Interleukin 1 Polymorphisms and Intervertebral Disc Degeneration
From: Epidemiology 2004;15: 626–633
Background: Enzymatic breakdown of the extracellular matrix, and possibly local inflammation, contributes to intervertebral disc degeneration. We investigated whether polymorphisms within the IL-1 gene locus are associated with lumbar disc degeneration and whether the effect of occupational physical load on disc degeneration is modified by the polymorphisms.
Methods: Genotypes were determined from 133 middle-aged men who underwent magnetic resonance imaging of the lumbar spine. The participants represented 3 occupations: 40 were machine drivers, 42 carpenters, and 51 office workers. We evaluated decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height as signs of degeneration in the L2/L3–L5/S1 discs.
Results: The odds ratio for disc bulges was 2.4 (95% confidence interval . 1.2– 4.8) and 1.9 (1.0 –3.7), in carriers of the IL-1.T889 or IL-1.T3954 alleles, respectively. The TT genotype of the IL-1. gene carried more than 3-fold risk of disc bulges as compared with the CC genotype.
Conclusions: IL-1 gene cluster polymorphisms could affect the risk of disc degeneration. The effect of physical workload seems to be modified by the IL-1 gene polymorphisms. Degeneration of the intervertebral disc is a process that begins early in life and is a consequence of a variety of intrinsic and extrinsic factors as well as of normal aging. Among the risk factors most commonly suspected of accelerating degeneration are occupational physical loading, back injury, and smoking. Epidemiologic studies of twins suggest that inheritance is the largest single determinant of disc degeneration. Recently, an association of disc degeneration with polymorphisms in the vitamin D receptor, collagen IX, aggrecan, and matrix metalloproteinase-3 (MMP-3) genes has been reported.
The initiation and sequence of disc degeneration is not well understood. It has been suggested to result from an enzymatic breakdown of the extracellular matrix and possibly from local inflammation. Disc degeneration involves biologic changes (which are most pronounced in the nucleus) and gross structural changes (which are more evident in the annulus and endplates). Common structural changes include radial fissures, rim tears in the annulus, increased radial bulging of the annulus, reduced disc height, end plate defects, and vertical bulging of the end plates into the adjacent vertebral bodies. The intervertebral disc contains cells that respond to differential loading by changing their biology.
Magnetic resonance imaging (MRI) is the most sensitive method for the evaluation of disc degeneration. Abnormalities of the lumbar intervertebral discs depicted by MRI can be divided into changes in signal intensity and changes in disc morphology (changes in disc height and disc contour). The main pathologic signs used to define intervertebral disc degeneration are low signal intensity of the nucleus pulposus and morphologic changes such as disc space narrowing, disc bulges and herniations, anular tears, and vertebral osteophytes.
Interleukin-1 (IL-1) is a cytokine that is produced in response to infection, injury, or antigenic challenge. It induces a broad spectrum of systemic changes in neurologic, metabolic, hematologic, and endocrinologic systems, and it plays a regulatory role both in health and disease. There are 3 members in the IL-1 gene family: IL-1., IL-1., and IL-1 receptor antagonist (IL-1RN). The first 2 are strong inducers of inflammation, whereas IL-1RN suppresses the effect of IL-1 by competitively inhibiting the binding of IL-1 to the IL-1 receptor. IL-1RN does not induce intracellular response and thus acts as an inhibitor of IL-1 activity.
The inflammatory response is regulated by a balance between pro- and antiinflammatory cytokines. One-hundredfold or greater levels of IL-1RN over IL-1 are necessary to functionally inhibit biologic effects of IL-1 on target cells.19 The balance between IL-1 and IL-1RN has been extensively studied in a variety of experimental animal models of disease, including arthritis, inflammatory bowel disease, leukemia and other cancers, osteoporosis, diabetes, central nervous system diseases, and arterial diseases. Local overproduction of IL-1 and/or underproduction of IL-1RN predispose to the development of each of these diseases.
The role of interleukin-1 has rarely been studied in the human intervertebral disc diseases, but it is believed to play a critical role in the induction of enzymes that destroy proteoglycans. IL-1. is expressed in cultured tissue of human aged discs. Takahashi et al. detected the presence of IL-1., IL-1., IL-6, and TNF-., and they observed an increased production of prostaglandin E2 in the disc tissues of 77 patients with disc herniation. Results from the study by Maeda and Kokubun showed that both the decline in proteoglycan synthesis and increased cell sensitivity to IL-1. with age could contribute to the degeneration of discs. Furthermore, they found that IL-1RN could be useful in inhibiting the degradation of the disc. Rannou and others8 showed that interleukin 1. increases the production of prostaglandin E2 and causes a dose-dependent increase in the secretion of type II phospholipase A2 activity in annulus fibrosus cells.
The inflammatory response is regulated by a balance between pro- and antiinflammatory cytokines. One-hundredfold or greater levels of IL-1RN over IL-1 are necessary to functionally inhibit biologic effects of IL-1 on target cells.19 The balance between IL-1 and IL-1RN has been extensively studied in a variety of experimental animal models of disease, including arthritis, inflammatory bowel disease, leukemia and other cancers, osteoporosis, diabetes, central nervous system diseases, and arterial diseases. Local overproduction of IL-1 and/or underproduction of IL-1RN predispose to the development of each of these diseases.
To date, several common variants have been identified in the IL-1 gene cluster. The most widely studied of these are the IL-1.(C889-T)21 and the IL-1.(C31-T, C511-T) promoter polymorphisms, the (C3954-T) polymorphism in exon 5 of the IL-1. gene24 and intron 2 variable number tandem repeat polymorphism (VNTR) of the IL-1RN gene. Dominici and coworkers26 found that the TT genotype increases the transcriptional activity of the IL-1. gene with respect to the CC genotype. The common IL-1. gene polymorphism (IL-1.T3954 allele), which is associated with increased IL-1 levels, also influences the degree of systemic inflammation as reflected by C-reactive protein and fibrinogen levels. Polymorphisms within these genes have been associated with a variety of diseases, including rheumatoid arthritis. There is evidence that the production of IL-1 might be influenced by environmental factors such as stress, trauma, body weight, and smoking.
The purpose of the present study was to examine whether the IL-1. (C889-T), IL-1. (C3954-T), and IL-1RN (G1812-A, G1887-C, and T11100-C) gene polymorphisms, and their composite genotypes are associated with disc degeneration among middle-aged working men. Decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height were used as signs of disc degeneration. We also investigated whether the association of disc degeneration with occupational physical load is modified by the IL-1 gene cluster polymorphisms.
The height of the L3/L4 and L4/L5 discs was visually classified by an experienced radiologist and a trained physician using a 4-point scale (0 . normal, 1 . slightly decreased, 2 . distinctly decreased, and 3 . severely decreased). Interobserver agreement (weighted kappa) was 0.73 for the L3/L4 disc and 0.58 for the L4/L5 disc. The data of the experienced radiologist were used for the data analysis. None of the discs in this sample had a severely decreased disc height. This variable was dichotomized as normal (0) and decreased (.1) disc height.
The findings in the L2–S1 region were combined. The multilevel disc degeneration for each sign (decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height) was assessed as the number of disc levels (L2–S1) with the same degenerative change. These variables were grouped into 3 categories: normal (none of the discs), single-level (one disc), and multilevel (2 or more discs).
A summary score of overall degenerative changes (dark nucleus pulposus, disc bulges, and decreased disc height) was calculated based on the number of discs with the degenerative changes using a 2-step algorithm. First, the score of overall degenerative changes at each disc level separately was determined as the co-occurrence of the decreased signal intensity of the nucleus pulposus (score 0–1), disc bulges (score 0–1), and decreased disc height (score 0–1) for the L3/L4 and L4/L5 discs and as the co-occurrence of the decreased signal intensity of the nucleus pulposus (score 0–1) and disc bulges (score 0–1) for the L2/L3 and L5/S1 discs. Thus, the resulting score for the L3/L4 and L4/L5 disc levels ranged from 0 to 3, with 0 indicating no degenerative changes, 1 indicating occurrence of disc bulges or decreased disc height but normal signal intensity of the nucleus pulposus, 2 indicating simultaneous presence of decreased signal intensity of the nucleus pulposus with disc bulges or decreased disc height, and 3 indicating simultaneous presence of decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height. The score for the L2/L3 and L5/S1 disc levels ranged from 0 to 2, with 0 indicating no degenerative changes, 1 indicating occurrence of disc bulges without decreased signal intensity of the nucleus pulposus, and 2 indicating simultaneous presence of decreased signal intensity of the nucleus pulposus and disc bulges. Second, the score of each disc level (L2–S1) was summed resulting in the summary score ranging from 0 to 11, with 0 indicating no degenerative changes at any disc level and 11 indicating maximum degeneration. This variable was categorized in 3 groups as normal or minor changes (0–1) some degeneration (2–3), and extended degeneration (.4) for the analysis.
In summary, we found evidence for an effect of the IL-1 gene cluster polymorphisms on the risk of disc degeneration. The TT genotype of the IL-1. gene was associated with more than a 3-fold increase in the risk of disc bulges among middle-aged occupationally active men. In addition, among carpenters, the IL-1 gene cluster polymorphisms were associated with an increased risk of degenerative changes in the disc.
