Missense Mutations in the MEFV Gene Are Associated with Fibromyalgia Syndrome and Correlate with Elevated IL-1β Plasma Levels

Abstract

BackgroundFibromyalgia syndrome (FMS), a common, chronic, widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, has both genetic and environmental contributions. Patients and their parents have high plasma levels of the chemokines MCP-1 and eotaxin, providing evidence for both a genetic and an immunological/inflammatory origin for the syndrome (Zhang et al., 2008, Exp. Biol. Med. 233: 1171–1180).Methods and FindingsIn a search for a candidate gene affecting inflammatory pathways, among five screened in our patient samples (100 probands with FMS and their parents), we found 10 rare and one common alleles for MEFV, a gene in which various compound heterozygous mutations lead to Familial Mediterranean Fever (FMF). A total of 2.63 megabases of genomic sequence of the MEFV gene were scanned by direct sequencing. The collection of rare missense mutations (all heterozygotes and tested in the aggregate) had a significant elevated frequency of transmission to affecteds (p = 0.0085, one-sided, exact binomial test). Our data provide evidence that rare missense variants of the MEFV gene are, collectively, associated with risk of FMS and are present in a subset of 15% of FMS patients. This subset had, on average, high levels of plasma IL-1β (p = 0.019) compared to FMS patients without rare variants, unaffected family members with or without rare variants, and unrelated controls of unknown genotype. IL-1β is a cytokine associated with the function of the MEFV gene and thought to be responsible for its symptoms of fever and muscle aches.ConclusionsSince misregulation of IL-1β expression has been predicted for patients with mutations in the MEFV gene, we conclude that patients heterozygous for rare missense variants of this gene may be predisposed to FMS, possibly triggered by environmental factors.

Systematic review with meta-analysis: cytokines in fibromyalgia syndrome

“…Cytokine levels were investigated with ELISA in twelve studies [11-14,19,23-25,28,30,31,34], with bead-based immunoassays in five studies [17,20,26,29,33], with FACS analysis in two studies [10,21], with quantitative real-time PCR in one study [30], with reverse transcription PCR in one study [27], with immunohistochemistry in one study [15]. …”

Significance of MEFV gene R202Q polymorphism in Turkish familial Mediterranean fever patients

“…There was some evidence suggesting that R202Q homozygosity increases risk of FMF (Giaglis et al, 2007). Homozygosity of R202Q has also been detected in 100 Fibromyalgia Syndrome (FMS) probands (6%) (Feng et al, 2009).…”

Update on the genetics of the fibromyalgia syndrome

“…This polymorphism has also been associated with FMS [45,46], although another study was negative [47]. Missense mutations in the Mediterranean fever (MEFV) gene, responsible for familial MF, have also been reported [48].…”