title: Discovery of potential new gene variants and inflammatory cytokine associations with fibromyalgia syndrome by whole exome sequencing.
abstract: Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder affecting 2% to 5% of the general population. Both genetic and environmental factors may be involved. To ascertain in an unbiased manner which genes play a role in the disorder, we performed complete exome sequencing on a subset of FMS patients. Out of 150 nuclear families (trios) DNA from 19 probands was subjected to complete exome sequencing. Since >80,000 SNPs were found per proband, the data were further filtered, including analysis of those with stop codons, a rare frequency (<2.5%) in the 1000 Genomes database, and presence in at least 2/19 probands sequenced. Two nonsense mutations, W32X in C11orf40 and Q100X in ZNF77 among 150 FMS trios had a significantly elevated frequency of transmission to affected probands (p = 0.026 and p = 0.032, respectively) and were present in a subset of 13% and 11% of FMS patients, respectively. Among 9 patients bearing more than one of the variants we have described, 4 had onset of symptoms between the ages of 10 and 18. The subset with the C11orf40 mutation had elevated plasma levels of the inflammatory cytokines, MCP-1 and IP-10, compared with unaffected controls or FMS patients with the wild-type allele. Similarly, patients with the ZNF77 mutation have elevated levels of the inflammatory cytokine, IL-12, compared with controls or patients with the wild type allele. Our results strongly implicate an inflammatory basis for FMS, as well as specific cytokine dysregulation, in at least 35% of our FMS cohort.
authors.affiliation: Department of Immunology, 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: Xiwei
authors.initials: X
authors.lastname: Wu
authors.forename: Allen
authors.initials: A
authors.lastname: Mao
authors.forename: Frances
authors.initials: F
authors.lastname: Chang
authors.forename: Xutao
authors.initials: X
authors.lastname: Deng
authors.forename: Harry
authors.initials: H
authors.lastname: Gao
authors.forename: Ching
authors.initials: C
authors.lastname: Ouyang
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dery
authors.forename: Keith
authors.initials: K
authors.lastname: Le
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
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood; D002648:Child; D016207:Cytokines / Q000097:blood*; D059472:Exome / Q000235:genetics*; D005260:Female; D005356:Fibromyalgia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D055815:Young Adult
chemical_list: D015415:Biomarkers; C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D016207:Cytokines; D012333:RNA, Messenger