Skip to main content

Advertisement

SpringerLink
Log in

Association of collagen I, IX and vitamin D receptor gene polymorphisms with radiological severity of intervertebral disc degeneration in Southern European Ancestor

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Purpose

Several genomic loci have been previously found to be associated with intervertebral disc degeneration, so far. Data are mostly derived from northern European countries whereas data derived from Southern European Ancestor are limited. This study aimed to evaluate the association between radiological disease severity of lumbar disc degeneration and certain genetic loci in a sample of participants from Southern Europe.

Methods

Seventy-five patients with mild to severe lumbar disc degeneration and 25 healthy controls were enrolled into the study. In each subject, each lumbar intervertebral disc was separately examined to obtain a total radiological score for disease severity. In addition, single-nucleotide polymorphisms of predefined genetic samples were analyzed in all participants: COL1A1 Sp1, COL9a2 Trp2, COL9a3 Trp3, and VDR TaqI.

Results

Degeneration scores were significantly worse in cases with COL1A1 Sp1, COL9a3 Trp3, and VDR TaqI mutations; however, COL9a2 Trp2 mutation was not associated with a difference in the severity of disc degeneration. In addition, subjects with mutation in more than one gene sample (n = 20) had significantly worse degeneration scores than the remaining study participants (n = 80) (17.70 ± 2.72 vs. 21.81 ± 1.81, p < 0.001).

Conclusion

Single-nucleotide polymorphisms occurring in COL1A1, COL9a3 and VDR genes seem to be associated with the development of lumbar disc degeneration in this cohort, possibly with even more pronounced association when multiple mutations are present in the same individual. By further prospective twin studies in associated genes and analyses of their relationship with environmental factors in an internationally sampled large cohort will make a more clear-minded conclusion about their association with disc degeneration, which would yield better appreciation and clinical planning of some predisposed people for these pathologies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

SNP:

Single-nucleotide polymorphism

M:

Male

F:

Female

MRI:

Magnetic resonance imaging

CT:

Computed tomography

References

  1. Kelsey JL (1978) Epidemiology of radiculopathies. Adv Neurol 19:385–398

    CAS  PubMed  Google Scholar 

  2. McCowin PR, Borenstein D, Wiesel SW (1991) The current approach to the medical diagnosis of low back pain. Orthop Clin N Am 22:315–325

    CAS  Google Scholar 

  3. Buckwalter JA (1995) Aging and degeneration of the human intervertebral disc. Spine (Phila Pa 1976) 20:1307–1314

    CAS  Google Scholar 

  4. Battie MC, Videman T, Kaprio J, Gibbons LE, Gill K, Manninen H, Saarela J, Peltonen L (2009) The Twin Spine Study: contributions to a changing view of disc degeneration. Spine J 9:47–59. doi:10.1016/j.spinee.2008.11.011

    Article  PubMed  Google Scholar 

  5. Battie MC, Videman T, Gibbons LE, Fisher LD, Manninen H, Gill K (1995) 1995 volvo award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging findings in identical twins. Spine (Phila Pa 1976) 20:2601–2612

    Article  CAS  Google Scholar 

  6. 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. doi:10.1002/1529-0131(199902)42:2<366:AID-ANR20>3.0.CO;2-6

    Article  CAS  PubMed  Google Scholar 

  7. Videman T, Leppavuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L, Koskenvuo M (1998) Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine (Phila Pa 1976) 23:2477–2485

    Article  CAS  Google Scholar 

  8. Jones G, White C, Sambrook P, Eisman J (1998) Allelic variation in the vitamin D receptor, lifestyle factors and lumbar spinal degenerative disease. Ann Rheum Dis 57:94–99

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T (2002) The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am 84-A:2022–2028

    PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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 metalloproteinase-3 gene. J Bone Joint Surg Br 83:491–495

    Article  CAS  PubMed  Google Scholar 

  13. 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 (Phila Pa 1976) 30:2445–2451

    Article  Google Scholar 

  14. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 26:1873–1878

    Article  CAS  Google Scholar 

  15. Pluijm SM, van Essen HW, Bravenboer N, Uitterlinden AG, Smit JH, Pols HA, Lips P (2004) Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis 63:71–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Tilkeridis C, Bei T, Garantziotis S, Stratakis CA (2005) Association of a COL1A1 polymorphism with lumbar disc disease in young military recruits. J Med Genet 42:e44. doi:10.1136/jmg.2005.033225

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Wrocklage C, Wassmann H, Paulus W (2000) COL9A2 allelotypes in intervertebral disc disease. Biochem Biophys Res Commun 279:398–400. doi:10.1006/bbrc.2000.3967

    Article  CAS  PubMed  Google Scholar 

  18. Karppinen J, Paakko E, Raina S, Tervonen O, Kurunlahti M, Nieminen P, Ala-Kokko L, Malmivaara A, Vanharanta H (2002) Magnetic resonance imaging findings in relation to the COL9A2 tryptophan allele among patients with sciatica. Spine (Phila Pa 1976) 27:78–83

    Article  Google Scholar 

  19. Noponen-Hietala N, Kyllonen E, Mannikko M, Ilkko E, Karppinen J, Ott J, Ala-Kokko L (2003) Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 62:1208–1214

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Jim JJ, Noponen-Hietala N, Cheung KM, Ott J, Karppinen J, Sahraravand A, Luk KD, Yip SP, Sham PC, Song YQ, Leong JC, Cheah KS, Ala-Kokko L, Chan D (2005) The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine (Phila Pa 1976) 30:2735–2742

    Article  Google Scholar 

  21. 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 51:1063–1067. doi:10.1007/s10038-006-0062-9

    Article  CAS  PubMed  Google Scholar 

  22. Higashino K, Matsui Y, Yagi S, Takata Y, Goto T, Sakai T, Katoh S, Yasui N (2007) The alpha2 type IX collagen tryptophan polymorphism is associated with the severity of disc degeneration in younger patients with herniated nucleus pulposus of the lumbar spine. Int Orthop 31:107–111. doi:10.1007/s00264-006-0117-8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Rathod TN, Chandanwale AS, Gujrathi S, Patil V, Chavan SA, Shah MN (2012) Association between single nucleotide polymorphism in collagen IX and intervertebral disc disease in the Indian population. Indian J Orthop 46:420–426. doi:10.4103/0019-5413.97261

    Article  PubMed Central  PubMed  Google Scholar 

  24. Solovieva S, Lohiniva J, Leino-Arjas P, Raininko R, Luoma K, Ala-Kokko L, Riihimaki H (2002) COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction. Spine (Phila Pa 1976) 27:2691–2696. doi:10.1097/01.BRS.0000035266.44292.FA

    Article  Google Scholar 

  25. Solovieva S, Lohiniva J, Leino-Arjas P, Raininko R, Luoma K, Ala-Kokko L, Riihimaki H (2006) Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J 15:613–619. doi:10.1007/s00586-005-0988-1

    Article  PubMed Central  PubMed  Google Scholar 

  26. Kales SN, Linos A, Chatzis C, Sai Y, Halla M, Nasioulas G, Christiani DC (2004) The role of collagen IX tryptophan polymorphisms in symptomatic intervertebral disc disease in Southern European patients. Spine (Phila Pa 1976) 29:1266–1270

    Article  Google Scholar 

  27. Videman T, Gibbons LE, Battie MC, Maravilla K, Vanninen E, Leppavuori J, Kaprio J, Peltonen L (2001) The relative roles of intragenic polymorphisms of the vitamin d receptor gene in lumbar spine degeneration and bone density. Spine (Phila Pa 1976) 26:E7–E12

    Article  CAS  Google Scholar 

  28. Cheung KM, Chan D, Karppinen J, Chen Y, Jim JJ, Yip SP, Ott J, Wong KK, Sham P, Luk KD, Cheah KS, Leong JC, Song YQ (2006) Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine (Phila Pa 1976) 31:1143–1148. doi:10.1097/01.brs.0000216530.41838.d3

    Article  Google Scholar 

  29. Videman T, Saarela J, Kaprio J, Nakki A, Levalahti E, Gill K, Peltonen L, Battie MC (2009) Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum 60:470–481. doi:10.1002/art.24268

    Article  CAS  PubMed  Google Scholar 

  30. Kelempisioti A, Eskola PJ, Okuloff A, Karjalainen U, Takatalo J, Daavittila I, Niinimaki J, Sequeiros RB, Tervonen O, Solovieva S, Kao PY, Song YQ, Cheung KM, Chan D, Ala-Kokko L, Jarvelin MR, Karppinen J, Mannikko M (2011) Genetic susceptibility of intervertebral disc degeneration among young Finnish adults. BMC Med Genet 12:153. doi:10.1186/1471-2350-12-153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Eskola PJ, Kjaer P, Daavittila IM, Solovieva S, Okuloff A, Sorensen JS, Wedderkopp N, Ala-Kokko L, Mannikko M, Karppinen JI (2010) Genetic risk factors of disc degeneration among 12-14-year-old Danish children: a population study. Int J Mol Epidemiol Genet 1:158–165

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Oishi Y, Shimizu K, Katoh T, Nakao H, Yamaura M, Furuko T, Narusawa K, Nakamura T (2003) Lack of association between lumbar disc degeneration and osteophyte formation in elderly japanese women with back pain. Bone 32:405–411

    Article  CAS  PubMed  Google Scholar 

  33. Sakai Y, Matsuyama Y, Hasegawa Y, Yoshihara H, Nakamura H, Katayama Y, Imagama S, Ito Z, Ishiguro N, Hamajima N (2007) Association of gene polymorphisms with intervertebral disc degeneration and vertebral osteophyte formation. Spine (Phila Pa 1976) 32:1279–1286. doi:10.1097/BRS.0b013e318059af8a

    Article  Google Scholar 

  34. Virtanen IM, Karppinen J, Taimela S, Ott J, Barral S, Kaikkonen K, Heikkila O, Mutanen P, Noponen N, Mannikko M, Tervonen O, Natri A, Ala-Kokko L (2007) Occupational and genetic risk factors associated with intervertebral disc disease. Spine (Phila Pa 1976) 32:1129–1134. doi:10.1097/01.brs.0000261473.03274.5c

    Article  Google Scholar 

  35. Nunes FTB, Conforti-Froes NDT, Negrelli WF, Souza DRS (2007) Genetic and environmental factors involved on intervertebral disc degeneration. Acta Ortop Bras 15:09–13

    Article  Google Scholar 

  36. Yuan HY, Tang Y, Lei L, Xiao GB, Liang YX, Wang S, Xia ZL (2010) Synergistic interaction between MMP-3, VDR gene polymorphisms and occupational risk factors on lumbar disc degeneration. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 28:334–338

    CAS  PubMed  Google Scholar 

  37. Eser B, Cora T, Eser O, Kalkan E, Haktanir A, Erdogan MO, Solak M (2010) Association of the polymorphisms of vitamin D receptor and aggrecan genes with degenerative disc disease. Genet Test Mol Biomarkers 14:313–317. doi:10.1089/gtmb.2009.0202

    Article  CAS  PubMed  Google Scholar 

  38. Omair A, Lie BA, Reikeras O, Brox JI (2012) An association study of interleukin 18 receptor genes (IL18R1 and IL18RAP) in lumbar disc degeneration. Open Orthop J 6:164–171. doi:10.2174/1874325001206010164

    Article  PubMed Central  PubMed  Google Scholar 

  39. Cervin Serrano S, Gonzalez Villareal D, Aguilar-Medina M, Romero-Navarro JG, Romero Quintana JG, Arambula Meraz E, Osuna Ramirez I, Picos-Cardenas V, Granados J, Estrada-Garcia I, Sanchez-Schmitz G, Ramos-Payan R (2014) Genetic polymorphisms of interleukin-1 alpha and the vitamin d receptor in mexican mestizo patients with intervertebral disc degeneration. Int J Genom 2014:302568. doi:10.1155/2014/302568

    Google Scholar 

  40. 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:e97027. doi:10.1371/journal.pone.0097027

    Article  PubMed Central  PubMed  Google Scholar 

  41. Vieira LA, De Marchi PL, dos Santos AA, Christofolini DM, Barbosa CP, Fonseca FL, Bianco B, Rodrigues LM (2014) Analysis of FokI polymorphism of vitamin D receptor gene in intervertebral disc degeneration. Genet Test Mol Biomarkers 18:625–629. doi:10.1089/gtmb.2014.0030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Zawilla NH, Darweesh H, Mansour N, Helal S, Taha FM, Awadallah M, El Shazly R (2014) Matrix metalloproteinase-3, vitamin D receptor gene polymorphisms, and occupational risk factors in lumbar disc degeneration. J Occup Rehabil 24:370–381. doi:10.1007/s10926-013-9472-7

    Article  CAS  PubMed  Google Scholar 

  43. Chen W, Li G, Sun H, Ye W, Huang D, Su P, Zhang Z (2012) Association of vitamin D receptor gene polymorphism in Han people with lumbar degenerative disc disease. Afr J Pharm Pharmacol 6:1211–1215

    CAS  Google Scholar 

  44. Jordan KM, Syddall H, Dennison EM, Cooper C, Arden NK (2005) Birthweight, vitamin D receptor gene polymorphism, and risk of lumbar spine osteoarthritis. J Rheumatol 32:678–683

    CAS  PubMed  Google Scholar 

  45. Karppinen J, Paakko E, Paassilta P, Lohiniva J, Kurunlahti M, Tervonen O, Nieminen P, Goring HH, Malmivaara A, Vanharanta H, Ala-Kokko L (2003) Radiologic phenotypes in lumbar MR imaging for a gene defect in the COL9A3 gene of type IX collagen. Radiology 227:143–148. doi:10.1148/radiol.2271011821

    Article  PubMed  Google Scholar 

  46. Matsui Y, Mirza SK, Wu JJ, Carter B, Bellabarba C, Shaffrey CI, Chapman JR, Eyre DR (2004) The association of lumbar spondylolisthesis with collagen IX tryptophan alleles. J Bone Joint Surg Br 86:1021–1026

    Article  CAS  PubMed  Google Scholar 

  47. Koshizuka Y, Ogata N, Shiraki M, Hosoi T, Seichi A, Takeshita K, Nakamura K, Kawaguchi H (2006) Distinct association of gene polymorphisms of estrogen receptor and vitamin D receptor with lumbar spondylosis in post-menopausal women. Eur Spine J 15:1521–1528. doi:10.1007/s00586-005-0005-8

    Article  PubMed  Google Scholar 

  48. Colombini A, Brayda-Bruno M, Ferino L, Lombardi G, Maione V, Banfi G, Cauci S (2015) Gender differences in the VDR-FokI polymorphism and conventional non-genetic risk factors in association with lumbar spine pathologies in an Italian case-control study. Int J Mol Sci 16:3722–3739. doi:10.3390/ijms16023722

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Mayer JE, Iatridis JC, Chan D, Qureshi SA, Gottesman O, Hecht AC (2013) Genetic polymorphisms associated with intervertebral disc degeneration. Spine J 13:299–317. doi:10.1016/j.spinee.2013.01.041

    Article  PubMed Central  PubMed  Google Scholar 

  50. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH (1996) Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 14:203–205. doi:10.1038/ng1096-203

    Article  CAS  PubMed  Google Scholar 

  51. Williams FM, Spector TD (2007) The genetics of osteoporosis. Acta Reumatol Port 32:231–240

    PubMed  Google Scholar 

  52. Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, Johnson CC, Liu J, Gong Y, Warman ML, Prockop DJ, Mayne R, Ala-Kokko L (1999) Complete sequence of the 23-kilobase human COL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants. J Biol Chem 274:22469–22475

    Article  CAS  PubMed  Google Scholar 

  53. Pihlajamaa T, Vuoristo MM, Annunen S, Perala M, Prockop DJ, Ala-Kokko L (1998) Human COL9A1 and COL9A2 genes. Two genes of 90 and 15 kb code for similar polypeptides of the same collagen molecule. Matrix Biol 17:237–241

    Article  CAS  PubMed  Google Scholar 

  54. Zhu Y, Wu JJ, Weis MA, Mirza SK, Eyre DR (2011) Type IX collagen neo-deposition in degenerative discs of surgical patients whether genotyped plus or minus for COL9 risk alleles. Spine (Phila Pa 1976) 36:2031–2038. doi:10.1097/BRS.0b013e3181ffdd61

    Article  Google Scholar 

  55. Christakos S, Barletta F, Huening M, Dhawan P, Liu Y, Porta A, Peng X (2003) Vitamin D target proteins: function and regulation. J Cell Biochem 88:238–244. doi:10.1002/jcb.10349

    Article  CAS  PubMed  Google Scholar 

  56. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287. doi:10.1038/367284a0

    Article  CAS  PubMed  Google Scholar 

  57. 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. J Bone Jt Surg Am 77:1662–1670

    CAS  Google Scholar 

Download references

Acknowledgments

Murat Şakir Ekşi, M.D. was supported by a grant from Tubitak, The Scientific and Technological Research Council of Turkey (Grant Number: 1059B191400255).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Bahçeşehir University Medical Faculty, Çırağan Caddesi Osmanpaşa Mektebi Sokak No: 4–6, 34353, Beşiktaş, Istanbul, Turkey

    Zafer Orkun Toktaş, Baran Yılmaz, Türker Kılıç & Deniz Konya

  2. Department of Orthopedic Surgery, University of California at San Francisco, San Francisco, CA, USA

    Murat Şakir Ekşi

  3. Department of Radiology, Bahçeşehir University Medical Faculty, Istanbul, Turkey

    Mustafa Kemal Demir

  4. Department of Neurosurgery, Acıbadem University Medical Faculty, Istanbul, Turkey

    Serdar Özgen

Authors
  1. Zafer Orkun Toktaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murat Şakir Ekşi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baran Yılmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mustafa Kemal Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Serdar Özgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Türker Kılıç
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Deniz Konya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zafer Orkun Toktaş.

Ethics declarations

Conflict of interest

All the authors declare that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Toktaş, Z.O., Ekşi, M.Ş., Yılmaz, B. et al. 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, 2432–2441 (2015). https://doi.org/10.1007/s00586-015-4206-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-015-4206-5

Keywords

Search

Navigation