By: 12 August 2015
The role of genetics in the causes and perception of back pain

The role of genetics in the causes and perception of back pain

In the first of a three-part review of the role of genetics in the causes and perception of back pain, Iona Collins, Suzanne Docherty, Ray Iles and Masood Shafafy look at how pain is perceived and the structural causes of back pain

PART I: PAIN PERCEPTION AND AN OVERVIEW OF STRUCTURAL CAUSES OF BACK PAIN

Most adults will experience some sort of backache during their lifetime. In most cases, the pain is a self-limiting episode, but a minority of people experience intrusive pain of a chronic or recurring nature, which conveys social and economic disadvantages. Most non-specific backache has a non-specific cause, therefore, management of this condition is difficult. With the advent of gene mapping and ease of obtaining genetic data from venous blood samples, many studies are being published which suggest that non-specific backache may have a genetic influence. Also, more research into genetic associations of pain behaviour indicates that genetic polymorphisms appear to influence both pain perception and postoperative outcome following surgery for backache. These observations may lead to future individualised gene therapy.

A genetic predisposition to backache is one of the strongest predictors of chronic disabling backache [1]. Other factors also contribute, including variations in pain perception – a phenomenon which also has a genetic influence [2]. Occasionally, the backache is specifically due to an identifiable structural cause, such as acute backache secondary to a lumbar vertebral fracture. A proportion of people with chronic backache also have a specific structural and identifiable cause – backache can be derived from any spinal structure, or referred pain from posterior mediastinal structures, such as a bleeding abdominal aortic aneurysm, or a manifestation of systemic disease, such as ankylosing spondylitis. The predisposition to have a dissecting aortic aneurysm [3] or developing ankylosing spondylitis [4] also has a genetic basis.
Epidemiologic studies have shown that the prevalence of back pain differs between rural and urban communities, as well as between developing versus developed countries [5,6]. Detailed reports of backache, however, have been hampered by the lack of a universally agreed definition for this symptom. As an example of how big the backache issue appears to be in the developed world, the point prevalence of self-reported non-specific backache in the USA is 30% [5]. From an economic viewpoint, backache is the underlying cause of an estimated 12.5 per cent of all absence from work due to sickness in the UK [7].

Pain behaviour from a genetic and anatomical viewpoint
The anatomy and function of chronic pain sufferers’ brains differ from the normal population [8]. These differences have been established in people diagnosed with chronic low back pain [9], fibromyalgia [10], regional pain disorders [11] and irritable bowel syndrome [12]. Apkarian and associates showed reduced volumes of grey matter in the pre-frontal cortices and thalami of patients suffering with chronic low back pain – the changes were more striking in those patients who suffered with neuropathic pain rather than non-neuropathic pain. Also, the grey matter differences appeared to correlate with duration of the reported chronic pain [9].
However, it appears that structural brain changes are a consequence rather than a cause of chronic pain. A study by Rodriguez-Raecke et al. [13] demonstrated reversal of brain changes in a person with chronic pain from an osteoarthritic hip, which was subsequently treated with joint replacement. Similarly, Gwilym et al. showed that 16 patients with hip osteoarthritis demonstrated thalamic atrophy; however, the thalamic volume was restored to normal values at nine months following removal of the pain source by means of a total hip arthroplasty [14]. In conclusion, it appears that structural brain changes associated with chronic pain are seen as a consequence of the pain stimulus.
Certain pain syndromes have proven causal genetic mutations. Extreme pain disorder and erythermalgia are caused by a mutation in the Nav 1.7 voltage-gated sodium channel causing a gain of function. Both disorders are peripherally mediated dysfunctional pain diseases, with a known genetic and molecular cause [15]. Family studies have revealed clusters of low back pain sufferers; however, twin studies have failed to demonstrate a genetic link [16]. This could be due to the very loose definition of low back pain, which does not distinguish between acute and chronic back pain.
A further factor for consideration is the pharmacological influence of chronic pain and its effect on the brain. A recent study demonstrated that when people with chronic back pain took 30mg of oral morphine daily for one month, the reward and effect-processing areas of the brain volumetrically increased on MRI. Conversely, chronic back pain sufferers given placebo for six weeks did not develop these changes [17]. The patients given morphine experienced a significant improvement in their chronic back pain, compared with the control population. Did the decrease in pain, or the morphine itself, cause the brain changes demonstrated? The persistence of the brain changes for at least four months following cessation of the oral morphine and return of pain, imply that the morphine resulted in the changes seen. Certain people are genetically predisposed to developing morphine addiction [18] and this phenomenon may form a secondary gain mechanism for self-reported backache sufferers seeking pain medication.
May described how neuroplasticity of the nervous system has resulted in the persistence of pain perception despite removal of the initial pain source, resulting in chronic pain as a disease in its own right [19]. Dai et al. demonstrated that 69 patients with genetic variants of the catechol-O-methyltransferase (COMT) enzyme, which is involved with pain sensitivity and response to analgesia, have different surgical outcomes following surgery for lumbar disc degeneration, where preoperative symptoms had been present for at least six months [20]. This paper suggests that patients are genetically predetermined to have optimal or suboptimal outcomes following surgery for back pain, dependent on COMT enzyme activity. Another study focused on postoperative analgesic consumption in relation to COMT polymorphisms and, again, found a direct association between variants [21]. An animal experiment involving giving painful spinal stimuli to rats found that when the rats were given 30mg/kg of the COMT inhibitor OR486, the rats exhibited less pain, suggesting that inducing lower COMT activity may result in lower pain perception [22]. Finally, a pain perception experiment involving 202 volunteers demonstrated a spectrum of pain sensitivity to cutaneous and deep noxious stimuli. There was a strong association between COMT expression and pain sensitivity in this study, and broad variation in pain sensitivity among the normal volunteers tested was seen [2]. Unfortunately, studies on the main pain-relevant genes COMT, GCH1 and OPRM1 do not consistently correlate with differing pain perception and meta-analyses of current data are needed to condense and make sense of studies performed to date. It appears that too much emphasis may have been placed on single gene polymorphisms rather than looking at the broader genetic picture [23]. A meta-analysis of an OPRM1 genetic variant showed a significant but weak correlation between its expression and opioid requirements [24], which is a less exciting conclusion than the stronger associations reported by individual papers.
Spinal structures which may cause backache
Anterior column structures
The spinal structures are classified into two columns: anterior and posterior. The anterior column consists of the vertebral bodies, intervertebral discs and the ligaments, which prevent excessive spinal extension – the anterior and posterior longitudinal ligaments. The anterior column is the major load-bearing half of the spine and supraphysiologic loading primarily causes vertebral body fracture. Lower bone density correlates with a lower fracture threshold, so conditions such as osteoporosis predispose to painful vertebral body fractures. Multiple factors are related with intervertebral disc degeneration, or degenerate disc disease (DDD); however, there is controversy regarding correlation of backache with DDD. Again, genetic influences play a key role in the development of DDD [25–30]. This is summarised in detail in Part III of this review, which will be published in a future issue of Spinal Surgery News.

Posterior column structures
The spinous process, lamina, transverse processes, pars interarticularis, pedicles, facet joints and ligamentum flavum form the posterior column, as well as the intertransverse and interspinous ligaments. The posterior column is structurally more complex than the anterior column and biomechanically acts as a tension band. The facet joints are synovial joints and are therefore at risk of erosive and degenerative arthropathy, both of which have genetic predispositions. Ligamentum flaval hypertrophy is a common feature of spinal stenosis and degenerative spondylolisthesis, both of which are associated with backache. Several studies have demonstrated upregulation of gene expression in pathologically thickened ligamentum flavum. The metalloproteinases [31], transforming growth factor-β [32], platelet-derived growth factors [33] and other cytokines appear to act either independently or together to create an inflammatory-induced flaval thickening. Some have postulated that anti-inflammatory agents may halt this process [34]. Pars interarticularis fractures (spondylolysis) are frequently seen in patients suffering with backache. Roughly 15 per cent of spondylolytic spines progress to a lytic spondylolisthesis.

The genetics of spondylolysis
Several studies report the familial association of spondylolysis [35]; however, studies have also shown the initial absence of spondylolysis in children, with the subsequent development of pars fractures during adolescence. Graveyard excavations of spines from between the 11th and 14th centuries AD have reported a higher prevalence of spondylolysis compared with current epidemiological data, with their presence identified in skeletons of young adults [36].
Haukipuro in 1978 reported on the prevalence of spondylolysis in one family as 22 out of 105 spines radiographed (21 per cent) [35]. The author postulated that spondylolysis may have an autosomal dominant inheritance with approximately 75 per cent penetrance and, based on this observation, supported the concept of a spondylolysis gene [35].
Martin et al. found that five out of seven children under his care with osteopetrosis, or Albers–Schonberg disease had either cervical or lumbar spondylolysis, suggesting a genetic link [37].

The genetics of spondylolisthesis
Spondylolisthesis was classified according to Wiltse et al. in 1976 into the following categories: (i) dysplastic; (ii) isthmic; (iii) degenerative; (iv) traumatic; and (v) pathologic [38a]. The dysplastic and isthmic forms of spondylolisthesis have been investigated for heritability and a positive association has been found for both types. Reports of familial spondylolisthesis have been published since 1939 [38,39]. Marchetti and Bartolozzi [40] reflected on the developmental/possible genetic influence of lytic and isthmic spondylolisthesis in their classification (see box). Both spondylolysis and spondylolisthesis have been found in three unrelated families, all of whom had mutations of the CDMP-1 gene, which is a cartilage-specific member of the transforming growth factor-β superfamily. CDMP-1 has a key role in chondrogenesis, including vertebral endplate development [41]. Evidence is pointing toward an inherited lumbosacral morphology, such as the tilt angle of the sacral endplate, which predisposes the L5 pars to repetitive trauma with eventual lysis and slip development [36,42,43].
Both spondylolysis and spondylolisthesis are recognised as causes of backache, yet population screening for these conditions has not shown a strong association between pathology and symptom. From the Framingham heart study population, 188 adults were recruited and asked to complete self-reported backache questionnaires, as well as undergo CT imaging to identify posterior element pathology. A spondylolysis prevalence of 11 per cent was identified, with 79 per cent of these showing measurable lytic spondylolisthesis. The study, however, showed no significant correlation between these abnormalities and self-reported backache [44]. Similarly, a larger study population of 855 adults were CT screened for spondylolysis and asked to complete a self-reported backache questionnaire. The spondylolysis prevalence was 9 per cent and backache incidence over the preceding 12 months was 36 per cent. Again, there was no significant association between the two outcomes [45]. Meta-analytical studies are required to clearly correlate backache symptoms with both spondylolysis and spondylolisthesis.

The genetics of spinal deformity
Scheuermann’s kyphosis
Scheuermann’s kyphosis is associated with chronic, but not debilitating back pain. One study of 12 patients’ families showed that seven of the twelve families had an inherited form of Scheuermann’s kyphosis, with a largely autosomal dominant penetrance, although the precise genetic mutation was unknown [46]. Another report supported the genetic aetiology of Scheuermann by reporting on classic Scheuermann’s kyphosis exhibited in monozygotic twins. One twin had back pain, the other did not have any associated symptoms [47].

Adolescent idiopathic scoliosis
There is a significant association between adolescent idiopathic scoliosis (AIS) and back pain, with a point-prevalence being 11.4 per cent in non-scoliosis adolescents, versus 27.5 per cent in those with a scoliosis [48]. AIS, as its name suggests, was previously a diagnosis of exclusion, once other causes, such as Duchenne muscular dystrophy (dystrophin gene), neurofibromatosis 1 (chromosome 17 mutation) and 2 (chromosome 22 mutation), Marfan’s syndrome (FBN1 gene mutation) and other named syndromes, had been excluded. It now appears that AIS in fact has a polygenomic influence, with varying hereditability. The human genome project has facilitated intense research into identification of all the susceptibility genes related to AIS (approximately 300 SNPs identified to date), which has implications both for diagnosis, prediction of curve severity and hereditability risk [49].There is now a saliva test commercially available which predicts the likelihood of developing a severe scoliosis, based on the assessment of 53 of the SNPs with the highest association with scoliosis [50].

Coming next…
The role of genetics in the causes and perception of back pain. Part II: The genetics of metabolic bone diseases which influence back pain will be published in the Autumn 2015 issue of Spinal Surgery News.

Authors
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.

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