DOI QR코드

DOI QR Code

제2형 당뇨병과 MMP3 (A(-267)G, A658G, T813C)의 다형성과의 연관성

Matrix Metalloproteinase-3 Gene Polymorphisms (A(-267)G, A658G, T813C) is Associated with Type 2 Diabetes in Koreans

  • 유민 (계명대학교 자연과학대학 생물학과) ;
  • 김효정 (계명대학교 자연과학대학 생물학과) ;
  • 엽청 (계명대학교 자연과학대학 생물학과) ;
  • 김종원 (계명대학교 자연과학대학 생물학과) ;
  • 김수원 (계명대학교 자연과학대학 생물학과)
  • Yoo, Min (Department of Biology, College of Natural Sciences, Keimyung University) ;
  • Kim, Hyo-Jeong (Department of Biology, College of Natural Sciences, Keimyung University) ;
  • Qing, Ye (Department of Biology, College of Natural Sciences, Keimyung University) ;
  • Kim, Jong-Won (Department of Biology, College of Natural Sciences, Keimyung University) ;
  • Kim, Su-Won (Department of Biology, College of Natural Sciences, Keimyung University)
  • 투고 : 2010.03.25
  • 심사 : 2010.04.23
  • 발행 : 2010.04.30

초록

제2형 당뇨병은 복합적인 유전적 경향을 보이며, 당뇨병과 관련이 있는 것으로 알려진 여러 대립유전자들이 보고되어 있다. Matrix metalloproteinase (MMP)는 기질 금속단백효소로 세포외기질(extracellular matrix, ECM)을 선택적으로 분해하는 효소로서, 질환의 진행뿐만 아니라, 배 발생, 조직형성, 염증반응, 상처치유 등을 조절하는 것으로 알려져 있다. 이에 본 연구에서는 한국인에서 MMP3의 A(-267)G, A658G, T813C 유전자다형성이 제2형 당뇨병 환자와 어떤 연관성을 갖는지 알아보고자 하였다. 정상대조군 100명(남자 36명, 여자 64명)과 당뇨병 환자 200명(남자 108명, 여자 92명)을 대상으로 하였다. 그 결과 A(-267)G와 A658G 유전자다형성이 제2형 당뇨병과 연관이 있는 것으로 나타났기에, 제2형 당뇨병의 발병과 관련이 있을 것으로 생각된다. 향후 대상 환자 수와 대조군을 더욱 늘리는 등의 추가적인 연구를 할 필요가 있을 것으로 생각되며, DNA chip과 같은 유전자 수준에서의 진단법으로 발전시킬 수 있을 것이다.

Type 2 diabetes is a typical polygenic disease complex, for which several common risk alleles have been identified. Proteins in the matrix metalloproteinase-3 (MMP3) family are involved in the breakdown of the extracellular matrix in normal physiological processes such as embryonic development, reproduction and tissue remodeling, as well as in disease processes. Therefore, we investigated the genotype for the A(-267)G, A658G and T813C polymorphisms in the MMP3 gene in the Korean population and compared genotypes of patients with those of the control group. 200 patients (male 108, female 92), who had previously been diagnosed with type 2 diabetes (T2DM) and 100 control subjects (male 36, female 64) participated in this study. There was a strong association between A(-267)G and A658G polymorphism in the MMP3 gene and T2DM. The present study shows that MMP3 polymorphisms (A(-267)G and A658G) may be associated with the pathogenesis of T2DM. Further studies with a larger population may be needed for the development of diagnostic methods at a genetic level, such as DNA chip.

키워드

참고문헌

  1. Chung, A. W. Y., H. Luo, T. Tejerina, C. V. Breemena, and E. B. Okon. 2007. Enhanced cell cycle entry and mitogen-activated protein kinase-signaling and down regulation of matrix metalloproteinase-1 and -3 in human diabetic arterial vasculature. Atherosclerosis 195, 1-8. https://doi.org/10.1016/j.atherosclerosis.2006.09.009
  2. Doney, A. S., B. Fischer, J. E. Cecil, K. Boylan, F. E. McGuigan, S. H. Ralston, A. D. Morris, and C. N. Palmer. 2004. Association of the pro12ala and c1431t variants of PPARg and their haplotypes with susceptibility to type 2 diabetes. Diabetologia 47, 555-558. https://doi.org/10.1007/s00125-003-1323-1
  3. Egeblad, M. and Z. Werb. 2002. New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer 2, 161-174. https://doi.org/10.1038/nrc745
  4. Ferrara, N. 2001. Role of vasclar endothelial growth factor in regulation of physiological angiogenesis. Am. J. Physiol. Cell Physiol. 280, 1358-1366.
  5. Fukuyama, K., T. Ohara, Y. Hirota, K. Maeda, S. Kuno, M. Zenibayashi, T. Teranishi, K. Kouyama, E. Maeda, N. Sakamoto, and M. Ksauga. 2006. Association of the -112a>c polymorphism of the uncoupling protein 1 gene with insulin resistance in Japanese individuals with type 2 diabetes. Biochem. Biophys. Res. Commun. 339, 1212-1216. https://doi.org/10.1016/j.bbrc.2005.11.140
  6. Gloyn, A. L., Y. Hashim, S. J. Aschcroft, R. Ashfield, S. Wiltshire, and R. C. Turmer. 2001. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with type 2 diabetes mellitus (UKPDS 53). Diabet. Med. 18, 206-212. https://doi.org/10.1046/j.1464-5491.2001.00449.x
  7. Goldbourt, U. and H. N. Neufeld. 1986. Genetic aspects of arteriosclerosis. Arteriosclerosis 6, 357-377. https://doi.org/10.1161/01.ATV.6.4.357
  8. Groop, L., C. Forsblom, M. Lehtovirta, T. Tuomi, S. Karanko, M. Nissen, B. O. Ehrnstrom, B. Forsen, B. Isomaa, B. Snickars, and M. R. Taskinen. 1996. Metabolic consequences of family history of NIDDM (The Botnia Study). Diabetes 45, 1585-1593. https://doi.org/10.2337/diabetes.45.11.1585
  9. Grundy, S. M. 1999. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am. J. Cardiol. 83, 25F-29F.
  10. Hojilla, C. V., F. F. Mohammed, and R. Khokha. 2003. Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. British J. Cancer 89, 1817-1821. https://doi.org/10.1038/sj.bjc.6601327
  11. Hu, F. B. and A. Doria. 2004. Genetic variation at the adiponectin locus and risk of type 2 diabetes in women. Diabetes 53, 209-213. https://doi.org/10.2337/diabetes.53.1.209
  12. Lee, J. E., Y. K. Choi, H. A. Seo, J. H. Jeong, J. Y. Jeong, S. S. Moon, J. G. Kim, B. W. Kim, S. W. Kim, M. Yoo, J. Y. Kim, and I. K. Lee. 2010. Impact of ENPP1 and MMP3 gene polymorphisms on aortic calcification in patients withtype 2 diabetesin a Korean population. Diabetes Res. and Clin. Prac. 88, 87-96. https://doi.org/10.1016/j.diabres.2010.01.002
  13. Medley, T. L., B. A. Kingwell, C. D. Gatzka, P. Pillay, and T. J. Cole. 2003. Matrix metallopreteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ. Res. 92, 1254-1261. https://doi.org/10.1161/01.RES.0000076891.24317.CA
  14. Mensah, G. A., A. H. Mokdad, E. Ford, K. M. Narayan, W. H. Giles, F. Vinicor, and P. C. Deedwania. 2004. Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implication. Cardiol. Clin. 22, 485-504. https://doi.org/10.1016/j.ccl.2004.06.005
  15. Musi, N. 2006. AMP-activated protein kinase and type 2 diabetes. Curr. Med. Chem. 13, 583-589. https://doi.org/10.2174/092986706776055724
  16. Nam, J. H. and K. S. Park. 2004. Single nucleotide polymorphisms of matrix metalloproteinase in Koreans. Kor. J. Genetics 26, 289-296.
  17. Newby, A. C. 2005. Dual role of matrix metalloproteinases in intimal thickening and atherosclerotic plaque rupture. Physiol. Rev. 85, 1-31. https://doi.org/10.1152/physrev.00048.2003
  18. Poollanen, P. J., T. Lehtimaki, E. Ilveskoski, J. Mikkelsson, O. A. Kajander, P. Laippala, M. Perola, S. Goebeler, A. Penttila, K. M. Mattila, K. Syrjakoski, T. Koivula, S. T. Nikkari, and P. J. Karhunen. 2002. Coronary artery calcification is related to functional polymorphism of matrix metalloproteinase 3: the Helsinki Sudden Death Study. Atherosclerosis 164, 329-335. https://doi.org/10.1016/S0021-9150(02)00107-7
  19. Reaven, G. M. 1988. Role of insulin resistance in human disease. Diabetes 37, 1595-1607. https://doi.org/10.2337/diabetes.37.12.1595
  20. Robertson, W. B., J. P. Strong. 1968. Atherosclerosis in persons with hypertension and diabetes mellitus. Lab. lnvest. 18, 538-551.
  21. Ross, R. 1993. The pathogenesis of atherosclerosis; a perspective for the 1990s. Nature 362, 801-809. https://doi.org/10.1038/362801a0
  22. Schernthaner, G. 1996. Cardiovascular mortaality and morbidity in type-2 diabetes mellitus. Diabetes Res. Clin. Pract. 31, Suppl. S3-13. https://doi.org/10.1016/0168-8227(96)01224-7
  23. Stimvoll, M., B. J Goldstein, and T. W. van Gaeften. 2005. Type 2 diabetes; principles of pathogenesis and therapy. Lacet 365, 1333-1346.
  24. Wang, H., and J. A. Keiser. 1998. Vascular endothelial growth factor upregulatesthe expression of matrix metalloproteinase in vascular smooth muscle cells; role of flt-1. Circ. Res. 83, 832-840. https://doi.org/10.1161/01.RES.83.8.832
  25. Ye, S. 2006. Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovascular Research 69, 636-645. https://doi.org/10.1016/j.cardiores.2005.07.015
  26. Zhang, C., L. Qi, D. J. Humter, J. B. Meigs, J. E. Manson, R. M. van Dam, and F. B. Hu. 2006. Variant of transcription factor 7-like 2 (tcf7l2) gene and the risk of type 2 diabetes in large cohorts of U. S. Women and men. Diabetes 55, 2645-2648. https://doi.org/10.2337/db06-0643
  27. Zimmet, P. 2002. Addressing the insulin resistance syndrome. TCM. 12, 354-362.