Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Association of β3-Adrenergic Receptor Polymorphisms and High-Density Lipoprotein Cholesterol

고밀도 지단백 콜레스테롤과 베타 3-아드레날린성 수용체 유전자 변이와의 관련성

  • Yu, Byeng-Chul (Department of Preventive Medicine and Institute of Natural Products for Health Promotion, Kosin University) ;
  • Jeon, Man-Joong (Department of Preventive Medicine and Institute of Natural Products for Health Promotion, Kosin University) ;
  • Lee, Yong-Hwan (Department of Preventive Medicine and Institute of Natural Products for Health Promotion, Kosin University)
  • 유병철 (고신대학교 의과대학 예방의학교실 및 건강증진천연물연구소) ;
  • 전만중 (고신대학교 의과대학 예방의학교실 및 건강증진천연물연구소) ;
  • 이용환 (고신대학교 의과대학 예방의학교실 및 건강증진천연물연구소)
  • Published : 2009.05.30
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Abstract

The ${\beta}$3-adrenergic receptor (ADRB3) is expressed mainly in visceral adipose tissue and is thought to contribute to lipolysis and the delivery of free fatty acids to the portal vein. This study was aimed at evaluating the association between high-density lipoprotein cholesterol (HDL-C) and ADRB3 genetic polymophisms. A total of 991 healthy examinees who were examined in a university hospital, located in Busan City, between May and December 2006 were enrolled in this study. Height, weight, body mass index, waist circumference, and systolic and diastolic blood pressures of the subjects were examined. Intravenous concentrations of fasting blood glucose, total cholesterol, HDL-C, low-density lipoprotein cholesterol, and triglyceride were also measured. After extracting DNA from the subjects, mutations of the +188T>C (Trp64Arg) of exon 1 and +3893T>C of intron 2 on the ADRB3 gene were genotyped using the single base extension method. We have identified a novel mutation of ADRB3 that is located in intron 2. The frequency of its minor allele was 0.164. Both the +188T>C mutation of exon 1 and +3893T>C mutation of intron 2 were significantly associated with HDL-C. The mean concentration of serum HDL-C was significantly lower in the presence of their minor allele 'C'. These results suggest that both mutations of +188T>C of exon 1 and +3895T>C of intron 2 have significant associations with HDL-C in the Korean population.

지방분해와 열생산에 관여한다고 알려진 ADRB3 유전자의 염기서열 분석을 통하여 한국인에서 호발하는 유전자 다형성 부위를 먼저 확인한 후 이 유전자 다형성들과 HDL-C와의 연관성에 대하여 조사하고자 2006년 5월에서 12월 사이에 부산지역의 일개 대학병원에서 건강진단을 받은 991명을 대상으로 신장, 체중, 체질량지수, 허리둘레, 고밀도 지단백 콜레스테롤, 중성지방, 공복 혈당을 측정하였으며, 대상자들의 혈액에서 DNA를 분리하여 ADRB3 유전자에서 흔히 발생하는 유전자다형성 부위를 확인하였다. 연구결과 한국인에서 ADRB3 유전자의 intron2 +3893T>C의 변이를 처음으로 발견하였으며 열성 대립형질의 발현빈도는 0.164이었다. Exon1의 +188T>C와 intron2의 +3893T>C의 열성 대립형질인 C형이 있을 경우 HDL-C의 농도가 낮았다. 따라서 ADRB 유전자 다형성은 HDL-C과 관련이 있을 것으로 생각된다.

Keywords

References

  1. Chamberlain, P. D., K. H. Jennings, F. Paul, J. Cordell, A. Berry, S. D. Holmes, J. Park, J. Chambers, M. V. Sennitt, M. J. Stock, M. A. Cawthorne, P. W. Young, and G. J. Murphy. 1999. The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle. Int. J. Obes. Relat. Metab. Disord. 23, 1057-1065 https://doi.org/10.1038/sj.ijo.0801039
  2. Clement, K., C. Vaisse, B. S. Manning, A. Basdevant, B. Guy-Grand, J. Ruiz, K. D. Silver, A. R. Shuldiner, P. Froguel, and A. D. Strosberg. 1995. Genetic variation in the beta3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N. Engl. J. Med. 333, 352-354 https://doi.org/10.1056/NEJM199508103330605
  3. Don, R. H., P. T. Cox, B. J. Wainwright, K. Baker, and J. S. Mattick. 1991. Touchdown PCR to circumvent spurious priming during gene amplification. Nucleic Acids Res. 19, 4008 https://doi.org/10.1093/nar/19.14.4008
  4. Dunajska, K., F. Lwow, A. Milewicz, D. Jedrzejuk, L. Laczmanski, K. Belowska-Bien, J. Urban, and A. Szuba. 2008. beta(3)-adrenergic receptor polymorphism and metabolic syndrome in postmenopausal women. Gynecol. Endocrinol. 24, 133-138 https://doi.org/10.1080/09513590801921686
  5. Emorine, L. J., S. Marullo, M. M. Briend-Sutren, G. Patey, K. Tate, C. Delavier-Klutchko, and A. D. Strosberg. 1989. Molecular characterization of the human beta 3-adrenergic receptor. Science 245, 1118-1121 https://doi.org/10.1126/science.2570461
  6. Friedewald, W. T., R. I. Levy, and D. S. Fredrickson. 1972. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18, 499-502
  7. Garcia-Rubi, E. and J. Calles-Escandon. 1999. Insulin resistance and type 2 diabetes mellitus: its relationship with the beta 3-adrenergic receptor. Arch. Med. Res. 30, 459-464 https://doi.org/10.1016/S0188-4409(99)00077-6
  8. Hamann, A., H. Benecke, Y. Le Marchand-Brustel, V. S. Susulic, B. B. Lowell, and J. S. Flier. 1995. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat. Diabetes 44, 1266-12738 https://doi.org/10.2337/diabetes.44.11.1266
  9. Hedrick, P. W. 1987. Gametic disequilibrium measures: proceed with caution. Genetics 117, 331-341
  10. Hegele, R. A., S. Harris, A. J. G. Hanley, H. Azouz, P. W. Connelly, and B. Zimman. Absence of association between genetic variation of the $\beta$3-adrenergic receptor and metabolic phenotypes in Oji-Cree. Diabetes Care 21, 851-854 https://doi.org/10.2337/diacare.21.5.851
  11. Kadowaki, H., K. Yasuda, K. Iwamoto, S. Otabe, K. Shimokawa, K. Silver, J. Walston, H. Yoshinaga, K. Kosaka, N. Yamada, Y. Saito, R. Hagura, Y. Akanuma, A. Shuldiner, Y. Yazaki, and T. Kadowaki. 1995. A mutation in the beta3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects. Biochem. Biophys. Res. Commun. 215, 555-560 https://doi.org/10.1006/bbrc.1995.2500
  12. Kissebah, A. H., G. E. Sonnenberg, J. Myklebust, M. Goldstein, K. Broman, R. G. James, J. A. Marks, G. R. Krakower, H. J. Jacob, J. Weber, L. Martin, J. Blangero, and A. G. Comuzzie. 2000. Quantitative trait loci on chromosomes3 and 17 influence phenotypes of the metabolic syndrome. Proc. Natl. Acad. Sci. 97, 14478-14483 https://doi.org/10.1073/pnas.97.26.14478
  13. Lehman, D. M., J. Hamlington, K. J. Hunt, R. J. Leach, R. Arya, H. Abboud, R. Duggirala, J. Blangero, H. H. Goring, and M. P. Stern. 2006. A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family. Diabetes Metab. Res. Rev. 22, 331-336 https://doi.org/10.1002/dmrr.620
  14. Li, L. S., F. Lonnqvist, H. Luthman, and P. Arner. 1996. Phenotypic characterization of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene in normal weight and obese subjects. Diabetologia 39, 857-860
  15. Lowell, B. B., V. S. Susulic, A. Hamann, J. A. Lawitts, J. Himms-Hagen, B. B. Boyer, L. P. Kozak, and J. S. Flier. 1993. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740-742 https://doi.org/10.1038/366740a0
  16. Masuo, K., T. Katsuya, Y. Fu, H. Rakugi, T. Ogihara, and M. L. Tuck. 2005. Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years. Circulation 28, 3429-3434
  17. Matsushita, Y., T. Yokoyama, N. Yoshiike, Y. Matsumura, C. Date, K. Kawahara, and H. Tanaka. 2003. The Trp64Arg polymorphism of the β3-adrenergic receptor gene is not associated with body weight or body mass index in Japanese: A longitudinal analysis. J. Clin. Endocrinol. Metab. 88, 5914-5920 https://doi.org/10.1210/jc.2003-030655
  18. Miyaki, K., S. Sutani, H. Kikuchi, I. Takei, M. Murata, K. Watanabe, and K. Omae. 2005. Increased risk of obesity resulting from the interaction between high energy intake and the Trp64Arg polymorphism of the $\beta$3-adrenergic receptor gene in healthy Japanese men. J. Epidemiol. 15, 203-210 https://doi.org/10.2188/jea.15.203
  19. Perfetti, R., H. Hui, K. Chamie, S. Binder, M Seibert, J. McLenithan, K. Silver, and J. D. Walston. 2001. Pancreatic beta-cells expressing the Arg64 variant of the beta(3)-adrenergic receptor exhibit abnormal insulin secretory activity. J. Mol. Endocrinol. 27, 133-144 https://doi.org/10.1677/jme.0.0270133
  20. Rissanen, J., J. Kuopusjarvi, J. Pihlajamaki, R. Sipilainen, S. Heikkinen, M. Vanhala, P. Kekalainen, J. Kuusisto, and M. Laakso. 1997. The Trp64Arg polymorphism of the beta3-Adrenergic receptor gene. Lack of association with NIDDM and features of insulin resistance syndrome. Diabetes Care 20, 1319-1323 https://doi.org/10.2337/diacare.20.8.1319
  21. Rho, Y. H., S. J. Choi, Y. H. Lee, J. D. Ji, and G. G. Song. 2007. The association between hyperuricemia and the Trp64Arg polymorphism of the beta-3 adrenergic receptor. Rheumatol. Int. 27, 835-839 https://doi.org/10.1007/s00296-006-0300-7
  22. Shiwaku, K., A. Nogi, E. Anuurad, K. Kitajima, B. Enkhmaa, K. Shimono, and Y. Yamane. 2003. Difficulty in losing weight by behavioral intervention for women with Trp64Arg polymorphism of the beta3-adrenergic receptor gene. Int. J. Obes. Relat. Metab. Disord. 27, 1028-1036 https://doi.org/10.1038/sj.ijo.0802375
  23. Tamaki, S., Y. Nakamura, Y. Tabara, T. Okamura, Y. Kita, T. Kadowaki, Y. Tsujita, M. Horie, T. Miki, and H. Ueshima. 2006. Relationship between metabolic syndrome and Trp64Arg polymorphism of the $\beta$3-adrenergic receptor gene ina general sample: the Shigaraki Study. Hypertens Res. 29, 891-896 https://doi.org/10.1291/hypres.29.891
  24. Thomas, G. N., B. Tomlinson, J. C. N. Chan, R. P. Young, and J. A. J. H. Critchley. 2000. The Trp64Arg polymorphism of the β3-adrnergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int. J. Obes. 24, 545-551 https://doi.org/10.1038/sj.ijo.0801193
  25. Urhammer, S. A., J. O. Clausen, T. Hansen, and O. Pedersen. 1996. 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 45,1115-1120 https://doi.org/10.2337/diabetes.45.8.1115
  26. Walston, J., K. Silver, C. Bogardus, W. C. Knowler, F. S. Celi, S. Austin, B. Manning, A. D. Strosberg, M. P. Stern, N. Raben, J. D. Sorkin, J. Roth, and A. R. Shuldiner. 1995. Time of onset of non-insulin-dependent diabetes mellitusand genetic variation in the beta3-adrenergic-receptor gene. N. Engl. J. Med. 333, 343-347 https://doi.org/10.1056/NEJM199508103330603
  27. Widen, E., M. Lehto, T. Kanninen, J. Walston, A. R. Shuldiner, and L. C. Groop. 1995. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N. Engl. J. Med. 333, 348-351 https://doi.org/10.1056/NEJM199508103330604
  28. Yoshida, T., N. Sakane, T. Umekawa, M. Sakai, T. Takahashi, and M. Kondo. 1995. Mutation of $\beta$3 adrenergic receptor gene and response to treatment of obesity. Lancet 1433-1434
  29. Yuan, X., K. Yamada, K. Koyama, F. Ichikawa, S. Ishiyama, A. Koyanagi, W. Koyama, and K. Nonaka. 1997. Beta 3-adrenergic receptor gene polymorphism is not a major genetic determinant of obesity and diabetes in Japanese general population. Diabetes Res. Clin. Pract. 37, 1-7 https://doi.org/10.1016/S0168-8227(97)00064-8