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Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis
  1. N Noponen-Hietala1,
  2. E Kyllönen2,
  3. M Männikkö1,
  4. E Ilkko3,
  5. J Karppinen4,
  6. J Ott5,
  7. L Ala-Kokko1,6
  1. 1Collagen Research Unit, Biocentre and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
  2. 2Department of Physical Medicine and Rehabilitation, Oulu University Hospital, Oulu, Finland
  3. 3Department of Radiology, Oulu University Hospital, Oulu, Finland
  4. 4Finnish Institute of Occupational Health, Helsinki, Finland
  5. 5Laboratory of Statistical Genetics, Rockefeller University, New York, NY, USA
  6. 6Center for Gene Therapy and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
  1. Correspondence to:
    Professor L Ala-Kokko
    Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-99, New Orleans, LA 70112, USA; lalakotulane.edu

Abstract

Background: Degenerative lumbar spinal stenosis (LSS) is usually caused by disc herniation or degeneration. Several genetic factors have been implicated in disc disease. Tryptophan alleles in COL9A2 and COL9A3 have been shown to be associated with lumbar disc disease in the Finnish population, and polymorphisms in the vitamin D receptor gene (VDR) (FokI and TaqI), the matrix metalloproteinase-3 gene (MMP-3) and an aggrecan gene (AGC1) VNTR have been reported to be associated with disc degeneration. In addition, an IVS6-4 a>t polymorphism in COL11A2 has been found in connection with stenosis caused by ossification of the posterior longitudinal ligament in the Japanese population.

Objective: To study the role of genetic factors in LSS.

Methods: 29 Finnish probands were analysed for mutations in the genes coding for intervertebral disc matrix proteins, COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, and AGC1. VDR and MMP-3 polymorphisms were also analysed. Sequence variations were tested in 56 Finnish controls.

Results: Several disease associated alleles were identified. A splice site mutation in COL9A2 leading to a premature translation termination codon and the generation of a truncated protein was identified in one proband, another had the Trp2 allele, and four others the Trp3 allele. The frequency of the COL11A2 IVS6−4 t allele was 93.1% in the probands and 72.3% in controls (p = 0.0016). The differences in genotype frequencies for this site were less significant (p = 0.0043).

Conclusions: Genetic factors have an important role in the pathogenesis of LSS.

  • single nucleotide polymorphism
  • collagen
  • intervertebral disc
  • stenosis
  • AGC1, gene coding for aggrecan
  • COL1A1 and COL1A2, genes coding for collagen I α1 and α2 chains
  • COL2A1, gene coding for collagen II α1 chain
  • COL9A1, COL9A2, and COL9A3, genes coding for collagen IX α1, α2, and α3 chains
  • COL11A1 and COL11A2, genes coding for collagen XI α1 and α2 chains
  • IVS, non-coding intronic sequence located between coding sequences
  • CS, chondroitin sulphate
  • CSGE, conformation sensitive gel electrophoresis
  • CT, computed tomography
  • LDD, lumbar disc disease
  • LSS, lumbar spinal stenosis
  • MMP, matrix metalloproteinase
  • MRI, magnetic resonance imaging
  • OLF, ossification of the ligamentum flavum
  • OPLL, ossification of the posterior longitudinal ligament
  • PCR, polymerase chain reaction
  • RT, reverse transcriptase
  • SNP, single nucleotide polymorphism
  • VDR, vitamin D receptor gene
  • VNTR, variable number of tandem repeats

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