Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Feb 1;101(3):584–587. doi: 10.1172/JCI512

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

B D Mitchell 1, J Blangero 1, A G Comuzzie 1, L A Almasy 1, A R Shuldiner 1, K Silver 1, M P Stern 1, J W MacCluer 1, J E Hixson 1
PMCID: PMC508601  PMID: 9449691

Abstract

The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.

Full Text

The Full Text of this article is available as a PDF (141.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Awata T., Katayama S. Genetic variation in the beta3-adrenergic receptor in Japanese NIDDM patients. Diabetes Care. 1996 Mar;19(3):271–272. doi: 10.2337/diacare.19.3.271b. [DOI] [PubMed] [Google Scholar]
  2. Borecki I. B., Bonney G. E., Rice T., Bouchard C., Rao D. C. Influence of genotype-dependent effects of covariates on the outcome of segregation analysis of the body mass index. Am J Hum Genet. 1993 Sep;53(3):676–687. [PMC free article] [PubMed] [Google Scholar]
  3. Bouchard C., Pérusse L. Genetics of obesity. Annu Rev Nutr. 1993;13:337–354. doi: 10.1146/annurev.nu.13.070193.002005. [DOI] [PubMed] [Google Scholar]
  4. Candelore M. R., Deng L., Tota L. M., Kelly L. J., Cascieri M. A., Strader C. D. Pharmacological characterization of a recently described human beta 3-adrenergic receptor mutant. Endocrinology. 1996 Jun;137(6):2638–2641. doi: 10.1210/endo.137.6.8641219. [DOI] [PubMed] [Google Scholar]
  5. Clément K., Vaisse C., Manning B. S., Basdevant A., Guy-Grand B., Ruiz J., Silver K. D., Shuldiner A. R., Froguel P., Strosberg A. D. 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 Aug 10;333(6):352–354. doi: 10.1056/NEJM199508103330605. [DOI] [PubMed] [Google Scholar]
  6. Comuzzie A. G., Blangero J., Mahaney M. C., Mitchell B. D., Hixson J. E., Samollow P. B., Stern M. P., MacCluer J. W. Major gene with sex-specific effects influences fat mass in Mexican Americans. Genet Epidemiol. 1995;12(5):475–488. doi: 10.1002/gepi.1370120505. [DOI] [PubMed] [Google Scholar]
  7. Comuzzie A. G., Hixson J. E., Almasy L., Mitchell B. D., Mahaney M. C., Dyer T. D., Stern M. P., MacCluer J. W., Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet. 1997 Mar;15(3):273–276. doi: 10.1038/ng0397-273. [DOI] [PubMed] [Google Scholar]
  8. Considine R. V., Sinha M. K., Heiman M. L., Kriauciunas A., Stephens T. W., Nyce M. R., Ohannesian J. P., Marco C. C., McKee L. J., Bauer T. L. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996 Feb 1;334(5):292–295. doi: 10.1056/NEJM199602013340503. [DOI] [PubMed] [Google Scholar]
  9. Davis S., Schroeder M., Goldin L. R., Weeks D. E. Nonparametric simulation-based statistics for detecting linkage in general pedigrees. Am J Hum Genet. 1996 Apr;58(4):867–880. [PMC free article] [PubMed] [Google Scholar]
  10. Elbein S. C., Hoffman M., Barrett K., Wegner K., Miles C., Bachman K., Berkowitz D., Shuldiner A. R., Leppert M. F., Hasstedt S. 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 Dec;81(12):4422–4427. doi: 10.1210/jcem.81.12.8954053. [DOI] [PubMed] [Google Scholar]
  11. Fujisawa T., Ikegami H., Yamato E., Takekawa K., Nakagawa Y., Hamada Y., Oga T., Ueda H., Shintani M., Fukuda M. Association of Trp64Arg mutation of the beta3-adrenergic-receptor with NIDDM and body weight gain. Diabetologia. 1996 Mar;39(3):349–352. doi: 10.1007/BF00418352. [DOI] [PubMed] [Google Scholar]
  12. Kurabayashi T., Carey D. G., Morrison N. A. 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 Oct;45(10):1358–1363. doi: 10.2337/diab.45.10.1358. [DOI] [PubMed] [Google Scholar]
  13. Lecomte E., Herbeth B., Nicaud V., Rakotovao R., Artur Y., Tiret L. Segregation analysis of fat mass and fat-free mass with age- and sex-dependent effects: the Stanislas Family Study. Genet Epidemiol. 1997;14(1):51–62. doi: 10.1002/(SICI)1098-2272(1997)14:1<51::AID-GEPI4>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  14. Li L. S., Lönnqvist 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 Jul;39(7):857–860. doi: 10.1007/s001250050521. [DOI] [PubMed] [Google Scholar]
  15. Maffei M., Halaas J., Ravussin E., Pratley R. E., Lee G. H., Zhang Y., Fei H., Kim S., Lallone R., Ranganathan S. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995 Nov;1(11):1155–1161. doi: 10.1038/nm1195-1155. [DOI] [PubMed] [Google Scholar]
  16. Mauriège P., Bouchard C. Trp64Arg mutation in beta 3-adrenoceptor gene of doubtful significance for obesity and insulin resistance. Lancet. 1996 Sep 14;348(9029):698–699. doi: 10.1016/S0140-6736(05)65601-2. [DOI] [PubMed] [Google Scholar]
  17. Mitchell B. D., Kammerer C. M., Blangero J., Mahaney M. C., Rainwater D. L., Dyke B., Hixson J. E., Henkel R. D., Sharp R. M., Comuzzie A. G. Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. Circulation. 1996 Nov 1;94(9):2159–2170. doi: 10.1161/01.cir.94.9.2159. [DOI] [PubMed] [Google Scholar]
  18. Moll P. P., Burns T. L., Lauer R. M. The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study. Am J Hum Genet. 1991 Dec;49(6):1243–1255. [PMC free article] [PubMed] [Google Scholar]
  19. Piétri-Rouxel F., St John Manning B., Gros J., Strosberg A. D. The biochemical effect of the naturally occurring Trp64-->Arg mutation on human beta3-adrenoceptor activity. Eur J Biochem. 1997 Aug 1;247(3):1174–1179. doi: 10.1111/j.1432-1033.1997.01174.x. [DOI] [PubMed] [Google Scholar]
  20. Price R. A., Ness R., Laskarzewski P. Common major gene inheritance of extreme overweight. Hum Biol. 1990 Dec;62(6):747–765. [PubMed] [Google Scholar]
  21. Rice T., Borecki I. B., Bouchard C., Rao D. C. Segregation analysis of body mass index in an unselected French-Canadian sample: the Québec Family Study. Obes Res. 1993 Jul;1(4):288–294. doi: 10.1002/j.1550-8528.1993.tb00623.x. [DOI] [PubMed] [Google Scholar]
  22. Rice T., Borecki I. B., Bouchard C., Rao D. C. Segregation analysis of fat mass and other body composition measures derived from underwater weighing. Am J Hum Genet. 1993 May;52(5):967–973. [PMC free article] [PubMed] [Google Scholar]
  23. 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 Feb;40(2):200–204. doi: 10.1007/s001250050663. [DOI] [PubMed] [Google Scholar]
  24. Tataranni P. A., Pratley R., Shuldiner A., Ravussin E. Beta 3-adrenergic receptor gene variant and lipid metabolism in Pima Indians. Diabetologia. 1997 Jan;40(1):123–124. [PubMed] [Google Scholar]
  25. Urhammer S. A., Clausen J. O., 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 Aug;45(8):1115–1120. doi: 10.2337/diab.45.8.1115. [DOI] [PubMed] [Google Scholar]
  26. Walston J., Silver K., Bogardus C., Knowler W. C., Celi F. S., Austin S., Manning B., Strosberg A. D., Stern M. P., Raben N. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. N Engl J Med. 1995 Aug 10;333(6):343–347. doi: 10.1056/NEJM199508103330603. [DOI] [PubMed] [Google Scholar]
  27. Widén E., Lehto M., Kanninen T., Walston J., Shuldiner A. R., Groop L. C. 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 Aug 10;333(6):348–351. doi: 10.1056/NEJM199508103330604. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES