title: 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).
  
  
  RESULTS
  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.
authors.affiliation: Division of Molecular Genetics, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: Jinong
authors.initials: J
authors.lastname: Feng
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Shen
authors.forename: Wenjia
authors.initials: W
authors.lastname: Song
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.forename: Frances
authors.initials: F
authors.lastname: Chang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Longmate
authors.forename: Claudia
authors.initials: C
authors.lastname: Marek
authors.forename: R Paul
authors.initials: RP
authors.lastname: St Amand
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Krontiris
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
authors.forename: Steve S
authors.initials: SS
authors.lastname: Sommer
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D005356:Fibromyalgia / Q000097:blood* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D000071198:Pyrin; D035781:Siblings; D013577:Syndrome
chemical_list: D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D000071198:Pyrin