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

Journal of Molecular Neuroscience volume 66, pages 378–382 (2018)Cite this 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.

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References

  • Ala-Kokko L (2002) Genetic risk factors for lumbar disc disease. Ann Med 34:42–47

    CAS  Article  Google Scholar 

  • Andersson GB (1999) Epidemiological features of chronic low-back pain. Lancet 354:581–585

    CAS  Article  Google Scholar 

  • 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 285:409–412

    CAS  Article  Google Scholar 

  • 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 41:1661–1667

    Article  Google Scholar 

  • 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 16:1015–1021

    CAS  Article  Google Scholar 

  • 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 77:1662–1670

    CAS  Article  Google Scholar 

  • 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):312–318

    Article  Google Scholar 

  • Buckwalter JA (1995) Aging and degeneration of the human intervertebral disc. Spine 20:1307–1314

    CAS  Article  Google Scholar 

  • Cawston TE, Billington C (1996) Metalloproteinases in the rheumatic diseases. J Pathol 180(2):115–117

    CAS  Article  Google Scholar 

  • Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253(1–2):269–285

    CAS  Article  Google Scholar 

  • Collins M, Raleigh SM (2009) Genetic risk factors for musculoskeletal soft tissue injuries. Med Sport Sci 54:136–149

    CAS  Article  Google Scholar 

  • 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):e97027

    Article  Google Scholar 

  • 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):1273–1278

    Article  Google Scholar 

  • 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):153

    CAS  Article  Google Scholar 

  • 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):338–345

    CAS  Article  Google Scholar 

  • 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):903

    CAS  Article  Google Scholar 

  • Matrisian LM (1990) Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6:121–125

    CAS  Article  Google Scholar 

  • 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 23:1029–1034

    CAS  Article  Google Scholar 

  • 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):691–694

    CAS  Article  Google Scholar 

  • 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):2552–2557

    Article  Google Scholar 

  • Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69(3):562–573

    CAS  Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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 285:1843–1849

    CAS  Article  Google Scholar 

  • 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):71–77

    CAS  Article  Google Scholar 

  • 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):1309–1320

    CAS  Article  Google Scholar 

  • 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):514–520

    CAS  Article  Google Scholar 

  • Sambrook PN, MacGregor AJ, Spector TD (1999) Genetic influences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum 42:366–372

    CAS  Article  Google Scholar 

  • 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):607

    CAS  Article  Google Scholar 

  • 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):1063

    CAS  Article  Google Scholar 

  • 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):148–152

    CAS  PubMed  Google Scholar 

  • 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 83:491–495

    CAS  Article  Google Scholar 

  • 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):2432–2441

    Article  Google Scholar 

  • 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):2445–2451

    Article  Google Scholar 

  • 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):470–481

    CAS  Article  Google Scholar 

  • 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 44:285–288

    CAS  Article  Google Scholar 

  • 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):13055–13060

    CAS  Article  Google Scholar 

  • 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):23–30

    CAS  Article  Google Scholar 

  • Zitting P, Rantakallio P, Vanharanta H (1998) Cumulative incidence of lumbar disc diseases leading to hospitalization up to the age of 28 years. Spine 23:2337–2343

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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

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Affiliations

  1. Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India

    Harshitha S.M. & Chetan G.K.

  2. Armed Forces Medical College, Pune, 411040, India

    Sibin M.K.

  3. Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India

    Dhananjaya I. Bhat

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  1. Harshitha S.M.
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  2. Sibin M.K.
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  3. Chetan G.K.
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  4. Dhananjaya I. Bhat
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Correspondence to Dhananjaya I. Bhat.

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S.M., H., M.K., S., G.K., C. et al. Association of CILP, COL9A2 and MMP3 Gene Polymorphisms with Lumbar Disc Degeneration in an Indian Population. J Mol Neurosci 66, 378–382 (2018). https://doi.org/10.1007/s12031-018-1182-3

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  • DOI: https://doi.org/10.1007/s12031-018-1182-3

Keywords

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