Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels

Abstract

Background: Fibromyalgia 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 findings: In 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-1beta (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-1beta is a cytokine associated with the function of the MEFV gene and thought to be responsible for its symptoms of fever and muscle aches.

Conclusions: Since misregulation of IL-1beta 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.

Figure 1. Missense mutation detected in the MEFV gene in FMS patients.

Part of the genomic organization of the MEFV gene and a map of the missense mutations in patients with Fibromyalgia Syndrome are illustrated.

Figure 2. Plasma chemokine/cytokine levels by MEFV genotypes in FMS patients and family members, and in unrelated controls.

Ctrl: plasma levels (pg/mL) for unrelated controls (n = 77) of unknown genotype. Wt no FMS: unaffected parents without variant alleles (n = 35). Wt FMS: FMS probands (n = 37) with wild type (non-variant) MEFV gene. R202Q: FMS probands and family members with R202Q genotype (n = 49). Rare: FMS patients with a rare variant of the MEFV gene (n = 14). P values are shown below each group. Boxplots indicate the median (heavy bar), central 50% of data (box) and range of observations (whiskers). P-values are from two-sided t-tests contrasting each group with the control group, using pooled variance, a logarithmic scale, and without any adjustment for multiple comparisons. In addition, subjects with the rare MEFV alleles compared to wt FMS patients had elevated levels of MIP-1α (p = 0.019); subjects with R202Q polymorphism compared to wt FMS patients had elevated levels of MCP-1 (p = 0.004).