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Missense mutations in the MEFV gene
Sunday 10 January 2010
Missense Mutations in the MEFV Gene Are Associated with Fibromyalgia Syndrome and Correlate with Elevated IL-1β Plasma Levels
Jinong Feng1,2#, Zhifang Zhang2#, Wenyan Li1, Xiaoming Shen1, Wenjia Song1, Chunmei Yang1, Frances Chang2, Jeffrey Longmate3, Claudia Marek4, R. Paul St. Amand4, Theodore G. Krontiris5, John E. Shively2*, Steve S. Sommer1*
1 Division of Molecular Genetics, Beckman Research Institute, City of Hope, Duarte, California, United States of America, 2 Department of Immunology, Beckman Research Institute, City of Hope, Duarte, California, United States of America, 3 Department of Biostatistics, Beckman Research Institute, City of Hope, Duarte, California, United States of America, 4 Fibromyalgia Treatment Center, Los Angeles, California, United States of America, 5 Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States of America
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-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.
Since 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.
Citation: Feng J, Zhang Z, Li W, Shen X, Song W, et al. (2009) Missense Mutations in the MEFV Gene Are Associated with Fibromyalgia Syndrome and Correlate with Elevated IL-1β Plasma Levels. PLoS ONE 4(12): e8480. doi:10.1371/journal.pone.0008480
Editor: Derya Unutmaz, New York University, United States of America
Received: October 24, 2009; Accepted: November 22, 2009; Published: December 30, 2009
Copyright: © 2009 Feng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by a grant from the Los Angeles Fibromyalgia Foundation and in part by an National Institutes of Health General Clinical Research Center Grant, M01 RR00043. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
The full article can be found here.
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