Three genes in the aggrecan degradation pathway act synergistically to predispose to degenerative disc disease

Abstract

Introduction. Degenerative disc disease (DDD) is a multifactorial disorder with genetic predisposition. Aggrecan (AGC1) is the major proteoglycan in the extracellular matrix of the intervertebral disc and is responsible for maintaining disc hydration. Impairment in the structural property of aggrecan through enzymatic degradation could contribute to DDD. Method. Using a previously established Southern Chinese population dataset of 804 individuals with MRI and DNA information, we performed a case-association study for the genes in the aggrecan degradation pathway, including MMP cluster, AGC1, ADAMTS-4,-5 and IL-1 cluster. SNP tags of these candidate genes were selected from HapMap and ABI SNPbrower databases. Polymorphisms were assayed by Sequenom method. Data analysis was carried out using Chi-square, HWE and Fisher’s exact tests. Interaction was analyzed by the set association approach and the combination methods. Result. 15 SNPs were selected from the original 65 SNPs by set association, three of which were detected to be very highly significant associated with IVD when all the three risk factors co-exist [p 0.00001, OR 2.11(1.51–2.95)]. The frequencies of all the three risk factors are 0.32 in controls and 0.50 in cases. Discussion. This is the first genetic study of any kind that demonstrates a combination of genetic predisposing factors within the same pathway are needed to predispose to disease. This has significant implications for the future study of DDD as well as other diseases, as genetic interactions will need to be specifically identified and examined. The combination of genes make good functional sense as they are all involved in the degradation pathway of aggrecan. Future work would need to demonstrate concentrate on how these changes result in DDD.