To our knowledge, the current study was one of the firsts to investigate the association of cytokine polymorphisms including IL-2 (-330T/G, + 166G/T), IL-12 (-1188A/C) and IFN-γ (= 874A/T) with intervertebral disc degeneration (IVDD) in Iranian patients. Among all the investigated SNPs, only the IL2 -330T/G was significantly associated with disease was twice more common in patients than controls. Besides, the haplotype of IL-2 (-330, + 166) was also significantly associated with IVDD, as the GT haplotypes was 42 times more frequent in IVDD patients. However, other investigated SNPs failed to show any association with IVDD in this population.
The role of immunity, as well as the cytokines of interest in the current study, were investigated in a number of sturdies so far. Although the biomarker levels of these cytokines were of interest in a number of studies or animal model investigations, the role of SNPs were not widely investigated in the literature.
The IFN-γ level would significantly change in low back pain. A recent investigation in 2019, indicated higher levels of IFN-γ in acute low back pain compared with chronic low back pain or healthy subjects. Interestingly, the IFN-γ level was not significantly different between chronic low back pain and asymptomatic individuals . A considerable number of patients with IVDD who experience chronic low back pain may require surgical intervention, nevertheless, some of them may not response to this treatment either. The IFN-γ expression level was associated with increased numeric rating scale, and higher levels of IFN-γ was detected in patients who did not respond to surgery. Spinal cord stimulation might be considered as an option for improving the pain and quality of life in these patients. However, in an investigation, IFN-γ level was not significantly altered after the stimulation . IFN-γ levels was associated with acute low back pain, although its association with chronic low back pain was not significant . While the IFN-γ SNP did not showed significant association with postoperative pain reduction in this study, the A allele of IFN-γ rs2069705 remarkably associated with higher ODI score in a study, as the patients with AA and GA genotypes had significantly higher ODI scores. In addition, the AG and GG genotypes of IFN-γ rs2069718 were associated with higher ODI scores in this Norwegian population .
The IL-12 mainly functions together with other cytokines such as IFN-γ. Accordingly, when comparing the cytokine levels in fragments of herniated discs, with degenerative disc tissue, both IL-12 and IFN-γ, as well as other cytokines (IL-4, IL-6) indicated higher levels in the fragments of herniated discs . On the other hands, the expression levels of these cytokines were not remarkably different between nucleous pulposus and anulus fibrosus of healthy discs obtained from autopsies .
Although the IL-2 plays an important role in inflammatory processes, its expression level was not significantly different between acute or chronic low back pain, or even the asymptomatic subjects . Moreover, the IL-2 level was not associated with VAS scores either in acute or chronic low back pain . In a study measuring the levels of different cytokines in low back pain, IL-2 levels in the sera of patients with low back pain were remarkably lower than controls, similar to other factors including IL-6, IL-4, and MMP-1. On the other hands, the serum levels of IL-12 and IFN-γ were not significantly different between patients and healthy controls . However, another study indicated higher levels of IL-2 and IL-12 in degenerated disc tissue compared to controls . Another study confirmed this finding, as both the mRNA level and protein level of IL-2 were higher in prolapsed NP cells than controls .
In an animal model of disc herniation in rats, presence of NP and IFN-γ in the dorsal nerve root of animals resulted in remarkable higher activity of nociceptive neurons . The intervertebral disc degeneration would affect different components of spinal cords, in addition to disc itself. The inflammatory process and destructive damages would also affect the spinal components such as epidural space, as the inflammation in this component would have compressive effect on nerve roots and cause more severe clinical manifestations. Accordingly, in a canine model of disc degeneration, the cytokine levels were assessed in different stages of disc extrusion. Importantly, the expression level of IL-2 was significantly decreased in disc extrusion, especially in the subacute stage . However, another animal model in rabbits showed contradictory results, as the IL-2 level was significantly increased not only in degenerated disc tissue, but also in the sera of animals. Moreover, in the current model, the effect of plasma vaporization ablation was evaluated for treatment of IVDD. The expression levels of IL-12, as well as some other cytokines such as IL-4 and TNF-α, were decreased after applying this method, which could indicate its effectiveness in treating IVDD . The mRNA expression of IL-2 was also remarkably higher in another model of disc herniation in rats . In an animal model of disc herniation in rats, dorsal root ganglions were exposed to NP, and epidural lavage indicated higher expression of IFN-γ, as well as other cytokines such as IL-4, IL-6, and TNF-α .
Taking limitations of current study to account, small sample size could be considered as one of them, and therefore, a much larger sample size could improve random error or increase the study power. Meanwhile, the genetic factors may have co-effect on each other, and therefore a wider panel measuring the role of different cytokines and other genetic factors could be helpful if better understanding of the role of each factor.