Fibromyalgia (FM) is a complex, centralized pain condition that is often difficult to diagnose and treat. FM is considered to have a genetic background due to its familial aggregation and due to findings from multiple candidate-gene studies implicating catecholaminergic and serotonergic neurotransmitter systems in chronic pain. However, a multi-factorial analysis of both genetic and environmental risk factors is lacking. A better characterization of the interplay of risk factors may assist in understanding the pathophysiology of FM, its clinical course, and assist in early diagnosis and treatment of the disorder. This retrospective study included 60,367 total participants from 237 clinics across the USA. Of those, 2713 had been diagnosed with fibromyalgia, as indicated by ICD code. Logistic regression was used to test for associations of diagnosed FM in study subjects with COMT SNPs and COMT haplotypes, which were previously found to be linked with pain sensitivity, as well as demographics such as age, sex, and ethnicity. The minor allele frequencies of COMT SNPs in the FM population were compared with 1000 Genomes data using a χ2 test to determine significant deviations from the estimated population allelic frequencies. FM diagnosis was strongly associated with sex, age, and ethnicity. Females, those between 49 and 63 years, and non-Caucasians were at higher risk of FM. Females had 1.72 increased odds of FM (p = 1.17 × 10− 30). African-Americans were 1.52 times more likely to have a diagnosis of FM compared to Caucasians (p = 3.11 × 10− 12). Hispanics were less likely to have a diagnosis of FM compared to Caucasians (p = 3.95 × 10− 7). After adjusting for sex and ethnicity, those in the low age group and mid age group had 1.29 (p = 1.02 × 10− 5) and 1.60 (p = 1.93 × 10− 18) increased odds of FM, respectively, compared to the high age group, where age was categorized by tertile (low (< 49), mid (49–63), and high (> 63)). The COMT haplotypes associated with pain sensitivity were not associated with FM, but African-Americans were 11.3 times more likely to have a high pain sensitivity COMT diplotype, regardless of FM diagnosis. However, the minor alleles of COMT SNPs rs4680, rs4818, rs4633 and rs6269 were overrepresented in the FM population overall, and varied when compared with ethnically-similar populations from 1000 Genomes. This is the largest study, to date, that examines demographic and genetic associations of FM in a diverse population. While pain sensitivity-associated COMT haplotypes were not found to be directly associated with FM diagnosis, the minor alleles that make up the COMT haplotypes were overrepresented in the FM population, suggesting a role of COMT in FM. Future studies are needed to elucidate the exact role of COMT variation in widespread pain conditions, such as FM. Clinically, this information can be used to provide insight into the pathways underlying FM and to identify those at greater risk of developing FM.

中文翻译：

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一大群纤维肌痛患者中儿茶酚-O-甲基转移酶单核苷酸多态性、种族和性别的关联

纤维肌痛 (FM) 是一种复杂的集中性疼痛状况，通常难以诊断和治疗。FM 被认为具有遗传背景，因为它具有家族聚集性，并且由于多项候选基因研究的结果表明慢性疼痛中的儿茶酚胺能和血清素能神经递质系统。然而，缺乏对遗传和环境风险因素的多因素分析。更好地描述风险因素的相互作用可能有助于了解 FM 的病理生理学及其临床过程，并有助于疾病的早期诊断和治疗。这项回顾性研究包括来自美国 237 家诊所的 60,367 名参与者。如 ICD 代码所示，其中 2713 人被诊断出患有纤维肌痛。逻辑回归用于测试研究对象中诊断出的 FM 与 COMT SNP 和 COMT 单倍型之间的关联，之前发现这与疼痛敏感性以及年龄、性别和种族等人口统计数据有关。使用 χ2 检验将 FM 群体中 COMT SNP 的次要等位基因频率与 1000 个基因组数据进行比较，以确定与估计的群体等位基因频率的显着偏差。FM 诊断与性别、年龄和种族密切相关。女性、49 至 63 岁的女性和非高加索人患 FM 的风险更高。女性患 FM 的几率增加 1.72 (p = 1.17 × 10− 30)。与白种人相比，非裔美国人被诊断为 FM 的可能性高 1.52 倍（p = 3.11 × 10− 12）。与白种人相比，西班牙裔被诊断为 FM 的可能性更低（p = 3. 95 × 10− 7)。在调整性别和种族后，与高年龄组相比，低年龄组和中年龄组的 FM 几率分别增加 1.29 (p = 1.02 × 10- 5) 和 1.60 (p = 1.93 × 10- 18)年龄组，其中年龄按三分位数分类（低（< 49）、中（49-63）和高（> 63））。与疼痛敏感性相关的 COMT 单倍型与 FM 无关，但无论 FM 诊断如何，非裔美国人具有高疼痛敏感性 COMT 双倍型的可能性高出 11.3 倍。然而，COMT SNPs rs4680、rs4818、rs4633 和 rs6269 的次要等位基因在整个 FM 人群中的比例过高，并且与来自 1000 个基因组的种族相似人群相比存在差异。这是迄今为止最大的一项研究，该研究检查了不同人群中 FM 的人口统计学和遗传关联。虽然没有发现与疼痛敏感性相关的 COMT 单倍型与 FM 诊断直接相关，但构成 COMT 单倍型的次要等位基因在 FM 人群中的比例过高，这表明 COMT 在 FM 中的作用。未来的研究需要阐明 COMT 变异在广泛疼痛状况（如 FM）中的确切作用。在临床上，这些信息可用于深入了解 FM 的潜在途径，并识别那些患 FM 风险更大的人。