Age and pro-inflammatory gene polymorphisms influence adjacent segment disc degeneration more than fusion does in patients treated for chronic low back pain
- 853 Downloads
Does lumbar fusion lead to accelerated adjacent segment disc degeneration (ASDD) or is it explained by genetics and aging? The influence of genetics on ASDD remains to be explored. This study assesses whether the disc space height adjacent to a fused segment is associated with candidate gene single nucleotide polymorphisms (SNPs).
Patients with low back pain from four RCTs (N = 208 fusion; 77 non-operative treatment) underwent standing plain radiography and genetic analyses at 13 ± 4 years follow-up. Disc space height was measured using a validated computer-assisted distortion-compensated roentgen analysis technique and reported in standard deviations from normal values. Genetic association analyses included 34 SNPs in 25 structural, inflammatory, matrix degrading, apoptotic, vitamin D receptor and OA-related genes relevant to disc degeneration. These were analysed for their association with disc space height (after adjusting for age, gender, smoking, duration of follow-up and treatment group) first, separately, and then together in a stepwise multivariable model.
Two SNPs from the IL18RAP gene (rs1420106 and rs917997) were each associated with a lower disc space height at the adjacent level (B = −0.34, p = 0.04 and B = −0.35, p = 0.04, respectively) and the MMP-9 gene SNP rs20544 was associated with a greater disc space height (B = 0.35, p = 0.04). Age (p < 0.001) and fusion (p < 0.008) were also significant variables in each analysis. The total explained variance in disc space height was for each SNP model 13–14 %, with 11–12 % of this being accounted for by the given SNP, 64–67 % by age and 19–22 % by fusion. In the multivariable regression analysis (with nine SNPs selected for entry, along with the covariates) the total explained variance in disc space height was 23 %, with the nine SNPs, age and fusion accounting for 45, 45 and 7 % of this, respectively.
Age was the most significant determinant of adjacent segment disc space height followed by genetic factors, specifically inflammatory genes. Fusion explained a statistically significant but small proportion of the total variance. Much of the variance remained to be explained.
KeywordsChronic low back pain Adjacent segment disc degeneration Lumbar fusion Single nucleotide polymorphism Inflammatory genes
We thank department of Immunology Oslo University Hospital-Rikshospitalet (IMMI), for providing us with the logistics for DNA purification and the Center for Interactive Genetics, Norwegian University of Life Sciences (UMB) Aas, for performing Sequenom analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
AO Spine funds were received via the Hansjorg Wyss Research Award. In the UK, the study was also supported by Thames Valley Comprehensive Local Research Network for National Institutes for Health Research. In Norway, the Norwegian Research Council grant funds were received to support this work. We thank them for providing the financial support.
- 11.Mannion AF, Leivseth G, Brox JI, Fritzell P, Hagg O, Fairbank JC (2014) ISSLS Prize winner: long-term follow-up suggests spinal fusion is associated with increased adjacent segment disc degeneration but without influence on clinical outcome: results of a combined follow-up from 4 randomized controlled trials. Spine 39:1373–1383PubMedCrossRefGoogle Scholar
- 13.Williams FM, Bansal AT, van Meurs JB, Bell JT, Meulenbelt I, Suri P, Rivadeneira F, Sambrook PN, Hofman A, Bierma-Zeinstra S, Menni C, Kloppenburg M, Slagboom PE, Hunter DJ, MacGregor AJ, Uitterlinden AG, Spector TD (2013) Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects. Ann Rheum Dis 72:1141–1148PubMedPubMedCentralCrossRefGoogle Scholar
- 14.Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M (2004) Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci USA 101:9757–9762PubMedPubMedCentralCrossRefGoogle Scholar
- 16.Brox JI, Reikeras O, Nygaard O, Sorensen R, Indahl A, Holm I, Keller A, Ingebrigtsen T, Grundnes O, Lange JE, Friis A (2006) Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: a prospective randomized controlled study. Pain 122:145–155PubMedCrossRefGoogle Scholar
- 17.Brox JI, Sorensen R, Friis A, Nygaard O, Indahl A, Keller A, Ingebrigtsen T, Eriksen HR, Holm I, Koller AK, Riise R, Reikeras O (2003) Randomized clinical trial of lumbar instrumented fusion and cognitive intervention and exercises in patients with chronic low back pain and disc degeneration. Spine. 28:1913–1921PubMedCrossRefGoogle Scholar
- 18.Fairbank J, Frost H, Wilson-MacDonald J, Yu LM, Barker K, Collins R (2005) Randomised controlled trial to compare surgical stabilisation of the lumbar spine with an intensive rehabilitation programme for patients with chronic low back pain: the MRC spine stabilisation trial. BMJ 330:1233PubMedPubMedCentralCrossRefGoogle Scholar
- 19.Fritzell P, Hagg O, Wessberg P, Nordwall A (2001) 2001 Volvo Award Winner in Clinical Studies: Lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish Lumbar Spine Study Group. Spine. 26:2521–2532 (discussion 2532–4) PubMedCrossRefGoogle Scholar
- 24.Zhernakova A, Festen EM, Franke L, Trynka G, van Diemen CC, Monsuur AJ, Bevova M, Nijmeijer RM, van ‘t Slot R, Heijmans R, Boezen HM, van Heel DA, van Bodegraven AA, Stokkers PC, Wijmenga C, Crusius JB, Weersma RK (2008) Genetic analysis of innate immunity in Crohn’s disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am J Hum Genet 82:1202–1210PubMedPubMedCentralCrossRefGoogle Scholar
- 25.Koskinen LL, Einarsdottir E, Dukes E, Heap GA, Dubois P, Korponay-Szabo IR, Kaukinen K, Kurppa K, Ziberna F, Vatta S, Not T, Ventura A, Sistonen P, Adany R, Pocsai Z, Szeles G, Maki M, Kere J, Wijmenga C, van Heel DA, Saavalainen P (2009) Association study of the IL18RAP locus in three European populations with coeliac disease. Hum Mol Genet 18:1148–1155PubMedCrossRefGoogle Scholar
- 29.Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren KA, Bowman C, Hammond A, Kirkham B, Jarvinen S, Niinimaki J, Veeger N, Haapea M, Torkki M, Tervonen O, Seitsalo S, Hurri H (2006) The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine 31:2759–2766PubMedCrossRefGoogle Scholar
- 30.Tiret L, Godefroy T, Lubos E, Nicaud V, Tregouet DA, Barbaux S, Schnabel R, Bickel C, Espinola-Klein C, Poirier O, Perret C, Munzel T, Rupprecht HJ, Lackner K, Cambien F, Blankenberg S (2005) Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation 112:643–650PubMedCrossRefGoogle Scholar
- 32.Omair A, Holden M, Lie BA, Reikeras O, Brox JI (2013) Treatment outcome of chronic low back pain and radiographic lumbar disc degeneration are associated with inflammatory and matrix degrading gene variants: a prospective genetic association study. BMC Musculoskelet Disord 14:105PubMedPubMedCentralCrossRefGoogle Scholar
- 34.Rajasekaran S, Kanna RM, Senthil N, Raveendran M, Cheung KM, Chan D, Subramaniam S, Shetty AP (2013) Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects. Spine J 13:1309–1320PubMedCrossRefGoogle Scholar
- 41.Dario AB, Ferreira ML, Refshauge K, Lima T, Ordonana JR, Ferreira PH (2015) The relationship between obesity, low back pain and lumbar disc degeneration when genetics and the environment are considered: a systematic review of twin studies. Spine J 15(5):1106–1117. doi: 10.1016/j.spinee.2015.02.001 PubMedCrossRefGoogle Scholar