Age and pro-inflammatory gene polymorphisms influence adjacent segment disc degeneration more than fusion does in patients treated for chronic low back pain.
OBJECTIVE
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.
Department of Orthopaedics, Oslo University Hospital-Rikshospitalet, Oslo, Norway. dr.ahmad.omair@gmail.com.|Department of Pathology, Shifa College of Medicine, Shifa Tameer e Millat University, H-8/4, Islamabad, Pakistan. dr.ahmad.omair@gmail.com.
Ahmad
A
Omair
Department of Research and Development, Spine Center Division, Schulthess Klinik, Zurich, Switzerland.
Anne F
AF
Mannion
Norwegian Computing Centre, Blindern, Oslo, Norway.
Marit
M
Holden
Institute of Clinical Medicine, Neuromuscular Disorders Research Group, UiT the Arctic University of Norway, Tromsø, Norway.
Gunnar
G
Leivseth
Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK.
Jeremy
J
Fairbank
Spine Center Göteborg, Gothenburg, Sweden.
Olle
O
Hägg
Neuro-Orthopedic Center, Länssjukhuset Ryhov, Jönköping, Sweden.
Peter
P
Fritzell
Department of Physical Medicine and Rehabilitation, Oslo University Hospital, University of Oslo, Oslo, Norway.
Jens I
JI
Brox
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging; D059350:Chronic Pain / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics*; D007403:Intervertebral Disc / Q000000981:diagnostic imaging; D055959:Intervertebral Disc Degeneration / Q000000981:diagnostic imaging / Q000209:etiology*; D017116:Low Back Pain / Q000628:therapy; D008159:Lumbar Vertebrae / Q000601:surgery; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D013123:Spinal Fusion; D055815:Young Adult
C115629:IL18RAP protein, human; D053728:Interleukin-18 Receptor beta Subunit; D020780:Matrix Metalloproteinase 9
Adjacent segment disc degeneration; Chronic low back pain; Inflammatory genes; Lumbar fusion; Single nucleotide polymorphism