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Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Objective: Typically, age and abnormal physical loading ("wear and tear") have been associated with the development of intervertebral disc degeneration. In the past decade, various additional etiologic factors for disc degeneration have been sporadically reported in the literature; however, many investigators continue to place tremendous emphasis on the effects of age and biomechanics associated with disc degeneration. The aim of this study was to provide additional insight into the notion that age and biomechanics are key factors in the development of disc degeneration. To this end, we addressed the prevalence of and risk factors associated with a unique pattern of disc degeneration of the lumbar spine, "skipped" level (nonconsecutive) disc degeneration (SLDD)., Methods: As part of a large genetics-based study in southern Chinese individuals (n = 1,989), a cross-sectional analysis was performed in subjects exhibiting disc degeneration in > or = 2 levels (n = 838) who were then categorized as having SLDD (n = 174) or non-SLDD (contiguous, multilevel; n = 664). Various radiographic parameters were assessed based on T2-weighted magnetic resonance imaging (MRI). Subject demographics were assessed, and univariate and multivariate logistic regression analyses were performed., Results: Overall, 8.7% of the whole population (n = 1,989) had SLDD, while it was present in 20.8% of subjects with multilevel disc degeneration (n = 838). SLDD was more prevalent in male subjects (adjusted odds ratio [OR] 1.48, 95% confidence interval [95% CI] 1.04-2.10, P = 0.028). SLDD was significantly associated with the presence of Schmorl's nodes (adjusted OR 2.72, 95% CI 1.78-4.15, P < 0.001), which also presented in levels with no disc degeneration. A history of disc bulge/extrusion (P = 0.004) and/or a history of back injury (P = 0.010) was significantly associated with non-SLDD, and a greater degree of overall severity of disc degeneration was also associated with non-SLDD. Other demographic and MRI findings did not significantly differ between groups., Conclusion: To our knowledge, this report is the first to describe the prevalence and risk factors associated with SLDD. Our study challenges the paradigm that age and biomechanics are the key factors associated with the development of disc degeneration. Although age and biomechanical factors may play a role in the manifestation of disc degeneration, our novel findings of SLDD patterns provide further awareness of and support for the notion that additional etiologic factors may play a role in the development of disc degeneration. Such factors warrant further investigation to shed light on the cause of disc degeneration.

Study Design: A cross-sectional population study of magnetic resonance imaging (MRI) changes. OBJECTIVE.: To examine the pattern and prevalence of lumbar spine MRI changes within a southern Chinese population and their relationship with back pain., Summary of Background Data: Previous studies on MRI changes and back pain have used populations of asymptomatic individuals or patients presenting with back pain and sciatica. Thus, the prevalence and pattern of intervertebral disc degeneration within the population is not known., Methods: Lumbar spine MRIs were obtained in 1043 volunteers between 18 to 55 years of age. MRI changes including disc degeneration, herniation, anular tears (HIZ), and Schmorl's nodes were noted by 2 independent observers. Differences were settled by consensus. Disc degeneration was graded using Schneiderman's classification, and a total score (DDD score) was calculated by the summation of the Schneiderman's score for each lumbar level. A K-mean clustering program was used to group individuals into different patterns of degeneration., Results: Forty percent of individuals under 30 years of age had lumbar intervertebral disc degeneration (LDD), the prevalence of LDD increasing progressively to over 90% by 50 to 55 years of age. There was a positive correlation between the DDD score and low back pain. L5-S1 and L4-L5 were the most commonly affected levels. Apart from the usual patterns of degeneration, some uncommon patterns of degeneration were identified, comprising of subjects with skip level lesions (intervening normal levels) and isolated upper or mid lumbar degeneration., Conclusion: LDD is common, and its incidence increases with age. In a population setting, there is a significant association of LDD on MRI with back pain.

Background: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD., Methods: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test., Results: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele., Conclusion: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.

Lumbar-disc degeneration (LDD) is a polygenic disease. Susceptibility genes reported so far are mainly extracellular matrix proteins. D14 allele of asporin (ASPN) is associated with osteoarthritis (OA). Candidate-gene association studies showed that the D14 allele is also significantly associated with LDD in Chinese and Japanese individuals. Meta-analysis showed that individuals harboring a D14 allele had higher risk with a summary odds ratio of 1.70 (p = 0.000013). ASPN expression in vertebral discs increased with age and degeneration. Our results indicate ASPN is a LDD gene in Asians, and common risk factors may be considered for OA and LDD.