Introduction

Fibromyalgia syndrome (FMS) is a concept in evolution. Previously identified and defined as a discrete rheumatological entity responsible for widespread pain and tenderness , fibromyalgia has subsequently evolved conceptually; currently, this clinical syndrome is perceived of not as a discrete entity but rather as part of a continuum representing an increased and heightened processing of pain within the nervous system . As such, individuals with or without other pain-related pathologies may exhibit varying degrees of “fibromyalgianess”, which may also fluctuate over the course of their illness . During this shift, the concept of centralized pain has been described and characterized, with FMS remaining the original “paradigmatic” centralized pain condition .

This evolution must be corroborated and explained in terms of incorporating genetic markers hitherto tied to the pathogenesis of FMS into the current concepts regarding the nature and taxonomy of FMS. This again poses somewhat of a challenge. Classically, medical genetics have strived to identify specific genetic markers, which could be linked to particular diagnoses. Thus, when describing an entity such as rheumatoid arthritis (RA) in textbook style, besides chapters on pathophysiology and diagnosis one would include a chapter on genetics, in which all genetic underpinnings of the nosological entity under consideration would be enumerated. A similar strategy was originally pursued by researchers who pioneered the genetics of FMS. Thus, target-gene studies explored the frequency with which it was possible to identify specific genetic polymorphisms among FMS patients, compared with healthy individuals. This strategy led to the identification of a number of targets, which will be covered in the following sections. However, as the conceptual framework of FMS continues to evolve, as described above, genetic information as well should no longer be thought of in terms such as “identifying the gene or genes responsible for FMS” but rather as incorporating genetic data relevant to the processing of pain and to pain centralization into the spectrum of centralized pain. Thus, the presence of such genetic markers might be anticipated to be increased in various conditions concerning chronic (presumably centralized) pain, such as temporal mandibular joint disorder (TMJD) or chronic pelvic pain . Moreover, one can easily anticipate a future in which individualized genetic data become regularly available, and in which such data will be able to aid both in the identification of centralized pain among patients suffering from other musculoskeletal disorders and in the tailoring of personalized treatment for such patients .

In the current review, we will attempt to cover evidence available on the genetic underpinnings of FMS, as well as demonstrating the relevance of these data to the understanding of centralized pain in general. Table 1 presents a compilation of the specific genetic markers covered in this review.

Familial aggregation in FMS

Early on in the study of FMS, it became apparent that familial aggregation plays an important role in the epidemiology of this disorder. An increased incidence of either FMS or muscle tenderness was demonstrated among parents and siblings of FMS patients . In a study investigating both FMS and sleep disorders among mothers and offspring, a significant concordance was observed between children and mothers regarding both traits . In other studies, 28% of offspring of FMS patients were identified as fulfilling FMS criteria as well as 28% of “close relatives.” The quality of life and the functional level of FMS-patient relatives were found to be relatively low in another study .

In the family study of fibromyalgia , Arnold et al. collected information from 533 relatives of 78 probands suffering from FMS and 272 relatives of 40 probands suffering from RA. FMS strongly aggregated in families, and the odds ratio of FMS in a relative of a proband with FMS versus that of a relative of a proband with RA was 8.5. Tenderness was also found to be strongly aggregated, and the findings were interpreted as implying the important role of genetic factors in the pathogenesis of FMS.

Familial aggregation in FMS

Early on in the study of FMS, it became apparent that familial aggregation plays an important role in the epidemiology of this disorder. An increased incidence of either FMS or muscle tenderness was demonstrated among parents and siblings of FMS patients . In a study investigating both FMS and sleep disorders among mothers and offspring, a significant concordance was observed between children and mothers regarding both traits . In other studies, 28% of offspring of FMS patients were identified as fulfilling FMS criteria as well as 28% of “close relatives.” The quality of life and the functional level of FMS-patient relatives were found to be relatively low in another study .

In the family study of fibromyalgia , Arnold et al. collected information from 533 relatives of 78 probands suffering from FMS and 272 relatives of 40 probands suffering from RA. FMS strongly aggregated in families, and the odds ratio of FMS in a relative of a proband with FMS versus that of a relative of a proband with RA was 8.5. Tenderness was also found to be strongly aggregated, and the findings were interpreted as implying the important role of genetic factors in the pathogenesis of FMS.

Candidate-gene studies

Subsequent to the observations regarding the significant familial aggregation of FMS, candidate-gene studies originally focused on target genes, which were considered to have a link with the pathogenesis of FMS. This strategy, which is inherently hampered by the huge number of potential targets, nonetheless led to some interesting findings.

Serotoninergic candidate genes

Decreased levels of serotonin in the serum and cerebrospinal fluid (CSF) were an early finding in FMS . This finding, together with the utility of reuptake inhibitors in the treatment of FMS, directed attention at the possibility of a genetic marker being linked with serotonin metabolism . The components of this system include the 5-hydroxytryptamine receptor 2A (5HT-2A, encoded by HTR2A) and 5HT transporter (5HTT, also known as sodium-dependent serotonin transporter, encoded by SLC6A4). An insertion/deletion polymorphism in the promoter region of SLC6A4 has most frequently been associated with chronic pain conditions, and the “short” (deletion) allele has been found to increase the risk of FMS , while the “long” (insertion) variant has been associated with an increased risk of TMJD .

Analyzing the promoter region of the serotonin transporter gene (5-HTT) in patients with fibromyalgia, Offenbaecher et al. were able to demonstrate an increased frequency of the S/S genotype of the 5-HTT gene among patients versus controls, with patients carrying this genotype also demonstrating higher levels of depression and psychological distress. This finding was subsequently replicated in a different population . The T102C polymorphism of the 5-HT2A receptor gene is another serotoninergic target gene investigated in FMS, although differences in the frequency of these polymorphisms between patients and controls did not reach statistical significance .

The serotonin receptor subunit genes, HTR3A and HTR3B , have been investigated for sequence variations in FMS patients. While this approach yielded several sequence variations, statistical computation rated all variants as probably non-disease-related polymorphisms . Similarly, a study investigating the 5-hydroxytryptamine (serotonin) 2A (5-HT2A) receptor (rs6313 and rs6311) gene revealed no differences in the frequencies of alleles and genotypes between patients and controls .

Studies of the HTR2A have also consistently shown that the silent 102T > C polymorphism is associated with an increased risk of both FMS and TMJD .

Role of the catechol-O-methyltransferase gene polymorphism in fibromyalgia

The sympathetic nervous system plays an intricate and incompletely understood role in the pathogenesis of chronic (as well as acute) pain. One aspect of this role is related to the observed decrease in CSF levels of catecholamine metabolites, observed in FMS patients . This finding has been interpreted as indicating a reduction in the sympathetic tone, which may be related to reduced pain inhibition. With this background, numerous studies have focused on genetic markers related to the metabolism of catecholamines, with special emphasis on the gene coding for catechol-O-methyltransferase (COMT). This enzyme plays an important catabolic role in the metabolism of catecholamines.

Most of the COMT studies to date have reported an increased risk of chronic pain associated with a nonsynonymous Val158Met (rs4680) polymorphism, encoding a protein with lower enzymatic activity . Others have studied haplotypes of the COMT gene, which modify both expression and activity .

COMT polymorphisms have been previously studied among FMS patients, and genotypic differences have been demonstrated between patients and healthy controls . In one study, an association was found between FMS and the COMT Val158Met polymorphism, with a dose–response effect of the COMT genotype on the number of pressure points reported . Similarly, Martínez-Jauand et al. also found that the frequency of genetic variations associated with a low COMT enzyme activity was significantly higher in FMS patients than in healthy volunteers, and that FMS individuals with the met / met genotype ( Val158Met single nucleotide polymorphism (SNP)) or the high-pain-sensitivity–average-pain-sensitivity (HPS–APS) haplotypes demonstrated a higher sensitivity to thermal and pressure pain stimuli than patients carrying the low-pain-sensitivity (LPS) haplotype or val alleles ( Val158Met SNP) . A recent meta-analysis has attempted to sum up the role of a genetically determined reduced COMT activity in FMS and other forms of chronic pain, that is, migraine, headache, and chronic widespread pain (CWP) in general. In this meta-analysis, FMS and CWP were the only types of chronic pain that could be associated with the COMT SNP rs4680 (Val158Met) . In addition to the COMT , other sympathetically related genetic markers have been studied in FMS and chronic pain. Arg16Gly (rs1042713) and Gln27Glu (rs1042714) are nonsynonymous SNPs in the β2-adrenergic receptor gene (ADRB2), which have both been associated with an increased risk of FMS and CWP . Here again, as with the COMT studies, investigating haplotype variants, which regulate β2-adrenergic receptor expression and internalization, has yielded promising results .

In addition to their apparent role in governing the genetic susceptability to FMS and chronic pain, the abovementioned adrenergic and serotoninergic markers have also been linked with other phenotypes, which are not directly pain-related, but which nonetheless may have a modifying interaction with chronic pain. Thus, the adrenergic-related ADRB2 and COMT have been associated with autonomic dysregulation , sleep dysfunction , and anxiety , as well as with pain processing . Similarly, serotoninergic-related genes such as SLC6A4 and HTR2A have been associated with depression and anxiety in FMS patients .

Dopamine receptor-related genes have previously been studied in the context of the genetics of personality traits such as novelty seeking . In view of the finding of an altered dopamine D2 receptor function in FMS , and of the apparent efficacy of the dopaminergic agent pramipexole in the treatment of FMS , the dopamine D4 receptor exon III repeat polymorphism has been studied and found to be significantly decreased in frequency among FMS patients who also demonstrated an association between this polymorphism and the low-novelty-seeking personality trait.

Human leukocyte antigens (HLAs) are another class of genetic markers, which have been studied in FMS and chronic pain. A number of major histocompatibility (MHC) class I and II antigens have been associated with chronic pain, including HLA-B58, HLA-DR4, HLA-DR5, and HLA-DR8 ; these results, however, have not been very consistent.

Alpha-1-antitrypsin polymorphisms are an interesting set of genetic markers, which have been associated with a complex behavioral phenotype including “intense creative energy” or “artist gene.” This polymorphism has also been associated with FMS , although another study was negative . Missense mutations in the Mediterranean fever (MEFV) gene, responsible for familial MF, have also been reported .

In view of the finding of the elevated CSF levels of substance P among FMS patients , a polymorphism in the TACR1 (NK1 receptor) gene has been studied in FMS patients of Ashkenazi Jews. The results, although not reaching statistical significance, showed a trend toward an increased frequency of the C allele among Ashkenazi FMS patients as compared to Ashkenazi healthy controls .

Guanosine triphosphate cyclohydrolase

Guanosine triphosphate cyclohydrolase (GCH1) is the rate-limiting enzyme in BH4 synthesis; this cofactor is essential for the synthesis of pain modulators, such as nitric oxide (NO) from arginine, serotonin from tryptophan, and biogenic amines from tyrosine . Variations in the GCH1 gene are closely associated with pain sensitivity. Changes in GCH1 enzyme activity can lead to higher BH4 levels and increased NO production, which enhances pain sensitivity, while specific GCH1 gene polymorphisms have a pain-protective role . With this in the background, Kim et al. have studied specific SNPs and haplotypes of the GCH1 gene among FMS patients . While the frequencies of alleles and genotypes of the four SNPs studied did not differ between FMS patients and healthy controls, the CCTA haplotype of GCH1 was associated with significantly lower pain sensitivity, and it occurred less frequently than the CCTT haplotype in patients with FMS. Thus, genetic variants affecting the function of the GCH1 gene may play a role in the processing of chronic pain.

The largest candidate-gene study to date has been published by Smith et al. This study included 496 FMS patients and 348 healthy controls. Genotyping was performed using a dedicated gene-array chip, the Pain Research Panel, which assays variants characterizing >350 genes known to be involved in the biologic pathways relevant to nociception, inflammation, and mood. Significant differences in allele frequencies between cases and controls were observed for three genes: GABRB3 , TAAR1 , and GBP1 . The investigators continued to perform a replication study on an independent cohort of FMS patients and controls, which showed an association of FMS with four genes, termed TAAR1, RGS4, CNR1 , and GRIA4 . Notably, TAAR1 was the only gene that was found to be significant in both parts of this study. This gene, trace amine-associated receptor, has previously been associated with modulating the activity of dopaminergic receptors, and it may thus be relevant for the development of chronic pain .

The CNR1 gene, which was also identified in the abovementioned candidate-gene study, codes the CB-1 cannabinoid receptor, which is the major receptor responsible for binding both endocannabinoids and exogenous cannabinoids. This receptor has an intriguing role in analgesia, and CNR1 variations have been previously demonstrated in various chronic pain conditions including migraine , irritable bowel syndrome (IBS) , and post-traumatic stress disorder (PTSD) . FMS has been hypothesized to be the result of a clinical endocannabinoid-deficient state ; however, increased circulating levels of anandamide, a major endocannabinoid, have been found among FMS patients , possibly representing an autoregulatory response to pain. Moreover, FMS has been shown to respond favorably to treatment with nabilone, a cannabinoid agent . Together, these findings raise the possibility that a subgroup of FMS patients may carry a defective CB-1 receptor due to CNR1 variations, and that this characteristic may be relevant regarding cannabinoid-based treatment.

The RGS4 gene, also differentially identified in the Smith study , negatively regulates protein-G signaling, and it may therefore play a modulatory role in the descending inhibition of pain perception. This gene is expressed in central nervous system (CNS) regions such as the locus coeruleus (LC), the bed nuclei of the stria terminalis, and the dorsal horn of the spinal cord . This gene, which has also been associated with schizophrenia , has been implicated in modulating the function of dopamine and glutamate receptors .

The GRIA4 gene, differentially identified in the Smith candidate-gene study, encodes the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, ionotropic glutamate receptor subunit 4, a receptor responsible for CNS fast excitatory transmission. Glutamate is an excitatory receptor, and it has been demonstrated to be elevated in specific pain-related brain areas in FMS , thus proposing a possible explanation for the significance of the GRIA4 gene.