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Association of CILP, COL9A2 and MMP3 Gene Polymorphisms with Lumbar Disc Degeneration in an Indian Population

  • Harshitha S.M.
  • Sibin M.K.
  • Chetan G.K.
  • Dhananjaya I. Bhat
Article

Abstract

Lumbar disc degeneration (LDD) is a multifactorial disorder caused by genetic and environmental factors. Polymorphisms in several structural and inflammatory genes like collagens, aggrecan, matrix metalloproteinases are associated with the risk of disc degeneration. In this study, we analyzed the role of a few important single nucleotide polymorphisms in cartilage intermediate layer protein (CILP), collagen 9A2 (COL9A2) and matrix metalloproteinase 3 (MMP3) genes in LDD from an Indian population. Two hundred patients with LDD and 200 healthy controls were recruited for the study. Genotyping was performed by allelic discrimination assay. The rs2073711 polymorphism (CILP gene - GG genotype) was associated with reduced risk of LDD in the Indian population (OR = 0.43, p = 0.016). The rs591058 polymorphism (MMP3 gene - TT genotype) is found to be associated with lower risk among women (OR = 0.34, p = 0.041). No significant association was found between COL9A2 polymorphism rs7533552 and the risk of LDD. We conclude that the CILP gene polymorphism (rs2073711) is associated with a lower risk of LDD, the MMP3 (rs591058) gene polymorphism is associated with LDD among women, and the TT genotype confers a lower risk of LDD.

Keywords

Lumbar disc degeneration (LDD) CILP MMP3 COL9A2 Polymorphism Indian population 

Notes

Acknowledgements

This study was financially supported by Science and Engineering Research Board (SERB) (EMR/2014/000614), Department of Science and Technology, Government of India.

Compliance with Ethical Standards

Conflict of Interest

The authors have declared that there is no conflict of interest financially or findings specified in this paper.

Supplementary material

12031_2018_1182_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 21 kb)

References

  1. Ala-Kokko L (2002) Genetic risk factors for lumbar disc disease. Ann Med 34:42–47CrossRefGoogle Scholar
  2. Andersson GB (1999) Epidemiological features of chronic low-back pain. Lancet 354:581–585CrossRefGoogle Scholar
  3. Annunen S, Paassilta P, Lohiniva J, Perala M, Pihlajamaa T, Karppinen J, Tervonen O, Kroger H, Lahde S, Vanharanta H, Ryhanen L, Goring HH, Ott J, Prockop DJ, Ala-Kokko L (1999) An allele of COL9A2 associated with intervertebral disc disease. Science 285:409–412CrossRefGoogle Scholar
  4. Bagheri MH, Honarpisheh AP, Yavarian M, Alavi Z, Siegelman J, Valtchinov VI (2016) MRI phenotyping of COL9A2/Trp2 and COL9A3/Trp3 alleles in lumbar disc disease: a case-control study in south-western Iranian population reveals a significant Trp3-disease association in males. Spine 41:1661–1667CrossRefGoogle Scholar
  5. Battie MC, Videman T, Gil K et al (1991) Volvo award in clinical sciences. Smoking and lumbar intervertebral disc degeneration: an MRI study of identical twins. Spine 16:1015–1021CrossRefGoogle Scholar
  6. Battie MC, Haynor DR, Fisher LD, Gill K, Gibbons LE, Videman T (1995) Similarities in degenerative findings on magnetic resonance images of the lumbar spines of identical twins. JBJS 77:1662–1670CrossRefGoogle Scholar
  7. Bell RD, Shultz SJ, Wideman L, Henrich VC (2012) Collagen gene variants previously associated with anterior cruciate ligament injury risk are also associated with joint laxity. Sports Health 4(4):312–318CrossRefGoogle Scholar
  8. Buckwalter JA (1995) Aging and degeneration of the human intervertebral disc. Spine 20:1307–1314CrossRefGoogle Scholar
  9. Cawston TE, Billington C (1996) Metalloproteinases in the rheumatic diseases. J Pathol 180(2):115–117CrossRefGoogle Scholar
  10. Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253(1–2):269–285CrossRefGoogle Scholar
  11. Collins M, Raleigh SM (2009) Genetic risk factors for musculoskeletal soft tissue injuries. Med Sport Sci 54:136–149CrossRefGoogle Scholar
  12. Colombini A, Brayda-Bruno M, Lombardi G, Croiset SJ, Vrech V, Maione V, Banfi G, Cauci S (2014) FokI polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the Italian population: a case-control study. PLoS One 9(5):e97027CrossRefGoogle Scholar
  13. Hyun SJ, Park BG, Rhim SC, Bae CW, Lee JK, Roh SW, Jeon SR (2011) A haplotype at the COL9A2 gene locus contributes to the genetic risk for lumbar spinal stenosis in the Korean population. Spine 36(16):1273–1278CrossRefGoogle Scholar
  14. Kelempisioti A, Eskola PJ, Okuloff A, Karjalainen U, Takatalo J, Daavittila I, Niinimäki J, Sequeiros RB, Tervonen O, Solovieva S, Kao PY (2011) Genetic susceptibility of intervertebral disc degeneration among young Finnish adults. BMC Med Genet 12(1):153CrossRefGoogle Scholar
  15. Laguette M-J, Abrahams Y, Prince S, Collins M (2011) Sequence variants within the 3′-UTR of the COL5A1 gene alters mRNA stability: implications for musculoskeletal soft tissue injuries. Matrix Biol 30(5):338–345CrossRefGoogle Scholar
  16. Liuke M, Solovieva S, Lamminen A, Luoma K, Leino-Arjas P, Luukkonen R, Riihimäki H (2005) Disc degeneration of the lumbar spine in relation to overweight. Int J Obes 29(8):903CrossRefGoogle Scholar
  17. Matrisian LM (1990) Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6:121–125CrossRefGoogle Scholar
  18. Matsui H, Kanamori M, Ishihara H, Yudoh K, Naruse Y, Tsuji H (1998) Familial predisposition for lumbar degenerative disc disease. A case-control study. Spine 23:1029–1034CrossRefGoogle Scholar
  19. Min SK, Nakazato K, Okada T, Ochi E, Hiranuma K (2009) The cartilage intermediate layer protein gene is associated with lumbar disc degeneration in collegiate judokas. Int J Sports Med 30(09):691–694CrossRefGoogle Scholar
  20. Min SK, Nakazato K, Yamamoto Y, Gushiken K, Fujimoto H, Fujishiro H, Kobayakawa Y, Hiranuma K (2010) Cartilage intermediate layer protein gene is associated with lumbar disc degeneration in male, but not female, collegiate athletes. Am J Sports Med 38(12):2552–2557CrossRefGoogle Scholar
  21. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69(3):562–573CrossRefGoogle Scholar
  22. Näkki A, Videman T, Kujala UM, Suhonen M, Männikkö M, Peltonen L, Battié MC, Kaprio J, Saarela J (2010) Candidate gene association study of magnetic resonance imaging-based hip osteoarthritis (OA): evidence for COL9A2 gene as a common predisposing factor for hip OA and lumbar disc degeneration. J Rheumatol.  https://doi.org/10.3899/jrheum.100080 CrossRefGoogle Scholar
  23. Paassilta P, Lohiniva J, Goring HH, Perala M, Raina SS, Karppinen J, Hakala M, Palm T, Kroger H, Kaitila I, Vanharanta H, Ott J, Ala-Kokko L (2001) Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 285:1843–1849CrossRefGoogle Scholar
  24. Pluijm SM, Van Essen HW, Bravenboer N, Uitterlinden AG, Smit JH, Pols HA, Lips P (2004) Collagen type I α1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis 63(1):71–77CrossRefGoogle Scholar
  25. Rajasekaran S, Kanna RM, Senthil N, Raveendran M, Cheung KM, Chan D, Subramaniam S, Shetty AP (2013) Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects. Spine J 13(10):1309–1320CrossRefGoogle Scholar
  26. Raleigh SM, van der Merwe L, Ribbans WJ, Smith RKW, Schwellnus MP, Collins M (2009) Variants within the MMP3 gene are associated with Achilles tendinopathy: possible interaction with the COL5A1 gene. Br J Sports Med 43(7):514–520CrossRefGoogle Scholar
  27. Sambrook PN, MacGregor AJ, Spector TD (1999) Genetic influences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum 42:366–372CrossRefGoogle Scholar
  28. Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio F, Mori M, Miyamoto Y, Masuda I, Tsunoda T (2005) A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet 37(6):607CrossRefGoogle Scholar
  29. Seki S, Kawaguchi Y, Mori M, Mio F, Chiba K, Mikami Y, Tsunoda T, Kubo T, Toyama Y, Kimura T, Ikegawa S (2006) Association study of COL9A2 with lumbar disc disease in the Japanese population. J Hum Genet 51(12):1063CrossRefGoogle Scholar
  30. Song HF, Wu ZH, Fei Q, Yan JZ, Liu Z, Zhang JG, Li SG, Qiu GX (2010) Association study of Trp2 allele polymorphism with degenerative disc disease in a Chinese Han nationality. Zhonghua Yi Xue Za Zhi 90(3):148–152PubMedGoogle Scholar
  31. Takahashi M, Haro H, Wakabayashi Y, Kawa-uchi T, Komori H, Shinomiya K (2001) The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metallo-proteinase-3 gene. J Bone Joint Surg 83:491–495CrossRefGoogle Scholar
  32. Toktaş ZO, Ekşi MŞ, Yılmaz B, Demir MK, Özgen S, Kılıç T, Konya D (2015) Association of collagen I, IX and vitamin D receptor gene polymorphisms with radiological severity of intervertebral disc degeneration in southern European ancestor. Eur Spine J 24(11):2432–2441CrossRefGoogle Scholar
  33. Valdes AM, Hassett G, Hart DJ, Spector TD (2005) Radiographic progression of lumbar spine disc degeneration is influenced by variation at inflammatory genes: a candidate SNP association study in the Chingford cohort. Spine 30(21):2445–2451CrossRefGoogle Scholar
  34. Videman T, Saarela J, Kaprio J, Näkki A, Levälahti E, Gill K, Peltonen L, Battié MC (2009) Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum 60(2):470–481CrossRefGoogle Scholar
  35. Virtanen IM, Song YQ, Cheung KM, Ala-Kokko L, Karppinen J, Ho DW, Luk KD, Yip SP, Leong JC, Cheah KS, Sham P (2007) Phenotypic and population differences in the association between CILP and lumbar disc disease. J Med Genet 44:285–288CrossRefGoogle Scholar
  36. Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM (1996) Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 271(22):13055–13060CrossRefGoogle Scholar
  37. Yuan HY, Tang Y, Liang YX, Lei L, Xiao GB, Wang S, Xia ZL (2010) Matrix metalloproteinase-3 and vitamin d receptor genetic polymorphisms, and their interactions with occupational exposure in lumbar disc degeneration. J Occup Health 52(1):23–30CrossRefGoogle Scholar
  38. Zitting P, Rantakallio P, Vanharanta H (1998) Cumulative incidence of lumbar disc diseases leading to hospitalization up to the age of 28 years. Spine 23:2337–2343CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Human GeneticsNational Institute of Mental Health and Neurosciences (NIMHANS)BangaloreIndia
  2. 2.Armed Forces Medical CollegePuneIndia
  3. 3.Department of NeurosurgeryNational Institute of Mental Health and Neurosciences (NIMHANS)BangaloreIndia

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