1Kathryn S. Cheah, 1,2J.J.T. Jim, 3N. Noponen-Hietala, 2K.M.C. Cheung, 4J. Ott, 5J. Karppinen, 6A. Sahraravand, 2K.D.K. Luk, 7S.P. Yip, 1,2Y.Q. Song, 2J.C.Y. Leong, 3,6,8L. Ala-Kokko, 1D. Chan
1Biochemistry Dept. University of Hong Kong, 21 Sassoon Rd, Hong Kong, 2Dept. of Orthopaedic Surgery, University of Hong Kong, Queen Mary Hospital, Pokfulam Rd, Hong Kong, 3Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland, 4Laboratory of Statistical Genetics, Rockefeller University, New York, New York, USA, 5Department of Physical Medicine and Rehabilitation,University of Oulu, Oulu, and Finnish Institute of Occupational Health, and Orton Orthopedic Hospital, Helsinki, Finland, 6Center for Gene Therapy,Tulane University Health Sciences Center, New Orleans, Louisiana, USA, 7Nursing and Health Sciences, Polytechnic University, Kowloon, Hong Hong, 8Department of Medicine,Tulane University Health Sciences Center, New Orleans, Louisiana, USA
Degenerative disc disease (DDD) is a common cause of low back pain and sciatica. Previous studies in the Finnish population suggested an association of changes in the collagen IX genes, COL9A2 and COL9A3, with genetic predisposition to low back pain with sciatica. Two amino acid substitutions in collagen IX, Gln326Trp in the a2(IX)-chain (Trp2 allele) and Arg103Trp in the a3(IX)-chain (Trp3 allele) were implicated. In Finns the incidence of the Trp2 allele is rare (4%) while the Trp3 is more common (24%). However, because subject selection was based solely on symptomatic criteria of sciatica for more than one month, and the controls were not scanned by MRI (magnetic resonance imaging), the contributions of these changes to DDD have not been clearly defined. The contributions of the Trp2 and Trp3 alleles to DDD also have not been studied in other populations.
In order to assess the contribution of the COL9A2 and COL9A3 Trp alleles to DDD and its pathology, we undertook a comprehensive study screening volunteers by MRI of the spine, and testing whether DDD pathology was associated with the COL9A2/COL9A3 changes. Lumbar DDD was defined by magnetic resonance imaging (MRI) on 804 Southern Chinese volunteers between 18-55 years. Presence of pathogenic changes in the intervertebal discs such as annular tears, disc herniations and end-plate changes (Schmorl's nodes) were documented. The frequency of the Trp2 and Trp3 alleles were determined and correlated with MRI findings. Additional mutations in the three collagen IX genes (COL9A1, COL9A2, COL9A3) were screened for in 150 randomly chosen subset of individuals.
We found that the Trp3 allele was absent, while the Trp2 allele was present in 20% of the population. For individuals between 30 to 39 years of age, the Trp2 allele was associated with a 4-fold increase in risk of developing annular tears. The predisposition of Trp2 individuals to annular tears at a younger age than disc degeneration is interesting, and supports the hypothesis that annular tears precede disc degeneration. For individuals 40 to 49 years of age, there was a 2.4-fold increase in risk of developing DDD, and Schmorl's nodes. Affected Trp2 individuals develop a more severe form of the disease when compared to age-matched unaffected individuals. Our study is the largest-scale population study to date, using precisely defined, sensitive and specific criteria for DDD (MRI). We show for the first time that the Trp2 allele is a significant age-dependent risk factor for DDD in Southern Chinese. These findings suggest that collagen IX plays an important role in maintaining tissue integrity, and that when its structure is altered, the disc is more prone to degeneration with cumulative loading.
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