Radiographic Progression of Lumbar Spine Disc Degeneration Is Influenced by Variation at Inflammatory Genes

Valdes, Ana M.; Hassett, Geraldine; Hart, Deborah; Spector, Tim D.

doi:10.1097/01.brs.0000184369.79744.a5

Cited by 80 publications

(68 citation statements)

References 33 publications

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“…Several studies have found familial predisposition to LDD, including early onset sciatica and lumbar disc herniation. In addition, mutations or polymorphisms in several genes have been reported to be associated with either the presence or severity of disc degeneration, including gene coding for collagen IX and XI [2,12,13], aggrecan [9], cartilage intermediate layer protein [18], vitamin D receptor [22], interleukin-1 [19], matrix metalloproteinase-3(MMP-3) [20], tissue inhibitor of metalloproteinase-1(TIMP-1) [21], and cyclooxygenase-2 [21].…”

Section: Introductionmentioning

confidence: 99%

Association between the -1306C/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults

et al. 2007

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Matrix metalloproteinase-2 (MMP-2) has been shown to play a pivotal role in the pathophysiology of lumbar disc disease (LDD). Increased expression and activity of MMP-2 has been documented in degenerative discs. The polymorphism -1306C/T in the promoter region of MMP-2 gene was reported to influence gene transcription and expression. The objective of this study was therefore to investigate the possible association of MMP-2 -1306C/T polymorphism with the occurrence and the clinical characteristics of LDD. MMP-2 genotypes were determined by polymerase chain reaction (PCR) and direct DNA sequencing in a case-control study involving 162 younger patients with LDD and 318 age-and sex-matched healthy adults. The results showed that the frequency of MMP-2 -1306CC genotype was significantly higher in LDD patients when compared with controls. Subjects with the CC genotype had nearly threefold increased risk for LDD (odds ratio 3.08; 95% confidence interval 1.84-5.16) compared with subjects carrying at least one variant T allele. Furthermore, this genotype was found to correlate with more severe grades of disc degeneration observed on magnetic resonance imaging scan. These findings suggest that MMP-2 -1306C/T polymorphism may be a genetic risk factor related to LDD susceptibility in the young adult population.

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Section: Introductionmentioning

confidence: 99%

Association between the -1306C/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults

et al. 2007

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“…These factors have been shown to have only modest effects (10) and much variability remains unexplained. Genetic factors make an important contribution to LDD (11)(12)(13), and although one radiographic study of identical twins suggested familial clustering (14), the relative genetic and environmental contribution to SN has yet to be formally evaluated.…”

Section: Introductionmentioning

confidence: 99%

Schmorl's nodes: Common, highly heritable, and related to lumbar disc disease

Williams¹,

Manek²,

Sambrook³

et al. 2007

Arthritis & Rheumatism

138

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Objective. Schmorl's nodes (SN) are common, but little is known of their relationship with degenerative change and back pain or genetic and environmental factors influencing their expression. We studied healthy female twin volunteers to determine the prevalence and clinical features associated with SN. Methods. Serial sagittal T1-and T2-weighted magnetic resonance images of the lower thoracic and lumbar spine were analyzed in 516 healthy female twins (150 monozygotic and 366 dizygotic). The images were scored for lumbar degenerative change. Presence of SN was noted at cranial and caudal vertebral levels T9 to L5. Data on physical activity and back pain were collected by questionnaire. Heritability of SN was calculated using variance components modeling. Results. SN were found in 30% of subjects. Of the 374 SN, 153 (41%) were in the lumbar spine and 221 (59%) were in the thoracic spine. SN heritability was >70%. There was a positive association between SN and lumbar disc disease (LDD). SN were more frequent in subjects with back pain (for >2 SN: odds ratio [OR] 2.68, 95% confidence interval [95% CI] 1.11-6.47, P ‫؍‬ 0.03), but this was largely accounted for by the association of SN with LDD (OR 1.97, 95% CI 0.78 -5.0, P ‫؍‬ 0.15 adjusted for LDD). No independent association of SN with back pain was identified. Conclusion. SN are common in middle-aged women and are strongly genetically determined. They are associated with lumbar degenerative change, which is a risk factor for back pain, but are not themselves an independent risk factor for back pain.

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“…Among the 11 genes that have been investigated in 21 studies previously performed, 9 (AGC1, COL1A1, COL9A2, COL5A1, COL9A3, COL11A2, IL1, IL2, and MMP3) were associated with disc degeneration, pathologic changes, or associated symptoms in at least 1 study (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, phenotypes vary widely, and the studies included both symptoms assumed to be associated with disc pathology and qualitative assessments of disc degeneration.…”

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confidence: 99%

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Videman

Saarela

Kaprio

et al. 2009

Arthritis & Rheumatism

125

104

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Objective. To examine the allelic diversity of structural, inflammatory, and matrix-modifying gene candidates and their association with disc degeneration.Methods. Subjects were 588 men ages 35-70 years. We investigated associations of single-nucleotide polymorphisms in AGC1 and in 12 collagen, 8 interleukin, and 4 matrix metalloproteinase genes with quantitative magnetic resonance imaging measurements of disc desiccation and disc bulging and height narrowing scores, after controlling for age and suspected risk factors. Analyses were performed using QTDT software. P values were derived from 1,000 permutations, and empirical P values for global significance also were applied.Results. Twelve of the 99 variants in 25 selected candidate genes provided evidence of association (P < 0.05) with disc signal intensity in the upper and/or lower lumbar regions. Allelic variants of AGC1 (rs1042631; P ‫؍‬ 0.001), COL1A1 (rs2075555; P ‫؍‬ 0.005), COL9A1 (rs696990; P ‫؍‬ 0.00008), and COL11A2 (rs2076311; P ‫؍‬ 0.018) genes provided the most significant evidence of association with disc signal intensity. The same variants of AGC1 (P ‫؍‬ 0.010) and COL9A1 (P ‫؍‬ 0.014), as well as variants in the COL11A1 gene (rs1463035 [P ‫؍‬ 0.004]; rs1337185 [P ‫؍‬ 0.015]) were also associated with disc bulging, as was AGC1 with disc height narrowing (rs1516797; P ‫؍‬ 0.005). In addition, 4 allelic variants in the immunologic candidate genes (rs2071375 in IL1A [P ‫؍‬ 0.027]; rs1420100 in IL18RAP [P ‫؍‬ 0.005]) were associated with disc signal intensity.Conclusion. Genetic variants account for interindividual differences in disc matrix synthesis and degradation. The accuracy of the quantitative disc signal intensity measurements we used likely enhanced our ability to observe these associations. Our findings shed light on possible mechanisms of degeneration and support the view that disc degeneration is a polygenetic condition.Intervertebral disc degeneration is a suspected cause of common back pain (1), but both the etiology and pathogenesis of disc degeneration are poorly understood (2). A 1992 review of relevant scientific literature identified physical demands of occupational and leisure activities as primary risk factors, while the role of genetics was uncertain (3). However, results from later twin studies suggested that heredity plays a major role, accounting for an estimated 34-74% of variance in disc degeneration (4,5).

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Radiographic Progression of Lumbar Spine Disc Degeneration Is Influenced by Variation at Inflammatory Genes

Abstract: Our results suggest a role for genes regulating inflammatory pathways in the radiographic progression of spine degeneration. This could prove a fruitful area for future therapeutics for the spine and other joints.

Cited by 80 publications

References 33 publications

Association between the -1306C/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults

Association between the -1306C/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults

Schmorl's nodes: Common, highly heritable, and related to lumbar disc disease

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

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