Abstract
Purpose
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).
Methods
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.
Results
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.
Conclusions
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.
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References
Hoy D, March L, Brooks P, Blyth F, Woolf A, Bain C, Williams G, Smith E, Vos T, Barendregt J, Murray C, Burstein R, Buchbinder R (2014) The global burden of low back pain: estimates from the global burden of disease 2010 study. Ann Rheum Dis 73:968–974
de Schepper EI, Damen J, van Meurs JB, Ginai AZ, Popham M, Hofman A, Koes BW, Bierma-Zeinstra SM (2010) The association between lumbar disc degeneration and low back pain: the influence of age, gender, and individual radiographic features. Spine 35:531–536
Adams MA, Roughley PJ (2006) What is intervertebral disc degeneration, and what causes it? Spine 31:2151–2161
Cheung KM, Karppinen J, Chan D, Ho DW, Song YQ, Sham P, Cheah KS, Leong JC, Luk KD (2009) Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine. 34:934–940
Frymoyer JW (1992) Lumbar disk disease: epidemiology. Instr Course Lect 41:217–223
Liuke M, Solovieva S, Lamminen A, Luoma K, Leino-Arjas P, Luukkonen R, Riihimaki H (2005) Disc degeneration of the lumbar spine in relation to overweight. Int J Obes (Lond) 29:903–908
Mayer JE, Iatridis JC, Chan D, Qureshi SA, Gottesman O, Hecht AC (2013) Genetic polymorphisms associated with intervertebral disc degeneration. Spine J 13:299–317
Christensen FB (2004) Lumbar spinal fusion. Outcome in relation to surgical methods, choice of implant and postoperative rehabilitation. Acta orthopaedica Scandinavica Supplementum 75:2–43
Lee MJ, Dettori JR, Standaert CJ, Brodt ED, Chapman JR (2012) The natural history of degeneration of the lumbar and cervical spines: a systematic review. Spine 37:S18–S30
Park P, Garton HJ, Gala VC, Hoff JT, McGillicuddy JE (2004) Adjacent segment disease after lumbar or lumbosacral fusion: review of the literature. Spine 29:1938–1944
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 39:1373–1383
Videman T, Saarela J, Kaprio J, Nakki A, Levalahti E, Gill K, Peltonen L, Battie MC (2009) Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum 60:470–481
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 72:1141–1148
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 101:9757–9762
Panoutsopoulou K, Zeggini E (2013) Advances in osteoarthritis genetics. J Med Genet 50:715–724
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 122:145–155
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. 28:1913–1921
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 330:1233
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)
Frobin W, Brinckmann P, Biggemann M, Tillotson M, Burton K (1997) Precision measurement of disc height, vertebral height and sagittal plane displacement from lateral radiographic views of the lumbar spine. Clin Biomech (Bristol, Avon) 12(Suppl 1):S1–S63
Frobin W, Brinckmann P, Biggemann M (1997) Objective measurement of the height of lumbar intervertebral disks from lateral roentgen views of the spine. Z Orthop Ihre Grenzgeb 135:394–402
Battie MC, Videman T, Gibbons LE, Fisher LD, Manninen H, Gill K (1995) 1995 Volvo Award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging findings in identical twins. Spine. 20:2601–2612
Battie MC, Lazary A, Fairbank J, Eisenstein S, Heywood C, Brayda-Bruno M, Varga PP, McCall I (2014) Disc degeneration-related clinical phenotypes. Eur Spine J 23(Suppl 3):S305–S314
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 82:1202–1210
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 18:1148–1155
Myhr CB, Hulme MA, Wasserfall CH, Hong PJ, Lakshmi PS, Schatz DA, Haller MJ, Brusko TM, Atkinson MA (2013) The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNgamma production by PBMC. J Autoimmun 44:8–12
Doita M, Kanatani T, Ozaki T, Matsui N, Kurosaka M, Yoshiya S (2001) Influence of macrophage infiltration of herniated disc tissue on the production of matrix metalloproteinases leading to disc resorption. Spine 26:1522–1527
Park JY, Kuh SU, Park HS, Kim KS (2011) Comparative expression of matrix-associated genes and inflammatory cytokines-associated genes according to disc degeneration: analysis of living human nucleus pulposus. J Spinal Disord Tech 24:352–357
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 31:2759–2766
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 112:643–650
Kauppila LI (1997) Prevalence of stenotic changes in arteries supplying the lumbar spine. A postmortem angiographic study on 140 subjects. Ann Rheum Dis 56:591–595
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 14:105
Omair A, Lie BA, Reikeras O, Brox JI (2012) An Association Study of Interleukin 18 Receptor Genes (IL18R1 and IL18RAP) in Lumbar Disc Degeneration. Open Orthopaed J 6:164–171
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 13:1309–1320
Gologorsky Y, Chi J (2014) Genetic predisposition to lumbar disc degeneration. Neurosurgery 74:N10–N11
Eser B, Cora T, Eser O, Kalkan E, Haktanir A, Erdogan MO, Solak M (2010) Association of the polymorphisms of vitamin D receptor and aggrecan genes with degenerative disc disease. Genet Test Mol Biomark 14:313–317
Valdes AM, Hassett G, Hart DJ, Spector TD (2005) Radiographic progression of lumbar spine disc degeneration is influenced by variation at inflammatory genes: a candidate SNP association study in the Chingford cohort. Spine 30:2445–2451
Miller JA, Schmatz C, Schultz AB (1988) Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine 13:173–178
Chou R, Qaseem A, Snow V, Casey D, Cross JT Jr, Shekelle P, Owens DK (2007) Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American college of physicians and the American pain society. Ann Intern Med 147:478–491
Illien-Junger S, Lu Y, Qureshi SA, Hecht AC, Cai W, Vlassara H, Striker GE, Iatridis JC (2015) Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice. PLoS One 10:e0116625
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
Acknowledgments
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.
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Funding
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.
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Omair, A., Mannion, A.F., Holden, M. et al. Age and pro-inflammatory gene polymorphisms influence adjacent segment disc degeneration more than fusion does in patients treated for chronic low back pain. Eur Spine J 25, 2–13 (2016). https://doi.org/10.1007/s00586-015-4181-x
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DOI: https://doi.org/10.1007/s00586-015-4181-x