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

Abstract

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).

Short aggrecan gene repetitive alleles associated with lumbar degenerative disc disease in Turkish patients

“…They also reported three studies about the aggrecan gene in different populations (Finnish, Japanese, Canadian). Videman et al (2009) [IL], and matrix metalloproteinase [MMP] genes). AGC1 was associated with disc desiccation, bulging, and height narrowing, and COL9A1 and COL9A2 were associated with disc desiccation and bulging.…”

HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort

“…This pattern was similar to that found by Lee et al 15 Polymorphisms in COL11A2 have been implicated in susceptibility to skeletal and cartilage disorders, and hearing loss. [27][28][29][30][31][32] HLA-DPB1 is an attractive candidate gene for RA within this region, as it has an important role in the immune system by presenting peptides to CD4 þ T cells. Furthermore, the other two genes encoding classical HLA class II molecules, HLA-DRB1 and HLA-DQA1, are established RA risk genes.…”

CASE-REPORT Association between an ACAN gene variable number tandem repeat polymorphism and lumbar disc herniation: a case control study

“…According to Videman et al (2009), the process of disc degeneration involves desiccation, collagen fragmentation, and failures in the annulus fibrosus, resulting in disc height narrowing. Zhang et al (2008), Eser et al (2010), and Mayer et al (2013) indicate several genes that have been associated with DDD, including the human aggrecan gene (ACAN).…”