In 2003, researchers successfully sequenced the entire human genome. While 99.9 percent of our genome turns out to be similar, human beings clearly differ from one another. Scattered across the genome are small variations in the DNA sequence, the most common being single nucleotide polymorphisms or SNPs – single base-pair changes in the DNA code.
When an SNP occurs within a gene, it gives rise to different variants of that gene. Different gene variants (called alleles) can have a multitude of effects on the body, from determining how fast we metabolize caffeine to influencing our long-term muscular response to resistance training. Some SNPs are also associated with an altered risk of disease.
With the growth of direct-to-consumer genetic testing, increasing numbers of patients have access to their genetic data,1 including what SNPs and gene variants they carry. Is any of this information useful to practitioners?
Why Genes Matter
As with many other health conditions, both genes and environment play a role in the development of musculoskeletal disorders. A crude measure of the relative input of genes is "heritability" – the proportion of differences in disease risk within a population that can be explained by variation in genes.
Heritability estimates suggest various musculoskeletal conditions have a substantial genetic component to their etiology. For example, heritability estimates for lumbar disc degeneration range from 34-75 percent.2 With regards to neck pain, large-scale studies of Danish twins put the heritability at 44 percent.3 Furthermore, given that modifiable risk factors for musculoskeletal conditions (e.g., physical inactivity) are also influenced by genetics,4 it would be myopic to ignore the contribution of genes.
Genes Involved in Specific Musculoskeletal Disorders
Although implicating genetics more broadly, heritability figures do not pinpoint specific genes in the development of musculoskeletal conditions. Moreover, such conditions are typically complex, polygenic disorders – they involve multiple genes acting in concert with one another and with environmental factors.
Nevertheless, variants of single genes can still give rise to small, but significant downstream variation in disease risk. Consider the COL5A1 gene, which encodes a component of type V collagen and plays a role in regulating the width of collagen fibrils. An SNP (rs12722) of this gene creates two different versions of the gene, the T allele and A allele. Several studies demonstrate that the T allele is linked to an increased risk of chronic Achilles tendinopathy.5 Similarly, certain alleles of the MMP3 gene, which encodes an enzyme involved in tissue remodelling, have been shown to at least double the risk of Achilles tendinopathy.6
Genome-wide association studies (GWAS) have identified several other SNPs/gene variants that are linked to an increased risk of musculoskeletal disease. These include IL6 and lumbar disc degeneration,7 COL1A1 and anterior cruciate ligament (ACL) tears,8 and COMT and fibromyalgia.9
Yet in many of the above cases, the mechanisms by which genes confer increased disease risk remain unknown. For example, although it is hypothesized that changes in type V:type I collagen ratios may weaken the Achilles tendon, it is not yet known how variation in COL5A1 genes enhances susceptibility to Achilles tendinopathy. Furthermore, some SNPs may not affect disease risk directly, but simply act as indirect markers of other risk-associated genes.
Knowing Your Patients' Genetic Makeup: Clinical Applications
Given our ignorance of the functional significance of many SNPs, it's reasonable to question the clinical utility of genetic data. Here are three areas in which knowledge of patients' genetic makeup could be useful:
1. Improved prevention of disease. Genetic data may prove a useful tool in the practice of preventive medicine. By understanding a patient's genetic susceptibility to a condition, practitioners can alter the focus of interventions to minimize the patient's risk of developing that condition. Patients with COL5A1 and MMP3 risk alleles for Achilles tendinopathy, for instance, may benefit from preventive strategies such as targeted eccentric exercise to strengthen the plantar flexors.10
2. Better treatment. Some gene variants also may alter a patient's course of illness and response to treatment. Variation of the COMT gene, for example, has been shown to affect both experience of pain and response to analgesics in chronic pain conditions.11 Practitioners could use this type of genetic data to tailor more effective physical and psychological treatments.
Such customization of treatment to patients' genetic-makeup also comports with a wider trend toward personalized health care.
3. Maintenance of a healthy weight. It's well-established that increased BMI (body mass index) elevates the risk of musculoskeletal pain conditions. At least two mechanisms underlie this relationship. First, carrying additional body mass increases mechanical stress on bones, joints and muscles. Second, the accumulation of visceral body fat enhances the production of pro-inflammatory and pain-sensitizing cytokines.12
Overweight and obese patients with musculoskeletal conditions therefore clearly stand to benefit from a reduction in body weight; but can their genetic data help?
Ample research links a variant of the FTO (fat mass and obesity-associated) gene with an increased risk of obesity. Patients carrying the risk allele are 70 percent more likely to become obese, a phenomenon thought to be mediated by decreased satiety following meals and increased neural responsiveness to food, both of which lead to overeating.13
By using genetic data to identify at-risk patients, practitioners could implement diet and exercise measures to promote weight loss, thereby improving both musculoskeletal outcomes and overall patient health.
References
"The Market for Direct-to-Consumer Genetic Health Testing." Kalorama Information, 2018.
Riihimäki H. Musculoskeletal Disorders. In: Ahrens W, Pigeot I (eds) Handbook of Epidemiology. New York, NY: Springer, 2014.
Fejer R, Hartvigsen J, Ohm Kyvik K. Heritability of neck pain: a population-based study of 33 794 Danish twins. Rheumatology, 2005; 45(5):589-594.
Santos DMDV, et al. Genetics of physical activity and physical inactivity in humans. Behavior Genetics, 2012;42(4):559-578.
Collins M, Raleigh SM. Genetic risk factors for musculoskeletal soft tissue injuries. Genetics and Sports, 2009;54:136-149.
Ibid.
Diatchenko L, et al. The phenotypic and genetic signatures of common musculoskeletal pain conditions. Nature Reviews Rheumatology, 2013;9(6):340.
Collins, et al., Op Cit.
Diatchenko, et al., Op Cit.
Hess GW. Achilles tendon rupture: a review of etiology, population, anatomy, risk factors, and injury prevention. Foot & Ankle Specialist, 2010;3(1):29-32.
Omair A, et al. Genetic contribution of catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic association study. BMC Musculoskeletal Dis, 2012;13(1):76.
Nawrocki AR, Scherer, PE. The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Current opinion in pharmacology, 2004;4(3):281-289.
Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends in Genetics, 2010;26(6):266-274.
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