hoffstedt J, Shimizu M, Sjostedt S, Lonnqvist F . Determination of beta 3-adrenoceptor mediated lipolysis in human fat cells. Obes Res 1995; 3: 447–457.

    Article  CAS  Google Scholar 

  39. Katzmarzyk PT, Perusse L, Bouchard C . Genetics of abdominal visceral fat levels. Am J Human Biol 1999; 11: 225–235.

    Article  Google Scholar 

  40. 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  CAS  Google Scholar 

  41. Pasquali R, Casimirri F, Labate AM, Tortelli O, Pascal G, Anconetani B et al. Body weight, fat distribution and the menopausal status in women. The VMH Collaborative Group. Int J Obes Relat Metab Disord 1994; 18: 614–621.

    CAS  PubMed  Google Scholar 

  42. Ley CJ, Lees B, Stevenson JC . Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr 1992; 55: 950–954.

    Article  CAS  Google Scholar 

  43. Aloia JF, McGowan DM, Vaswani AN, Ross P, Cohn SH . Relationship of menopause to skeletal and muscle mass. Am J Clin Nutr 1991; 53: 1378–1383.

    Article  CAS  Google Scholar 

  44. 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  CAS  Google Scholar 

  45. Demark-Wahnefried W, Peterson BL, Winer EP, Marks L, Aziz N, Marcom PK et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2001; 19: 2381–2389.

    Article  CAS  Google Scholar 

  46. Aslani A, Smith RC, Allen BJ, Pavlakis N, Levi JA . Changes in body composition during breast cancer chemotherapy with the CMF-regimen. Breast Cancer Res Treat 1999; 57: 285–290.

    Article  CAS  Google Scholar 

  47. Demark-Wahnefried W, Winer EP, Rimer BK . Why women gain weight with adjuvant chemotherapy for breast cancer. J Clin Oncol 1993; 11: 1418–1429.

    Article  CAS  Google Scholar 

  48. Slentz CA, Aiken LB, Houmard JA, Bales CW, Johnson JL, Tanner CJ et al. Inactivity, exercise, and visceral fat. STRRIDE: a randomized, controlled study of exercise intensity and amount. J Appl Physiol 2005; 99: 1613–1618.

    Article  Google Scholar 

  49. Santeusanio F, Di Loreto C, Lucidi P, Murdolo G, De Cicco A, Parlanti N et al. Diabetes and exercise. J Endocrinol Invest 2003; 26: 937–940.

    Article  CAS  Google Scholar 

  50. Irwin ML, Yasui Y, Ulrich CM, Bowen D, Rudolph RE, Schwartz RS et al. Effect of exercise on total and intra-abdominal body fat in postmenopausal women: a randomized controlled trial. JAMA 2003; 289: 323–330.

    Article  Google Scholar 

  51. Warren M, Schreiner PJ, Terry JG . The relation between visceral fat measurement and torso level – is one level better than another? The Atherosclerosis Risk in Communities Study 1990–1992. Am J Epidemiol 2006; 163: 352–358.

    Article  Google Scholar 

  52. Bernstein L, Henderson BE, Hanisch R, Sullivan-Halley J, Ross RK . Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst 1994; 86: 1403–1408.

    Article  CAS  Google Scholar 

  53. Gilliland FD, Li YF, Baumgartner K, Crumley D, Samet JM . Physical activity and breast cancer risk in hispanic and non-hispanic white women. Am J Epidemiol 2001; 154: 442–450.

    Article  CAS  Google Scholar 

  54. International Agency for Research on Cancer. Weight Control and Physical Activity. IARC Handbooks for Cancer Prevention vol. 6 IARC Press: Lyon, France, 2002.

  55. Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA . Physical activity and survival after breast cancer diagnosis. JAMA 2005; 293: 2479–2486.

    Article  CAS  Google Scholar 

  56. Marti A, Corbalan MS, Martinez-Gonzalez MA, Martinez JA . TRP64ARG polymorphism of the beta 3-adrenergic receptor gene and obesity risk: effect modification by a sedentary lifestyle. Diabetes Obes Metab 2002; 4: 428–430.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract Nos. N01-PC-35139, N01-PC-35139 and NIH/NCI/PC-67010. Initial data collection for the Los Angeles County patients was supported by the National Institute of Child Health and Human Development through contract N01 HD 3–3175. The collection of California cancer incidence data used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885 103885. The ideas and opinions expressed herein are those of the author, and no endorsement by the State of California, Department of Health Services, is intended or should be inferred.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R McKean-Cowdin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McKean-Cowdin, R., Li, X., Bernstein, L. et al. The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases. Int J Obes 31, 1110–1118 (2007). https://doi.org/10.1038/sj.ijo.0803554

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803554

Keywords

This article is cited by

Search

Quick links