Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Polymorphisms of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Gene Are Not Associated with the Osteonecrosis of Femoral Head in Korean

한국인에서 HMG-CoA reductase 유전자다형성과 대퇴골두무혈성괴사증과의 연관성 분석

  • Kim, Tae-Ho (Skeletal Diseases Genome Research Center, Kyungpook National University, Department of Medicine, Kyungpook University School of Medicine) ;
  • Hong, Jung-Min (Skeletal Diseases Genome Research Center, Kyungpook National University) ;
  • Lee, Sang-Han (Department of Food Science & Biotechnology, Kyungpook National University) ;
  • Park, Eui-Kyun (Skeletal Diseases Genome Research Center, Kyungpook National University, Department of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University) ;
  • Kim, Shin-Yoon (Skeletal Diseases Genome Research Center, Kyungpook National University, Department of Orthopedic Surgery, Kyungpook National University School of Medicine)
  • 김태호 (경북대학교병원 골격계질환유전체연구센터, 경북대학교 의학과) ;
  • 홍정민 (경북대학교병원 골격계질환유전체연구센터) ;
  • 이상한 (경북대학교 식품공학과) ;
  • 박의균 (경북대학교병원 골격계질환유전체연구센터, 경북대학교 치과대학 병리 및 재생의학교실) ;
  • 김신윤 (경북대학교병원 골격계질환유전체연구센터, 경북대학교 정형외과학교실)
  • Published : 2008.04.30
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Abstract

Osteonecrosis of the femoral head (ONFH) is a multifactorial disease and certain individuals are more at risk or may be predisposed to it. An altered lipid metabolism is one of the major risk factors for osteonecrosis, especially corticosteroid therapy and alcoholism. 3-hydroxy-3-methylglutaryl coenzyme A. (HMG-CoA) reductase inhibitors, stalin used as lipid-clearing agent, have been known to decrease the risk of osteonecrosis in patients receiving steroids and affect coagulation and fibrinolysis. Therefore we evaluated the association of HMG-CoA reductase gene polymorphisms and haplotypes between osteonecrosis patients and normal controls. We directly sequenced the HMG-CoA reductase gene in 24 Korean individuals, and identified five sequence variants. Four SNPs (-6933C>T, -6045T>G, +12673G>A, and +18128C>T) were selected and genotyped in 349 male ONFH patients and 300 male control subjects. The genotypes, allele frequencies, and haplotypes of the polymorphisms in the total patients as well as in the subgroup by etiology were not significantly different from those in the control group. In addition, no significant differences between each genotype of the polymorphisms and plasma lipid level could be found in the control group. These results suggest that the polymorphisms and haplotypes of HMG-CoA reductase gene are unlikely to be associated with a susceptibility to ONFH.

대퇴골두무혈성괴사증은 다원적인 질병으로 특정 집단의 경우 더 많은 위험성을 내포하고 있다. 특히 스테로이드의 과용과 알코올 남용 등으로 인한 지질대사의 변화는 골괴사증의 주요 원인 중 하나이다. 본 연구는 골괴사 환자와 대조군 사이에서 HMG-CoA reductase 유전자의 다형성과 질환발생과의 연관성에 대해 알아보았다. 24명의 한국인을 대상으로 HMG-CoA reductase 유전자를 시퀀싱하여 5곳의 유전자 다형성을 확인하였다. 349명의 남성 환자와 300명의 남성 대조군을 대상으로 네 곳(-6933C>T, -6045T>G, +12673G>A, +18128C>T)의 유전자다형성의 빈도를 비교하였다. 그 결과 HMG-CoA reductase 유전자의 다형성과 질환발생 및 혈장 지질농도와는 어떠한 상관관계도 보이지 않았다.

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References

  1. Asano, T., K. A. Takahashi, M. Fujioka, S. Inoue, K. Ueshima, T. Hirata, M. Okamoto, Y. Satomi, H. Nishino, T. Tanaka, Y. Hirota and T. Kubo. 2004. Relationship between postrenal transplant osteonecrosis of the femoral head and gene polymorphisms related to the coagulation and fibrinolytic systems in Japanese subjects. Transplantation 77, 220-225 https://doi.org/10.1097/01.TP.0000101433.99651.96
  2. Assouline-Dayan, Y., C. Chang, A. Greenspan, Y. Shoenfeld and M. E. Gershwin. 2002. Pathogenesis and natural history of osteonecrosis. Semin. Arthritis. Rheum. 32, 94-124 https://doi.org/10.1053/sarh.2002.33724b
  3. Atsumi, T. and Y. Kuroki. 1992. Role of impairment of blood supply of the femoral head in the pathogenesis of idiopathic osteonecrosis. Clin. Orthop. Relat. Res. 277, 22-30
  4. Ferrari, P., V. Schroeder, S. Anderson, L. Kocovic, B. Vogt, D. Schiesser, H. P. Marti, R. Ganz, F. J. Frey and H. P. Kohler. 2002. Association of plasminogen activator inhibitor- 1 genotype with avascular osteonecrosis in steroid- treated renal allograft recipients. Transplantation 74, 1147-1152 https://doi.org/10.1097/00007890-200210270-00016
  5. Gardeniers, J. W. M. 1993. The ARCO perspective for reaching one uniform staging system of osteonecrosis, pp. 375-380, In Scoutens, A, J. Arlet, J. W. M. Gardeniers, S. P. F. Hughes (eds.), Bone Circulation and Vascularization in Normal and Pathologic Conditions. Plenum Press, New York
  6. Glueck, C. J., R. Freiberg, H. I. Glueck, T. Tracy, D. Stroop and Y. Wang. 1995. Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator inhibitor, high lipoprotein (a), and therapy with Stanozolol. Am. J. Hematol. 48, 213-220 https://doi.org/10.1002/ajh.2830480402
  7. Glueck, C. J., R. Freiberg, T. Tracy, D. Stroop and P. Wang. 1997. Thrombophilia and hypofibrinolysis: pathophysiologies of osteonecrosis. Clin. Orthop. Relat. Res. 334, 43-56
  8. Glueck, C. J., P. Wang, R. N. Fontaine, L. Sieve-Smith, T. Tracy and S. K. Moore. 1999. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism 48, 1589-1595 https://doi.org/10.1016/S0026-0495(99)90250-0
  9. Glueck, C. J., R. A. Freiberg, R. N. Fontaine, T. Tracy and P. Wang. 2001. Hypofibrinolysis, thrombophilia, osteonecrosis. Clin. Orthop. Relat. Res. 386, 19-33 https://doi.org/10.1097/00003086-200105000-00004
  10. Goldstein, J. L. and M. S. Brown. 1990. Regulation of the mevalonate pathway. Nature 343, 425-430 https://doi.org/10.1038/343425a0
  11. Hedrick, P. W. 1987. Gametic disequilibrium measures: proceed with caution. Genetics 117, 331-341
  12. Hong, J. M., T. H. Kim, S. C. Chae, K. H. Koo, Y. J. Lee, E. K. Park, J. Y. Choi, H. M. Ryoo and S. Y. Kim. 2007. Association study of hypoxia inducible factor 1alpha (HIF1alpha) with osteonecrosis of femoral head in a Korean population. Osteoarthritis Cartilage 15, 688-694 https://doi.org/10.1016/j.joca.2006.12.007
  13. Jones, J. P. Jr. 1992. Intravascular coagulation and osteonecrosis. Clin. Orthop. Relat. Res. 277, 41-53
  14. Kim, S. Y., J. S. Suh, E. K. Park, W. B. Jung, J. W. Kim, K. H. Koo and C. Y. Kim. 2003. Factor V Leiden gene mutation in femoral head osteonecrosis. J. Kor. Ortho. Res. Soc. 6, 259-264
  15. Koo, K. H., R. Kim, Y. S. Kim, I. O. Ahn, S. H. Cho, H. R. Song, Y. S. Park, H. Kim and G. J. Wang. 2002. Risk period for developing osteonecrosis of the femoral head in patients on steroid treatment. Clin. Rheumatol. 21, 299-303 https://doi.org/10.1007/s100670200078
  16. Koo, K. H., J. S. Lee, Y. J. Lee, K. J. Kim, J. J. Yoo and H. J. Kim. 2006. Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis. J. Orthop. Res. 24, 1722-1728 https://doi.org/10.1002/jor.20164
  17. Krysiak, R., B. Okopien and Z. Herman. 2003. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs 63, 1821-1854 https://doi.org/10.2165/00003495-200363170-00005
  18. Lee, J. S., K. H. Koo, Y. C. Ha, K. K. Koh, S. J. Kim, J. R. Kim, H. R. Song and S. H. Cho. 2003. Role of thrombotic and fibrinolytic disorders in osteonecrosis of the femoral head. Clin. Orthop. Relat. Res. 417, 270-276
  19. Livak, K. J. 1999. Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet. Anal. 14, 143-149 https://doi.org/10.1016/S1050-3862(98)00019-9
  20. Miyanishi, K., T. Yamamoto, T. Irisa, A. Yamashita, S. Jingushi, Y. Noguchi and Y. Iwamoto. 2002. Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis. Bone 30, 185-190 https://doi.org/10.1016/S8756-3282(01)00663-9
  21. Mont, M. A. and D. S. Hungerford. 1995. Non-traumatic avascular necrosis of the femoral head. J. Bone Joint Surg. Am. 77, 459-474 https://doi.org/10.2106/00004623-199503000-00018
  22. Moskal, J. T., R. E. Topping and L. L. Franklin. 1997. Hypercholesterolemia: an association with osteonecrosis of the femoral head. Am. J. Orthop. 26, 609-612
  23. Mundy, G., R. Garrett, S. Harris, J. Chan, D. Chen, G. Rossini, B. Boyce, M. Zhao and G. Gutierrez. 1999. Stimulation of bone formation in vitro and in rodents by statins. Science 286, 1946-1949 https://doi.org/10.1126/science.286.5446.1946
  24. Noa, M., S. Mendoza, R. Mas, N. Mendoza and F. Leon. 2004. Effect of D-003, a mixture of very high molecular weight aliphatic acids, on prednisolone-induced osteoporosis in Sprague-Dawley rats. Drugs R. D. 5, 281-290 https://doi.org/10.2165/00126839-200405050-00004
  25. Pritchett, J. W. 2001. Statin therapy decreases the risk of osteonecrosis in patients receiving steroids. Clin. Orthop. Relat. Res. 386, 173-178 https://doi.org/10.1097/00003086-200105000-00022
  26. Qin, Z. S., T. Niu and J. S. Liu. 2002. Partition-ligation-expectation- maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am. J. Hum. Genet. 71, 1242-1247 https://doi.org/10.1086/344207
  27. Undas, A., K. E. Brummel-Ziedins and K. G. Mann. 2005. Statins and blood coagulation. Arterioscler. Thromb. Vasc. Biol. 25, 287-294
  28. van Beek, E., C. Lowik, M. Karperien and S. Papapoulos. 2006. Independent pathways in the modulation of osteoclastic resorption by intermediates of the mevalonate biosynthetic pathway: The role of the retinoic acid receptor. Bone 38, 167 https://doi.org/10.1016/j.bone.2005.08.011
  29. Wang, G. J., D. E. Sweet, S. I. Reger and R. C. Thompson. 1977. Fat-cell changes as a mechanism of avascular necrosis of the femoral head in cortisone-treated rabbits. J. Bone Joint Surg. Am. 59, 729-735 https://doi.org/10.2106/00004623-197759060-00003
  30. Wang, G. J., J. G. Rawles, S. L. Hubbard and W. G. Stamp. 1983. Steroid-induced femoral head pressure changes and their response to lipid-clearing agents. Clin. Orthop. Relat. Res. 174, 298-302
  31. Wiesbauer, F., C. Kaun, G. Zorn, G. Maurer, K. Huber and J. Wojta. 2002. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br. J. Pharmacol. 135, 284-292 https://doi.org/10.1038/sj.bjp.0704454
  32. Wozney, J. M. 2002. Overview of bone morphogenetic proteins. Spine 27, S2-S8 https://doi.org/10.1097/00007632-200208151-00002
  33. Zalavras, C. G., G. Vartholomatos, E. Dokou and K. N. Malizos. 2002. Factor V Leiden and prothrombin gene mutations in femoral head osteonecrosis. Thromb. Haemost. 87, 1079-1080 https://doi.org/10.1055/s-0037-1613138
  34. Zalavras, C. G., G. Vartholomatos, E. Dokou and K. N. Malizos. 2004. Genetic background of osteonecrosis: associated with thrombophilic mutations? Clin. Orthop. Relat. Res. 251-255
  35. Zizic, T. M., C. Marcoux, D. S. Hungerford, J. V. Dansereau and M. B. Stevens. 1985. Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythematosus. Am. J. Med. 79, 596-604 https://doi.org/10.1016/0002-9343(85)90057-9