Discovery of Potential New Gene Variants and Inflammatory Cytokine Associations with Fibromyalgia Syndrome by Whole Exome Sequencing

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 (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.纤维肌痛综合征（Fibromyalgia Syndrome, FMS）是一种慢性肌肉骨骼疼痛性疾病，影响普通人群的2%至5%，其发病可能涉及遗传与环境双重因素。为无偏倚地明确在该疾病中发挥致病作用的基因，我们对部分纤维肌痛综合征患者开展了全外显子组测序（complete exome sequencing）。本研究纳入150个核心家系（三联体），对其中19名先证者的DNA进行了全外显子组测序。由于每名先证者可检测到超过80000个单核苷酸多态性（Single Nucleotide Polymorphism, SNPs），研究团队对测序数据进行了进一步筛选，包括分析携带终止密码子以及频率罕见的变异位点；其中，ZNF77在150个纤维肌痛综合征三联体中向受累先证者的传递频率显著升高（两组检验P值分别为0.026和0.032），且该变异分别在13%和11%的纤维肌痛综合征患者中存在。在携带我们所报道的多种变异的9名患者中，有4名的症状起病年龄介于10至18岁之间。与健康对照或携带野生型等位基因（wild-type allele）的纤维肌痛综合征患者相比，携带C11orf40突变的患者亚组其血浆中炎性细胞因子MCP-1和IP-10的水平显著升高。类似地，与对照或携带野生型等位基因的患者相比，携带ZNF77突变的患者其炎性细胞因子IL-12的水平显著升高。本研究结果有力证实，在我们纳入的至少35%的纤维肌痛综合征队列中，该病的发病存在炎症基础，并伴随特定的细胞因子失调。