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This dissertation, Genetics and Molecular Characterization of Degenerative Disc Disease by Jin-to, Jim, 詹展韜, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Genetics and Molecular Characterization of Degenerative Disc Disease Submitted by JIM JIN TO For the degree of Doctor of Philosophy at the University of Hong Kong in June 2005 Low back pain and sciatica are usually caused by degenerative disc disease (DDD). Although they are common, the aetiology of these conditions is poorly understood. Better treatment and prevention require more rigorous investigation of their genetic and environmental causes. A Finnish study found an association between DDD and two alleles of collagen IX, Trp2 and Trp3 of the COL9A2 and COL9A3 genes respectively. We have examined this in a larger sample of a different ethnic population using more objective criteria to define the disease, and carried out molecular characterization of the identified mutation in surgically retrieved human intervertebral disc specimens. Lumbar DDD, the presence of annular tears and disc and end-plate herniations were defined using manetic resonance imaging in 804 Southern Chinese volunteers aged 18-55 years. These were correlated with the frequencies of the Trp2 and Trp3 alleles of collagen IX. The Trp2 allele was present in 20% of the population and was mainly associated with a 2.4-fold increase in the risk of developing DDD. Affected Trp2 individuals had more severe degeneration. The Trp3 allele was absent from the Southern Chinese population. Trp2 allele did not demonstrate a strong effect in comparison to environmental factors, suggesting its role as a predisposing factor rather than a causative mutation. This large scale population study using MRI to define DDD demonstrates that the Trp2 allele is a genetic risk factor for the development and severity of disc degeneration. The contrasting Trp2 and Trp3 allele frequencies between Finns and Chinese is the first indication that the genetic risk factors for DDD does vary between ethnic groups. Functional characterization of Trp2 is needed to confirm the biological relevance of the genetic association. Functional role of the Trp2 allele was studied by comparison of 4 intervertebral disc specimens carrying the Trp2 allele to 4 that do not. Changes in the collagen matrix and the non-collagenous matrix proteins were analyzed. Collagen matrix metabolism and stability were analyzed by fractionating the extracellular matrix in buffers of increasing extraction strengths. Proteomic profiling of the non-collagenous matrix proteins was performed by mean of two dimensional-polyacrylamide gel electrophoresis (2D-PAGE). Stable collagen matrix of Trp2 positive specimens was found to be less degradable than the Trp2 negative specimens. Profile comparison revealed that Trp2 positive and negative specimens were not significantly different from one another in their non-collagenous matrix protein contents. A novel protein, osteoglycin/mimecan, previously unknown to be presence in the intervertebral disc was identified by 2D-PAGE and could serve as a candidate for future genetic study. The molecular consequences of Trp2 on the disc extracellular matrix do not appear to be drastic, confirming its role as a predisposing risk factor. Difference in collagen matrix degradability represented the biological consequence of presence of Trp2 allele and provided further supported for its genetic association. The combination of genetic and proteomic approaches provide a good study model f

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