Genetic Factors in Fibromyalgia and Chronic Widespread Pain
Pain is influenced equally by genetic and environmental factors, working in concert to control how humans process it. Pain sensitivity falls on a bell-shaped curve in the general population. The higher the volume control setting, the more pain a person will experience, irrespective of nociceptive input (see Figure 1).
During the past decade pain research has focused on single nucleotide polymorphisms (SNPs) to help decipher which genes may be involved in pain generation. In fact, similar genetic factors have been identified among patients with fibromyalgia and chronic widespread pain (CWP). Investigations have looked for altered DNA sequence variations of a single nucleotide (A, T, C, or G). Other genetic advances in pain research include genome-wide association studies (GWAS) and epigenetics.
This review will highlight the latest clinical data on genetic factors that influence chronic pain conditions.
Chronic Widespread Pain
Genetic factors are associated with every chronic pain disorder, including CWP and fibromyalgia.1,2 Approximately 40% of the CWP heritability estimates were attributable to genetic effects. In a study from Norway, researchers found a 20% to 40% increased odds of chronic musculoskeletal pain (CMP) in adult sons and daughters of parents with CWP.3 “Both sons and daughters had an odds ratio of 1.6 (95% CI 1.4 to 1.9) when both parents reported CMP, compared to when none of the parents had CMP,” noted the authors. Interestingly, genetic risk does not always mean clinical disability. For example, in the Norway study, the odds of inheriting CWP were not influenced by whether the parent had limited ability to work or enjoy leisure time.3
Clinical cohort studies have also demonstrated that fibromyalgia clusters among families and that fibromyalgia co-aggregates with major mood disorders. In a study from 2004, Arnold and co-workers found an 8.5-fold greater risk of fibromyalgia in relatives of a patient (proband) with fibromyalgia compared to relatives of a patient with rheumatoid arthritis (RA) (see Figure 2).2 They also found a greater number of tender points in the relatives of probands with fibromyalgia compared to those with RA. Fibromyalgia also correlated with the presence of major mood disorder (major depressive disorder or bipolar disorder). The comorbidity of fibromyalgia with depression impacts diagnostic and therapeutic decisions. Treating clinicians must always screen for mood disturbances in any patient with CWP. Optimal pharmacologic and nonpharmacologic therapy should improve depression as well as chronic pain.
In 2013, Arnold et al performed the first genome-wide linkage scan and confirmed that fibromyalgia aggregates in families.4 They reported an estimated sibling recurrence risk ratio of 13.6, consistent with values reported for other complex disorders to which multiple genetic and environmental factors likely contribute. One major locus for fibromyalgia was found on the chromosome 17p11.2–q11.2 region.
Twin studies have been instrumental in linking chronic pain to genetic factors.5,6 In a study of more than 15,000 twins, the prevalence of CWP was 4.1%, and the ratio of women to men was 3.3 to 1.6 There were modest genetic influences for both women and men. These investigators also found considerable co-occurrences in CWP cases with chronic fatigue, joint pain, depressive symptoms, and irritable bowel syndrome (IBS).7 This led the investigators to conclude that associations between CWP and most comorbidities were mediated by unmeasured genetic and family environmental factors in the general population.7
A person’s response to pain has also been linked to genetics. A landmark twin study revealed a 22% to 55% genetic component for pain sensitivity.8 To measure pain response, the researchers produced a variety of painful stimuli, including heat pain threshold (HPT), the pain rating during induction of a thermal burn, the secondary areas of punctate hyperalgesia and brush-evoked allodynia following the induction of a 45°C thermal burn, and the pain ratings during the iontophoresis of adenosine triphosphate (ATP) and acid.8 The authors concluded that “our study demonstrates the importance of genetic factors in determining human experimental pain sensitivity.”
A later study also found a significantly increased likelihood of multisite CWP among monozygotic twins as compared to dizygotic twins when reporting pain.9 The clinical features of fatigue and depression, as well as levels of dehydroepiandrosterone (DHEAS), were interrelated in a multivariate twin design of 463 British female twin pairs.10 The researchers reported a strong genetic relationship between DHEAS levels and CWP and depression. Lastly, in a large twin study, CWP was found in 15% of the population, and there was a correlation of CWP with neuropathic pain as well as age, elevated body mass index, female gender, and smoking.11
Role of COMT in Pain Perception
The first gene that was closely linked to increased pain sensitivity in patients with fibromyalgia and chronic pain was catechol-O-methyltransferase (COMT).12 COMT is one of several enzymes that degrade dopamine, noradrenaline, and adrenaline, which play major roles in pain perception. Three genetic variants (haplotypes) of the gene encoding COMT were designated as low pain sensitivity (LPS), average pain sensitivity (APS), and high pain sensitivity (HPS), respectively. These haplotypes encompass more than 90% of the human population, and 5 combinations of these haplotypes were strongly associated with variation in the sensitivity to experimental pain.
Certain personality traits, including anxiety, have also been associated with polymorphic variants of the dopamine system that heighten pain response. Heightened anxiety, where a patient focuses and magnifies painful sensations, is called catastrophizing. Researchers have discovered an association between COMT genetic variants and pain intensity during episodes of catastrophizing.13 Experimental pain studies have demonstrated that the COMT polymorphism affects pain processing. For example, the carriers of the Met/Met genotype of the COMT gene demonstrated stronger pain-related signals seen on functional magnetic resonance imaging (fMRI) studies than did carriers of the Val/Val genotype.14
In another study involving motor vehicle accident (MVA) patients, researchers discovered an association between the COMT haplotype and developing pain after the accident.15 This study evaluated the association between COMT genotype and acute neck pain intensity and other patient characteristics in 89 Caucasian individuals presenting to the emergency department after an MVA. Individuals with a COMT pain-vulnerable genotype were more likely to report moderate to severe musculoskeletal neck pain, moderate or severe headache, and moderate or severe dizziness, noted the researchers. These subjects also took a longer time to recover following the MVA.