Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

The Genetic Variations of SQSTM1 Gene are Associated with Bone Density in the Korean Population

한국인에서 골밀도와 SQSTM1 유전자 변이의 연관성

  • Jin, Hyun-Seok (Department of Medical Genetics, School of Medicine, Ajou University) ;
  • Eom, Yong-Bin (Department of Biomedical Laboratory Science, Korea Nazarene University)
  • 진현석 (아주대학교 의과대학 의학유전학과) ;
  • 엄용빈 (나사렛대학교 임상병리학과)
  • Received : 2010.09.07
  • Accepted : 2010.10.27
  • Published : 2010.12.30
Download PDF
⟨ Previous Next ⟩

Abstract

Osteoporosis is a complex systemic skeletal disease and a major public health concern worldwide. It is a heritable disorder characterized mainly by low bone density and/or low trauma osteoporotic fractures, both of which have strong genetic determination. However, the specific genetic variants determining risk for low bone density are still largely unknown. Here, we performed association analysis to elucidate the possible relationship between genetic polymorphisms in the SQSTM1 gene and low bone density. By examining a total of 7225 (men: 3622, women: 3603) subjects from the Korean population in the Korean Association REsource (KARE) study, we discovered that SQSTM1 gene polymorphisms were associated with bone density. The results of the BD-RT (bone density estimated by T-score at distal radius) showed that three SNPs (rs513235, rs3734007, and rs11249661) within the SQSTM1 gene were significantly associated with bone density. The results of the BD-TT (bone density estimated by T-score at midshaft tibia) showed that four SNPs (rs513235, rs3734007, rs2241349, and rs11249661) were significantly associated with bone density. The three SNPs (rs513235, rs3734007, and rs11249661) had common significance in both BD-RT and BD-TT. In summary, we found statistically significant SNPs in the SQSTM1 gene that are associated with bone density traits. Therefore, our findings suggest SQSTM1 gene could be related to pathogenesis of osteoporosis.

골다공증은 복합적 전신 골격 질환으로, 공중 보건 분야의 전세계적인 주요한 관심 질환의 한 가지이다. 골다공증은 유전적 영향을 받는 질환으로, 낮은 골밀도와 적은 외력 의한 골다공성 골절 등의 특징을 보이며, 강한 유전성을 나타내는 질환이다. 그러나, 낮은 골밀도과 연관된 특정한 유전자의 다형성은 아직까지 많이 알려져 있지 않다. 본 연구에서는 SQSTM1 유전자의 유전적 다형성과 낮은 골밀도 사이의 상관성을 확인하기 위해, 한국인 유전체 연구(Korean Association Resource, KARE)에서 골밀도를 측정한 7,225명(남성: 3,622명, 여성: 3,603명)을 대상으로 SQSTM1 유전자 다형성과 골밀도 간의 선형 회기 분석을 하였다. BD-RT (원위 요골의 T 점수로 예측한 골밀도)에서 SQSTM1 유전자에서 3개의 SNP (rs513235, rs3734007, rs11249661)가 유의한 상관성이 있는 것으로 나타났으며, BD-TT (중위 경골의 T 점수로 예측한 골밀도)에서는 4개의 SNP (rs513235, rs3734007, rs2241349, rs11249661)가 유의한 상관성이 있는 것으로 나타났다. 특히 3개의 SNP (rs513235, rs3734007, rs11249661)는 BD-RT와 BD-TT 두 종류의 골밀도에서 공통적으로 유의한 상관성을 보였다. 이러한 결과로 미루어 골밀도와 SQSTM1 유전자의 다형성 간에 통계적으로 유의한 상관성을 가지며, SQSTM1 유전자는 골다공증의 발병과정에 관련이 있을 것으로 사료된다.

Keywords

References

  1. Cho, Y. S., M. J. Go, Y. J. Kim, J. Y. Heo, J. H. Oh, H. J. Ban, D. Yoon, M. H. Lee, D. J. Kim, M. Park, S. H. Cha, J. W. Kim, B. G. Han, H. Min, Y. Ahn, M. S. Park, H. R. Han, H. Y. Jang, E. Y. Cho, J. E. Lee, N. H. Cho, C. Shin, T. Park, J. W. Park, J. K. Lee, L. Cardon, G. Clarke, M. I. McCarthy, J. Y. Lee, B. Oh, and H. L. Kim. 2009. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527-534. https://doi.org/10.1038/ng.357
  2. Cody, J. D., F. R. Singer, G. D. Roodman, B. Otterund, T. B. Lewis, and M. Leppert. 1997. Genetic linkage of Paget disease of the bone to chromosome 18q. Am. J. Hum. Genet. 61, 1117-1122. https://doi.org/10.1086/301601
  3. Cole, R. E. 2008. Improving clinical decisions for women at risk of osteoporosis: dual-femur bone mineral density testing. J. Am. Osteopath Assoc. 108, 289-295.
  4. Duran, A., M. Serrano, M. Leitges, J. M. Flores, S. Picard, and J. P. Brown. 2004. The atypical PKC-interacting proein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev. Cell 6, 303-309. https://doi.org/10.1016/S1534-5807(03)00403-9
  5. Good, D. A., F. Busfield, B. H. Fletcher, P. K. Loveloc, D. L. Duffy, and J. B. Kesting. 2004. Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone 35, 277-282. https://doi.org/10.1016/j.bone.2004.01.010
  6. Hocking, L. J., G. J. Lucas, A. Daroszewska, J. Mangion, M. Olavesen, T. Cundy, G. C. Nicholson, L. Ward, S. T. Bennett, W. Wuyts, W. Van Hul, and S. H. Ralston. 2002. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum. Mol. Genet. 11, 2735-2739. https://doi.org/10.1093/hmg/11.22.2735
  7. Joung, I., J. L. Strominger, and J. Shin. 1996. Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Proc. Natl. Acad. Sci. USA 93, 5991-5995. https://doi.org/10.1073/pnas.93.12.5991
  8. Laurin, N., J. P. Brown, J. Morissette, and V. Raymond. 2002. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70, 1582-1588. https://doi.org/10.1086/340731
  9. Moscat, J. and M. T. Diaz-Meco. 2002. The atypical PKC scaffold protein P62 is a novel target for anti-inflammatory and anti-cancer therapies. Adv. Enzyme Regul. 42, 173-179. https://doi.org/10.1016/S0065-2571(01)00029-2
  10. Rabbee, N. and T. P. Speed. 2006. A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics 22, 7-12. https://doi.org/10.1093/bioinformatics/bti741
  11. Ralston, S. H. 2008. Pathogenesis of Paget's disease of bone. Bone 43, 819-825. https://doi.org/10.1016/j.bone.2008.06.015
  12. van Staa, T. P., P. Selby, H. G. Leufkens, K. Lyles, J. M. Sprafka, and C. Cooper. 2002. Incidence and natural history of Paget's disease of bone in England and Wales. J. Bone Miner Res. 17, 465-471. https://doi.org/10.1359/jbmr.2002.17.3.465
  13. Wooten, M. W., M. L. Seibenhener, V. Mamidipudi, M. T. Diaz-Meco, P. A. Barker, and J. Moscat. 2001. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J. Biol. Chem. 276, 7709-7712. https://doi.org/10.1074/jbc.C000869200