Every year, millions of people suffer from lower back pain, often caused by degeneration of the spongy discs that cushion the vertebrate. Under the Area of Excellence Programme, we search for genes that might affect people’s risk of a ‘bad back’.

Low back pain is remarkably common. It affects men and women equally, with an annual prevalence ranging from 15% to 45% and a mean point prevalence of 30%. In the USA, , it is the most common reason for people younger than 45 to have their activity limited, the second most frequent reason for visits to doctors, the fifth-ranking cause of admission to hospital, and the third most common reason for surgery.

The culprits of this pain are often the discs that sit between the vertebrae of the spine. These soft cushions act, in essence, as joints that allow the spine to flex. And, like other joints in the body, they can become damaged, making movement difficult and painful. This damage can be direct, such as from tumours, infections and fractures, but more often it is due to a gradual decay of the discs – termed lumbar disc degeneration (LDD) or degenerative disc disease (DDD).

As we age, water and proteins are lost from the discs, weakening them and making them more susceptible to tears and herniations. These changes can irritate the adjacent nerves, giving rise to sciatica – pain which shoots down the side or back of the leg.

While lumbar disc degeneration is thought to be an effect of ageing, the rate at which it occurs can vary between people. Certain occupations or sports activities, injuries and smoking may increase risk, but studies of twins suggests that such effects are only modest and that differences in lumbar disc degeneration risk can be explained primarily by genetic influences (1,2).

Risk genes

Numerous studies have been conducted searching for genetic factors that affect the risk of disc degeneration. Researchers have, in particular, examined genes that produce components of the disc or that regulate processes in the disc. Given the role of the disc as a joint, subject to loading and consequent wear and tear during daily activities, abnormalities such genes could render the disc structurally weaker and more susceptible to stress from repeated loading.

Disc genes that have been studied include

Components of the disc: Collagen II, Collagen IX, Aggrecan

Enzymes that control processes in the disc: Matrix matelloproteinase 3

Regulators of bone mineral density: Vitamin D receptor

With the exception of collagen II, all these genes have been shown to be associated to some extent with lumbar disc degeneration. Interestingly, the vitamin D receptor gene is also associated with osteoporosis. It has been reported that osteoporosis has an inverse relationship to osteoarthritis in the spine, while osteoarthritis in the spine is associated with lumbar disc degeneration.

For lumbar disc degeneration, the most thoroughly studied are genes for collagen IX. Studies on Finns have identified an association between lumbar disc degeneration and two amino acid substitutions in the alpha2 and alpha3 chains of type IX collagen, called Trp2 and Trp3, respectively. The Trp3 allele was found to increase the risk of lumbar disc degeneration three-fold, being present in 24 per cent of patients with sciatica and lumbar disc degeneration as opposed to 9 per cent of people without back pain. The Trp2 allele was rare, being found in only 6 of 157 people with back pain and in none of the 174 people without pain (3, 4).

Lumbar disc degeneration is equally common in different ethnic populations, but the genetic risk factors may not be the same. For example, an extensive study of more than 800 Southern Chinese people, using magnetic resonance imaging of the spine to accurately define disc degeneration, found that the frequencies of the Trp2 and Trp3 alleles were quite different to those in Finland. The Trp3 allele was not found at all, while the Trp2 allele was present in 20 per cent of the patients, conveying a 2.5-fold increase in risk of lumbar disc degeneration. It also showed, for the first time, that the Trp2 allele is a disposing factor that manifests in an age-dependent manner affecting the development and severity of disc degeneration (5).

The associations between the Trp2 and Trp3 alleles and lumbar disc degeneration suggest that collagen IX is important for disc integrity and that alteration in its structure can render the disc more prone to degeneration. The different prevalence of the Trp2 and Trp3 mutations in Finns and Southern Chinese is the first indication that the spectrum of genetic risk factors for lumbar disc degeneration varies between ethnic groups, and this could be true for other risk factors.

The AoE programme is continuing the search for genetic predispositions to intervertrbral disc degeneration using a candidate gene approach in a control-case association study aiming to study 100 genes. In addition, we have established a dataset of families with earlier on-set disc degeneration for a genome-wide search for predisposing genes. An understanding of the mechanism for these risk factors will be essential for future preventative and symptomatic cares.

References

1. Battie MC, Videman T, Gibbons LE, Fisher LD, Manninen H, Gill K. 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.
   
2. Sambrook PN, MacGregor AJ, Spector TD. Genetic influences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum 1999; 42(2):366-372.
   
3. Annunen S, Paassilta P, Lohiniva J, Perala M, Pihlajamaa T, Karppinen J et al. An allele of COL9A2 associated with intervertebral disc disease. Science 1999; 285(5426):409-412.
   
4. Paassilta P, Lohiniva J, Goring HH, Perala M, Raina SS, Karppinen J et al. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 2001; 285(14):1843-1849.
   
5. Jim J.J.T., Noponen-Hietala N., Cheung K.M.C, Ott J. Karppinen J., Sahraravand A., Luk K.D.K. Yip S.P., Song Y.Q., Leong J.C.Y., Sham P., Cheah K.S.E., Ala-kokko L. and Chan D. The Trp2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration (Spine, 2005, In press)

Links:

iCartiGD: Integrated Cartilage Gene Database for genetic study of cartilage

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