Division of Molecular Genetics, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
PLoS One. 2009 Dec 30;4(12):e8480. doi: 10.1371/journal.pone.0008480.
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).
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.
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.
纤维肌痛综合征（FMS）是一种常见的、慢性的、广泛的肌肉骨骼疼痛障碍，在普通人群中的发病率为 2%，女性发病率为 85%。它既有遗传因素，也有环境因素。患者及其父母的趋化因子 MCP-1 和 eotaxin 血浆水平较高，这为该综合征的遗传和免疫/炎症起源提供了证据（Zhang 等人，2008，Exp Biol Med 233: 1171-1180）。
在寻找影响炎症途径的候选基因时，在我们的患者样本（100 名纤维肌痛综合征患者及其父母）中筛选的 5 个基因中，我们发现了 MEFV 基因中有 10 个罕见和 1 个常见等位基因，该基因的各种复合杂合突变导致家族性地中海热（FMF）。对 MEFV 基因的 263 兆碱基对基因组序列进行了直接测序。罕见错义突变（所有杂合子，汇总测试）的集合具有显著增加的受影响个体的传递频率（p = 0.0085，单侧，精确二项式检验）。我们的数据提供了证据，表明 MEFV 基因的罕见错义变体共同与 FMS 的风险相关，并存在于 15%的 FMS 患者亚组中。该亚组的血浆 IL-1beta 水平较高（p = 0.019），与没有罕见变异的 FMS 患者、有或没有罕见变异的未受影响的家庭成员以及基因型未知的无关对照相比。IL-1beta 是一种与 MEFV 基因功能相关的细胞因子，被认为是其发热和肌肉疼痛症状的原因。
由于预测 MEFV 基因突变患者的 IL-1beta 表达失调，我们得出结论，该基因的罕见错义变体杂合子患者可能易患 FMS，可能由环境因素触发。
