This group of Mexican patients suffering from FM displayed different distribution of SCN9A rs6754031 genotypes when compared to ethnic; age; and gender matched controls. The difference was due mostly to the absence of the rs6754031 GG genotype in controls. Additionally; in this group of FM patients; the rs6754031 GG genotype is associated with severe disease; as assessed by the FIQ. To our knowledge there is no prior research linking rs6754031 with any particular illness. Although no causality could be derived from the present investigation; these preliminary results raise the possibility that some patients with severe FM may have a DRG sodium channelopathy.
We are not aware of previous studies looking at SCN9A sodium channels gene variation in FM. However; Reimann et al. studied several SCN9A polymorphisms in patients with different painful syndromes; including osteoarthritis; sciatica; amputee phantom pain; spine surgery and pancreatitis. They found a link of rs6746030 with pain intensity. They did not study the SNP rs6754031 that we found associated to FM severity [6
]. On the other hand; in our study; rs6746030 did not differentiate FM patients from controls. Evidence emerging from these two studies suggests that in different painful conditions; including FM; pain perception may be linked to dorsal root ganglia/sympathetic ganglia sodium channels gene variations. There may be different predisposing polymorphisms for different ethnic groups. In view of the fact that SCN9A Nav1.7 gene encodes sodium channels located preferentially in dorsal root ganglia and sympathetic ganglia; our results provide additional evidence to the concept that FM may be a sympathetically maintained neuropathic pain syndrome [12
]. Nav1.7 mutations induce electrical hyperactivity of sensory neurons in DRG; and; at the same time; produce hypo-reactivity of sympathetic ganglia neurons. This paradoxical behavior is also seen in FM. Generalized pain coexists with sympathetic hypo-reactivity to different types of stressors [13
After the submission of this manuscript Faber et al. published a gain of function SCN9A mutation associated to idiopathic small fiber neuropathy. This novel finding points to a broader role of Na(V) 1.7 mutations in painful neurological disease than previously considered from studies on rare genetic syndromes [14
Our previous genetic studies in this group of patients found an association of two catechol-o-methyl transferase (COMT) enzyme gene polymorphisms with FIQ subscales. COMT rs6269 was associated with pain and fatigue; and COMT rs165599 with morning stiffness and disability [9
]. Another study in this same group looking at adrenergic receptor (AR) gene polymorphisms disclosed an association between beta 2 adrenergic receptor AC haplotype and the presence of FM. In addition; patients with AR rs574584 GG genotype presented the highest FIQ score as compared with patients with other AR rs574584 genotypes. AR SNP rs574584 was associated with FIQ morning stiffness and with FIQ tiredness upon awakening [10
]. The results of these studies suggest a complex polygenic genetic predisposition for the development of FM. These three elements (catecholamines; adrenergic receptors; and sodium channels) could theoretically interact in the induction of FM pain.
We recognize limitations in this pilot study. The sample size is not large enough to withstand multiple comparisons of common gene polymorphisms; therefore a type II statistical error is possible. Nevertheless; the following two findings favor a real linkage between rs6754031 GG genotype and Mexican FM patients: 1) rs6754031 polymorphism was significantly different in both groups mostly due to an absence of the GG genotype in controls. 2) In the patients group the same rs6754031 GG genotype was associated to a severe disease. Studies in other ethnic groups with a larger sample size are needed to verify or amend these preliminary observations.
Another limitation of our study is the lack of rs6754031 functional profiling. Techniques such as patch methods or functional expression assays are beyond our capabilities. So; at the present time; the link between SCN9A polymorphism and severe FM is just associative. Nevertheless; our findings raise the possibility that DRG could be an important element in the pathogenesis of FM; a site in which physical; emotional; or infective stimuli could be converted into chronic pain [15
]. Genetic functional profiling [3
]; advanced imaging techniques [16
] or histology in the recently described FM animal model [17
] could test this novel proposal
The results of the present investigation may have potential therapeutic implications. If future investigations confirm the Nav1.7 sodium channels dysfunction in FM; then sodium channel blockers may become a therapeutic option. Preliminary evidence supports this contention. Lignocaine; a non-specific sodium channel blocker; appears to reduce FM pain [18
]. Duloxetine; another drug used in FM; blocks Nav1.7 sodium channels in a state-dependent manner [19
]. However; current channel blockers are weak and non-specific. Selective tetrodotoxin-resistant channel blockers are being developed and may in the future constitute a therapeutic option for FM pain (1).