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
PART 3: THE GENETICS 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 , 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) . 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 .
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 . Biological processes involved in the synthesis and break down of these intervertebral disc constituents are under the control of many different genes  with possible interaction between these genes and environmental factors . 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 .
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) ; 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 , Varlotta et al. in 1991  and Matsui et al. in 1992  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  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 . 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 . A smaller study of a younger group of Greek army recruits found similar results .
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 . 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 . 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 . 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  compared with the Finnish population (3.8 per cent) . 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 . 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 . A Greek study by Kales et al.  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 . 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.  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.  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 . 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 , 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.
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 . 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 ; 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 . Solovieva et al. later showed that VNTR polymorphism in 132 middle-aged Finnish men was significantly associated with higher risk of disc degeneration . 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.
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 . 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 , 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 .
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 . 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 . 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 . 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) .
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 . 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 . 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 ; 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 ; 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) .
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 . More recently, however, Min et al. showed this association in 89 Japanese judo athletes (OR=4.1) . 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 .
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 .
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 ; however, this has not been seen in Spanish  or British Caucasian populations .
The D14 allele has 14 aspartic acid repeats and has recently been found to be associated with lumbar disc degeneration in an Asian population . 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) . In an in vitro investigation, Gruber et al. showed the ASPN gene to be expressed at higher levels in the more degenerate human discs .
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.
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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.