By: 2 February 2016
Part 3: The role of genetics in the causes and perception of back pain

Part 3: The role of genetics in the causes and perception of back pain

In the final part of their review into the role of genetics in the causes and perception of back pain, Iona Collins, Suzanne Docherty, Ray Iles and Masood Shafafy discuss the controversial topics of disc degeneration and lumbar disc herniation



The functional unit of the spine called the motion segment consists of two vertebrae and the intervening disc. It is the most complex unit in the musculoskeletal system – both structurally and biomechanically. In addition to the numerous ligaments and muscles, the two vertebrae are connected to each other through two synovial joints posteriorly, known as facet joints, and a fibrocartilagenous joint anteriorly, called the intervertebral disc (IVD).

The function of the motion segment in health depends on the structural integrity of the individual components and their precise interactions in a biomechanical setting provided by the rest of the body. This, in turn, is hugely influenced by environmental factors. Because of this complexity in the structure and function and the interplay of various factors, attempting to explain how the unit fails in disease has always been extremely challenging – some may say impossible. The difficulties of this task arise from the fact that, on the one hand, numerous environmental risk factors such as smoking, obesity [70], sedentary lifestyle and certain occupations are thought to be associated with increased risk of self-reported back pain and intervertebral disc degeneration [71–73]. Disc degeneration is a hugely controversial topic. There are some who suggest that disc degeneration is not a pathological process, but simply a normal physiological ageing process.

On the other hand, the presence of backache and MRI appearance of disc degeneration do not reliably correlate. A degenerate disc, however, can cause other pathologies including symptomatic lumbar disc herniation, or the loss of disc height can result in foraminal spinal nerve compression.


Vertebral endplate damage and disc degeneration

A study by Shanmughanathan and co-workers showed that nerve growth factor (NGFβ) expression was significantly over-represented in people with MRI evidence of disc degeneration through endplate damage (P<0.0086) or disc degeneration alone (P<0.05) [74]. Also, there is a significant association between self-reported backache and type 1 modic endplate changes, especially if multiple endplate changes are seen on MRI [75].

The intervertebral disc has an outer tough annulus fibrosus, composed of type 1 collagen and a strongly hydrophilic core called the nucleus pulposus, which also has some collagen fibres, mainly type II, IX and XI. The gene COL11A1, which is associated with type XI collagen formation, has low levels of expression in Japanese people with lumbar disc degeneration [76]. Biological processes involved in the synthesis and break down of these intervertebral disc constituents are under the control of many different genes [77] with possible interaction between these genes and environmental factors [78]. Genetic influences on the nucleus pulposus play a role in the susceptibility of developing lumbar disc herniation. Karasugi and colleagues performed a joint Japanese and Finnish genetic study of 782 hospital patients with MRI-proven lumbar disc herniation causing concordant radicular pain of more than three months’ duration. Two different single nucleotide polymorphisms (SNPs) of the SKT gene had a high correlation with lumbar disc herniation. The group hypothesised that SKT malfunctions may result in nucleus pulposus abnormalities which increase the risk of disc herniation [25].

Intervertebral disc degenerative disease (DDD) is a polygenic phenomenon, involving many SNPs at different loci with variable and often weak penetrance. Depending on where these SNPs occur along the length of genes, they could be completely silent or could lead to over- or under-production of the intended proteins or production of a different protein altogether. The consequence therefore could be alteration in the dynamic equilibrium of the IVD and how it behaves biomechanically, leading to perhaps early or accelerated degeneration. Studies which aim to find a genetic answer for disc degeneration face two major difficulties: first, as disc degeneration is age related and is also under influence of many environmental factors, large population cohorts need to be investigated to get sufficient statistical power to take these factors into account. Monozygotic twin studies and studies involving DDD in the young are good alternatives. Secondly, given the complexity of the structure of the IVD and its degeneration process, where do we start to look for the candidate genes to investigate? In a study of the genetic basis for vertebral trabecular bone density, Zmuda and co-workers investigated 4311 expressed sequence tags in 383 candidate genes in 2018 subjects – and found only 11 SNPs in 10 genes that were consistently associated with volumetric bone mineral density (vBMD) [79]; the 11 SNPs explained only 4.7 per cent of the variation in vBMD. This outlines the difficulties faced and expected strength of findings in attempting such similar investigations with DDD.

Grobler et al. in 1979 [80], Varlotta et al. in 1991 [81] and Matsui et al. in 1992 [82] were among the first investigators who looked at disc herniation in juvenile and adolescent patients phenotypically and suggested an underlying familial tendency. This familial predisposition increased significantly to 42 per cent when children younger than 17 years old were compared in the Varlotta study [81] and 43.8 per cent when children younger than 18 years old were considered in a later similar study by Frino et al. in 2006 [83]. This is further supported by case reports of multilevel disc degenerations in the very young [84,85]. Such study findings in the young give relative confidence that other risk factors, such as age, smoking and occupation, have not yet had a major chance to confound the results. It appears that disc degeneration has a high heritability, ranging from 34 per cent to 61 per cent; however, the mode of the inheritance is complex, multigeneic and multifactorial. In order to find further explanation for this heritability, genes coding for the IVD building materials and those that code for the enzyme proteins that break them down, as well as the genes involved in the inflammatory process, need to be investigated.

The gene for the α-chain of collagen type I which is the main protein of annulus fibrosis and bone is called COLIA1 and has been extensively investigated. Polymorphisms of this gene have been linked to changes in bone mineral density, bone turnover and fractures [86–88]. In a prospective study of 966 men and women over the age of 65, Pluijm and co-workers showed that polymorphism of COLIA1 was associated with increased risk of DDD [89]. A smaller study of a younger group of Greek army recruits found similar results [90].


The genetics of collagen IX and its influence on disc degeneration

Collagen type IX, which is present in both the annulus fibrosis and nucleus pulposus, helps to bind matrix proteins together. It is postulated that collagen IX may play an important role in maintaining the physical integrity of the extracellular matrix and also plays a role in the matrix homoeostasis by acting as a molecular mediator [91]. With such important functions, it is therefore safe to assume that any change in the structure of collagen IX will result in alteration in the biomechanical behaviour of the intervertebral disc, predisposing it to degeneration.

Collagen IX has three chains (α1, α2 and α3) which are encoded by COL9A1, COL9A2 and COL9A3 genes, respectively. The Trp2 allele on COL9A2 and Trp3 allele on COL9A3 are mutations, which lead to Gln326Trp substitution on the α2 chain and Arg103Trp substitution on the α3 chain [92,93]. A Finnish study of 157 patients found the Trp2 allele to be present in 4 per cent of the symptomatic patients and none of the asymptomatic control [92]. Another Finnish study later revealed the frequency of the Trp3 allele to be 12.2 per cent among 171 individuals with radiologically proven lumbar disc degeneration (LDD), and 4.7 per cent of 321 people in the control group (P=0.00013). They concluded that the presence of at least one Trp3 allele increases the risk of LDD by about three fold [93]. In a large series of 804 volunteers, the frequency of the Trp2 allele was found to be much higher (20 per cent) among the Southern Chinese population [94] compared with the Finnish population (3.8 per cent) [92]. In contrast, the Trp3 allele was completely absent among the Chinese study population compared with its high frequency among the Finnish. This study used MRI to define disc degeneration and revealed that presence of the Trp2 allele was associated with a 4-fold increase in the risk of developing annular tear at 30–39 years of age, and a 2.4-fold increase in the risk of DDD and end-plate herniation at 40–49 years old [94]. It concluded that the Trp2 allele is a significant risk factor for the development and severity of DDD. In a similarly large Japanese study by Seki et al., however, no such association was found, albeit that they also found the Trp2 allele to be common among the Asian population [95]. A Greek study by Kales et al. [96] compared 105 cases of radiologically and surgically proven disc degeneration with 102 age-matched controls, and found no Trp2 among either group. The presence of Trp3 in both groups, which was 8.6 per cent and 4.9 per cent respectively, did not reach statistical significance in terms of association with DDD. They concluded that the presence of Trp2 or Trp3 alleles was likely to be a less significant susceptibility factor for DDD in Southern Europeans. A few years later, in another Japanese study, Higashino and coleagues looked for Trp2 and Trp3 alleles in 84 post-discectomy patients [97]. They found that 21.4 per cent of patients had the Trp2 allele and none had Trp3 and concluded that presence of Trp2 in patients under the age of 40 was associated with more severe disc degeneration. Kalichman et al. [77] concluded that the contrasting Trp2 and 3 allele frequencies in different populations indicate that genetic risk factors for DDD may vary between different ethnic groups. Mechanical testing on non-degenerate whole disc samples retrieved from young people undergoing scoliosis surgery by Aladin et al. [91] showed statistically significant differences in swelling pressure and compressive modulus between Trp2-positive and -negative samples. This study was the first attempt to relate genetic variation with altered mechanical behaviour that ultimately results in DDD.

Genetic evidence for the influence of collagen I and IX on disc degeneration

In a study of 135 middle-aged men, Solovieva et al. investigated possible links between MRI-proven disc degeneration and polymorphism in COL9A2, COL9A3 and COL11A2 (genes for the α2 chain of collagen XI), and COL2A1 (gene for the α1 chain of collagen II) genes, with a secondary aim to study the influence of interleukin-1β (IL-1β) gene polymorphism on the former gene polymorphisms [98]. Overall, only 2 per cent of the individuals studied had the Trp2 allele, confirming the low incidence of this allele among north Europeans and they were excluded. Of the remainder, 17.4 per cent had Trp3 alleles (16.6 per cent heterozygous, 0.8 per cent homozygous), 12.6 per cent had sequence variation for COL2A1 and 35.4 per cent had variation for COL11A2. Carriers of COL11A2 had an increased risk of disc bulges and the carriers of both Trp3 and COL11A2 (1.6 per cent) had degeneration at both levels. In the absence of IL-1β gene polymorphism, carriage of the Trp3 increased the risk of a dark nucleus pulposus [odds ratio (OR)=7.0], whereas in the presence of IL-1β, the Trp3 allele had no effect on DDD. It was therefore concluded that the effect of COL9A3 gene polymorphism might be modified by IL-1β gene polymorphism.

More recently, in a population study of 352 12–14-year-old Danish children [99], DDD was evaluated with MRI scans and genetic analysis was performed for COL9A3, COL11A2, IL1A, IL1B, IL6 and vitamin D receptor (VDR) genes. Of the 352 children studied, 30 boys and 36 girls had lumbar DDD. Of all the genes tested, only polymorphisms in IL1A and IL6 in the girls were associated with DDD (OR = 2.85 and 6.71, respectively). No such association was found among the boys.


Chondroitin sulphate

The extracellular matrix of the nucleus pulposus contains large aggregating proteoglycans called aggrecan. Proteoglycans have a core protein to which attaches glycosaminoglycans (GAGs), namely chondroitin sulphate and keratan sulphate, to form large protein-polysaccharide molecules that bind to a hyaluronic acid via a link protein to form the aggregates. The collagen and aggrecans interact to form a composite organic matrix that is strongly hydrophilic and resists compressive force. This function is related to the number of chondroitin sulphate chains attached to the core protein. Two adjacent areas of the aggrecan’s core protein where chondroitin sulphates attach are called CS1 and CS2 and the gene coding for CS1 exhibits size polymorphism [28]. It is known that the ratio of chondroitin sulphate and keratan sulphate changes with age.

Kawaguchi and co-workers first revealed that the shorter expressed variable numbers of tandem repeat (VNTR) polymorphism for the chondroitin sulphate attachment on the core protein was associated with risk of multilevel disc degeneration at an early age in young Japanese women [100]; however, this risk was not clearly quantified. In a 2006 literature review, Roughley et al. concluded that several studies had tried to show association between inferior aggrecan and early degeneration but the results had been ambiguous [101]. Solovieva et al. later showed that VNTR polymorphism in 132 middle-aged Finnish men was significantly associated with higher risk of disc degeneration [102]. The risk of dark nucleus pulposus was increased with the individuals who were homozygous for the A26 allele (OR=2.77). The observed odds ratio (OR) values for the joint effect of being a carpenter or a machine driver AND carrying the A26 allele were 2.91 and 3.38, respectively.


Other proteoglycans

Hyaluronan and proteoglycan link protein 1 (HAPLN1) is a member of the HAPLN family, and is a key component of the cartilage extracellular matrix [103,104]. Urano et al. analysed DNA from 622 post-menopausal Japanese women trying to find association between four SNPs in the HAPLN1 gene and radiographic features of spinal degeneration [105]. One SNP (TT genotype instead of CC or CT) was significantly over-represented in subjects with a higher score of osteophyte formation (OR=2.12) and disc space narrowing (OR=1.83). They concluded that a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration. As well as Slovieva et al., who demonstrated the occupational influence on DDD [94], Cong et al. also showed an additive and multiplicative interaction between the aggrecan gene VNTR polymorphism and smoking in symptomatic DDD in a group of northern Chinese men [106].


The role of vitamin D receptor polymorphisms in degenerative disc disease

Vitamin D receptors (VDR) are intracellular proteins that specifically bind with vitamin D3 to produce a variety of biologic effects, including bone mineralisation, which is why VDR gene polymorphisms are thought to contribute to disorders such as osteoporosis and osteoarthritis, and osteophyte formation.

Given the ubiquitous distribution of the VDR and because bone and cartilage are composed of a part of the same connective tissues as intervertebral discs, intragenic polymorphisms of the VDR gene have also been studied in DDD. In a study of monozygotic twins, Videman et al. revealed two intragenic polymorphisms of the vitamin D receptor gene to be associated with disc degeneration [107]. MRI quantitative signal measurements of T6-S1 discs were 12.9 per cent worse in men with the TaqI tt genotype, and 4.5 per cent worse in men with the Tt genotype, compared with signal intensity in men with the TT genotype (age-adjusted P=0.003).

Similarly, for Fok1 genotypes: for men with the ff and Ff genotypes, signal intensity was 9.3 per cent and 4.3 per cent lower, respectively, than those in men with FF genotypes (age-adjusted P=0.006). In the same year, a random population study of Australians over the age of 60 by Jones et al. revealed that genetic variation in the VDR gene was associated with severity of osteophytosis, presence of disc narrowing and weakly with presence of osteophytosis, but not with severity of disc narrowing [108]. Interestingly, current smoking increased both the presence (adjusted OR=9.70, 95% CI 2.08, 45.1) and severity (adjusted OR =2.91, 95% CI 1.16, 9.03) of spinal osteophytosis. In a follow-up study of their earlier research, Videman et al. concluded that TaqI polymorphisms of the VDR may not be specific to bone and were most strongly associated with intervertebral disc signal intensity and annular tears [109]. In the largest study related to VDR and DDD so far, of 804 southern Chinese volunteers, aged 18–55, after adjustment for age and sex, Cheung et al. demonstrated that the Taq I allele was significantly associated with degenerative disc disease (OR=2.61) [110].

The OR was even higher (5.97) for those younger than 40 years. It is not exactly clear why and how VDR polymorphism affects DDD. In their review of the literature, Kalichman et al. stated that VDR polymorphism may not be directly involved in the pathogenesis and may be merely a marker for other genes [28]. They also speculated that the VDR gene, due to its proximity to other genes such as COL2A1 and insulin-like growth factor type 1 (IGR-1) which are located on chromosome 12q and are expressed in IVD tissues and are involved in the synthesis of proteoglycans in the cells of the nucleus pulposus, may be collectively involved in the matrix homeostasis.


The genetics of matrix metalloproteinases and their role in degenerative disc disease

Matrix metalloproteinases (MMPs) are endopeptidases. MMP3 (stromelysin-1) is a member of this super family, which is a potent proteoglycan-degrading enzyme and plays a major role in intervertebral disc homoeostasis and pathology [111]. In a small study of 54 young female (aged 18–28 years) and 49 elderly (aged 64–94 years) male and female patients, Takahashi et al. revealed that 5A5A and 5A6A genotypes of the MMP3 gene were associated with more degeneration in the elderly but not in the young [112]; however, the findings need to be treated with some caution as the samples were small and heterogeneous and two methods of radiological assessment were used for different groups. In a longitudinal study by Valdes et al., 720 women were followed up for nine years and radiographic progression of LDD was compared with polymorphism in 25 genes [113]; polymorphisms in MMP3, TIMP1 (tissue inhibitor of metalloproteinase 1), and COX2 genes were associated with radiographic progression of DDD. More recently, in a study on southern Chinese volunteers aged 18 to 55, Song et al. revealed significant association between MRI-proven DDD and a 1607 promoter polymorphism of the MMP1 gene (OR=1.41, p value=0.027) [114].

Cartilage intermediate layer protein (CILP) is an extracellular matrix protein found in abundance in cartilaginous tissues including intervertebral discs. It has been implicated in common musculoskeletal disorders such as osteoarthritis [115,116]. A functional SNP (1184T/C) in the CILP gene has been studied as a possible link to LDD. This is thought to be regulated through TGF-β1 [116,117]. In 2007, a case control study of two populations of Finnish and Chinese by Virtanen et al. failed to demonstrate this association [118]. More recently, however, Min et al. showed this association in 89 Japanese judo athletes (OR=4.1) [119]. Another Japanese study of 601 athletes (403 male, 198 female), revealed a gender difference – in that CILP SNP 1184T/C was a risk factor in male collegiate athletes but not in females [120].

The quest for even more SNPs in more candidate genes has continued over the past recent years. Tag SNPs in the human SKT gene (K1AA1217) have been implicated in the aetiology of lumbar disc herniation [25].

Asporin (ASPN), also known as periodontal ligament-associated protein-1 (PLAP1) is present in the cartilage extracellular matrix and is reported to have a genetic association with osteoarthritis in the Japanese population [121,122]. The normal ASPN allele (D13) contains 13 aspartic acid repeats in 382 amino acids. There are at least 19 SNPs for the ASPN gene in the Japanese population with osteoarthritis [122]; however, this has not been seen in Spanish [123] or British Caucasian populations [124].

The D14 allele has 14 aspartic acid repeats and has recently been found to be associated with lumbar disc degeneration in an Asian population [125]. In a study of two large cohorts of Chinese and Japanese age-stratified populations, Song et al. showed that, overall, individuals possessing the D14 allele had a higher risk of MRI-proven LDD (OR=1.7, P=0.000013) [125]. In an in vitro investigation, Gruber et al. showed the ASPN gene to be expressed at higher levels in the more degenerate human discs [126].

The medical genetic science is in its infancy but is developing fast and with it more light will be shone on the genetic bases of degenerate diseases including DDD. So far, numerous SNPs in different genes have been linked with DDD and increasing numbers are coming into the equation. Despite this, we only have a few isolated pieces of an extremely complicated jigsaw puzzle and we don’t even know how they fit together.

Expecting a straightforward linear model description of such a multifactorial and multigeneic phenomenon would be too simplistic – and accepting it would be too naïve. Due to logistical difficulties, the majority of studies so far have focused on single genes only, without considering many of the gene–gene and environment–gene interactions that we know exist. The puzzle will only come together through large-scale, long-term, longitudinal population studies combined with whole-genome studies of those populations.



Backache is more complex than it first appears. The symptom is ill-defined and may be a manifestation of a generalised, genetically determined pain syndrome, or amplification and attenuation of a minor injury due to abnormal pain behaviour and structural brain changes. Numerous spinal structures are implicated in the generation of backache, as well as referred pain from extra-spinal structures. Backache may be the first presentation of a spondyloarthropathy or a manifestation of a metabolic bone disease. Adolescent sagittal spinal deformity (e.g. Scheuermann’s kyphosis) or rotational deformity (e.g. adolescent idiopathic scoliosis) may be associated with backache in young adults. The ubiquitously degenerate disc has been the focus of intense genetic research, with a sample of the multitude of studies discussed in this review.

As a greater understanding of the underlying genetics of disease evolves, the term non-specific backache may be left to the history books and each type of backache may have a specific individualised gene therapy.



  1. Karasugi et al. Association of the Tag SNPs in the Human SKT gene (KIAA1217) with lumbar disc herniation. Journal of Bone and Mineral Research 2009 vol 24 (9), 1537–1543
  2. Kalichman, Hunter. The genetics of intervertebral disc degeneration. Associated genes. Joint Bone Spine 2008 Jul;75(4), 388–396
  3. Battie et al. Heritability of lumbar flexibility and the role of disc degeneration and body weight. Journal of Applied Physiology 2008 104(2), 379–385.
  4. Heliovaara. Risk factors for low back pain and sciatica (review) Annals of Medicine 1989 21(4), 257–264
  5. Battie et al. 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 1995 20(24), 2601–2612
  6. Battie et al. Genetic and environmental effect on disc degeneration by phenotype and spinal level: a multivariate twin study. Spine 2008 33(25), 2801–2808
  7. Shanmughanathan et al. Single nucleotide polymorphism in the nerve growth factor beta (NGFβ) gene predisposes to lumbar disc degeneration. Oral presentation at ISSLS 2011. P14. Gothenburg, Sweden, 14–18 June
  8. Kuisma et al. Modic changes in endplates of lumbar vertebral bodies. Prevalence and association with low back and sciatic pain among middle-aged male workers. Spine 2007 Vol 32 (10) 1116–1122
  9. Mio et al. A functional polymorphism in COL11A1 , which encodes the α1 chain of type XI collagen, is associated with susceptibility to lumbar disc herniation. Am J Hum Genet 2001, 81, 1271–1277
  10. Kalichman and Hunter. The genetics of intervertebral disc degeneration. Associated genes. Joint Bone Spine 2008 75(4), 388–396
  11. Solovieva et al. COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction. Spine 2002 27(23), 2691–2696
  12. Zmuda et al. Genetic analysis of vertebral trabecular bone density and cross-sectional area in older men. Osteoporosis International 2011. 22(4), 1079–1090
  13. Grobler et al. Intervertebral disc herniation in the adolescent. Spine 1979 4(3), 267–278
  14. Varlotta et al. Familial predisposition for herniation of a lumbar disc in patients who are less than twenty-one years old. JBJS (A) 1991 73(1), 124–128
  15. Matsui et al. Familial predisposition and clustering for juvenile lumbar disc herniation. Spine 1992 17(11), 1323–1328
  16. Frino et al. Trends in adolescent lumbar disk herniation. Journal of Pediatric Orthopedics 2006 26(5), 579–581
  17. Obukhov et al. Multilevel lumbar disc herniation in 12-year-old twins. Childs Nervous System 1996 12(3), 169–171
  18. Gunzberg et al. Lumbar intervertbral disc prolapse in teenage twins. A case report and review of the literature. JBJS (B) 1990 72(5), 914–916
  19. Langdahl et al. An Sp1 binding site polymorphism in the COL1A 1 gene predicts osteoporotic fractures in both men and women. Journal of Bone and Mineral Research 1998 13(9), 1384–1389
  20. Keen et al. Association of polymorphism at the type 1 collagen (COL1A 1) locus with reduced bone mineral density, increased fracture risk and increased collagen turnover. Arthitis and Rheumatism 1999 42(2), 285–290.
  21. Harris et al. Association of the collagen type 1 alpha 1Sp1 polymorphism with five- year rates of bone loss in older adults. Calcified Tissue International 2000 66(4), 268–271
  22. Pluijm et al. Collagen type 1 alpha 1 Sp1 polymorphism, osteoporosis and intervertebral disc degeneration in older men and women. Annals of the Rheumatic Diseases 2004 63(1), 71–77
  23. Tilkeridis et al. Association of a COL1A1 polymorphism with lumbar disc disease in young military recruits. Journal of Medical Genetics 2005 42(7), e44
  24. Aladin et al. Expression of the Trp2 allele of COL9A2 is associated with alteration in the mechanical properties of human intervertebral discs. Spine 2007 32(25), 2820–2826
  25. Annunen et al. An allele of COL9A2 associated with intervertebral disc disease. Science 1999 285(5426), 409–412
  26. Paasilta et al. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 2001 285(14), 1843–1849
  27. Jim et al. The TRP2 allele of COL9A2 is an age-dependent risk-factor for the development and severity of intervertebral disc degeneration. Spine 2005 30(24) 2735–2742
  28. Seki et al. Association study of COL9A2 with lumbar disc disease in the Japanese population. Journal of Human Genetics 2006 51(12), 1063–1067
  29. Kales et al. The role of collagen IX tryptophan polymorphism in symptomatic intervertebral disc disease in Southern European patients. Spine 2004 29(11), 1266–1270
  30. Higashino et al. The alpha 2 type IX collagen tryptophan polymorphism is associated with the severity of disc degeneration in younger patients with herniated nucleus pulposus of the lumbar spine. International Orthopaedics 2007 31(1), 107–111
  31. Solovieva et al. Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. European Spine Journal 2006 15(5), 613–619
  32. Eskola et al. Genetic risk factors of disc degeneration among 12-14-year-old Danish children: a population study. International Journal of Molecular Epidemiology and Genetics. 2010 1(2), 158–165
  33. Kawaguchi et al. Association between an aggrecan gene polymorphism and lumbar disc degeneration. Spine 1999 24(23), 2456–2460
  34. Roughley et al. The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage. European Cells and Materials 2006 11, 1–7
  35. Solovieva et al. Association between the aggrecan gene variable number of tandem repeats polymorphism and intervertebral disc degeneration. Spine 2007 32(16), 1700–1705.
  36. Czipri et al. Genetic rescue of chonrodysplasia and the perinatal lethal effect of cartilage link protein deficiency. Journal of Biological Chemistry 2003 278(40), 39214–39223
  37. Neame and Barry. The link proteins. Experientia 1993 49(5), 393–402
  38. Urano et al. Single- nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women. European Spine Journal 2011 20(4), 572–577
  39. Cong et al. The interaction between aggrecan gene VNTR polymorphism and cigarette smoking in predicting incident symptomatic intervertebral disc degeneration. Connective Tissue Research 2010 51(5), 397–403
  40. Videman et al. Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine 1998 23(23), 2477–2485
  41. Jones e al. Allelic variation in the vitamin D receptor, lifestyle factors and lumbar spinal degenerative disease. Annals of the Rheumatic Diseases 1998 57(2), 94–99
  42. Videman et al. The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density. Spine 2001 26(3), E7–12
  43. Cheung et al. Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine 2006 31(10), 1143–1148
  44. Goupille et al. Matrix metalloproteinases: the clue to intervertberal disc degeneration? Spine 1998 23(14), 1612–1626
  45. Takahashi et al. The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene. JBJS(B) 2001 83(4), 491–495
  46. Valdes et al. Radiographic progression of lumbar spine disc degeneration is influences by variation at inflammatory genes: a candidate SNP association study in the Chingford cohort. Spine 2005 30(21), 2445-2451
  47. Song et al. Association between promoter-1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese. BMC Medical Genetics 2008 9, 38
  48. Lorenzo et al. A novel cartilage protein (CILP) present in the mid-zone of human articular cartilage increases with age. Journal of Biological Chemistry 1998 273(36), 23463–23468
  49. Mori et al. Transcriptional regulation of the cartilage intermediate layer protein (CILP) gene. Biochemical and Biophysical Research Communications 2006 341(1), 121–127
  50. Seki et al. A functional SNP in CILP encoding cartilage intermediate layer protein is associated with susceptibility to lumbar disc disease. Nature Genetics 2005 37(6), 607–612
  51. Virtanen et al. Phenotypic and population differences in the association between CILP and lumbar disc disease. Journal of Medical Genetics 2007 44(4), 285–288
  52. Min et al. The cartilage intermediate layer protein gene is associated with lumbar disc degeneration in collegiate judokas. International Journal of Sports Medicine 2009 30(9), 691–694
  53. Min et al. Cartilage intermediate layer protein gene is associated with lumbar disc degeneration in male, but not female, collegiate athletes. American Journal of Sports Medicine 2010 38(12), 2252–2257
  54. Kizawa et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nature Genetics 2005 37(2), 138–144
  55. Iida et al. High-resolution SNP map of ASPN, a susceptibility gene for osteoarthritis. Journal of Human Genetics 2006 51(2), 151–154
  56. Rodriguez-Lopez et al. Lack of association of a variable umber of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians. Arthritis Research and Therapy 2006 8(3), R55
  57. Mustafa et al. Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population. Arthritis and Rheumatism 2005 52(11), 3502–3506
  58. Song et al. association of the asporin D14 allele wih lumbar disc degeneration in Asians. American Journal of Human Genetics 2008 82(3), 744–747
  59. Gruber et al. Asporin, a susceptibility gene in osteoarthritis, is expressed at higher levels in the more degenerate human intervertberal disc. Arthritis Research and Therapy 2009 11(2), R47


Iona Collins is a consultant orthopaedic spinal surgeon at Morriston Hospital in Swansea.

Suzanne Docherty is a haematology SpR at Norfolk and Norwich University Hospitals NHS Foundation Trust.

Ray Iles is chief executive officer at MAP Diagnostics.

Masood Shafafy is a consultant orthopaedic spinal surgeon at Queens Medical Centre in Nottingham.

All authors contributed equally to this work.