Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States.
Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States.
Front Immunol. 2019 Jun 27;10:1475. doi: 10.3389/fimmu.2019.01475. eCollection 2019.
MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA), obesity, and altered metabolism. Although RA is associated with both obesity and altered metabolism, expression of RA-related microRNA in the setting of these cardiometabolic comorbidities is unclear. Our objective was to determine relationships between six RA-related microRNAs and RA disease activity, inflammation, body composition, and metabolic function. Expression of plasma miR-21, miR-23b, miR-27a, miR-143, miR-146a, and miR-223 was measured in 48 persons with seropositive and/or erosive RA (mean DAS-28-ESR 3.0, SD 1.4) and 23 age-, sex-, and BMI-matched healthy controls. Disease activity in RA was assessed by DAS-28-ESR. Plasma cytokine concentrations were determined by ELISA. Body composition was assessed using CT scan to determine central and muscle adipose and thigh muscle tissue size and tissue density. Plasma and skeletal muscle acylcarnitine, amino acid, and organic acid metabolites were measured via mass-spectroscopy. Plasma lipoproteins were measured via nuclear magnetic resonance (NMR) spectroscopy. Spearman correlations were used to assess relationships for microRNA with inflammation and cardiometabolic measures. RA and control associations were compared using Fisher transformations. Among RA subjects, plasma miR-143 was associated with plasma IL-6 and IL-8. No other RA microRNA was positively associated with disease activity or inflammatory markers. In RA, microRNA expression was associated with adiposity, both visceral adiposity (miR-146a, miR-21, miR-23b, and miR-27a) and thigh intra-muscular adiposity (miR-146a and miR-223). RA miR-146a was associated with greater concentrations of cardiometabolic risk markers (plasma short-chain dicarboxyl/hydroxyl acylcarnitines, triglycerides, large VLDL particles, and small HDL particles) and lower concentrations of muscle energy substrates (long-chain acylcarnitines and pyruvate). Despite RA and controls having similar microRNA levels, RA, and controls differed in magnitude and direction for several associations with cytokines and plasma and skeletal muscle metabolic intermediates. Most microRNAs thought to be associated with RA disease activity and inflammation were more reflective of RA adiposity and impaired metabolism. These associations show that microRNAs in RA may serve as an epigenetic link between RA inflammation and cardiometabolic comorbidities.
microRNAs 已被证实与类风湿关节炎（RA）、肥胖和代谢改变的发病机制有关。虽然 RA 与肥胖和代谢改变都有关，但在这些合并的心血管代谢疾病中，与 RA 相关的 microRNA 的表达情况尚不清楚。我们的目的是确定六种与 RA 相关的 microRNA 与 RA 疾病活动、炎症、身体成分和代谢功能之间的关系。 在 48 名血清阳性和/或侵蚀性 RA 患者（平均 DAS-28-ESR3.0，SD1.4）和 23 名年龄、性别和 BMI 匹配的健康对照者中，测量了血浆 miR-21、miR-23b、miR-27a、miR-143、miR-146a 和 miR-223 的表达。通过 DAS-28-ESR 评估 RA 中的疾病活动。通过 ELISA 测定血浆细胞因子浓度。通过 CT 扫描评估身体成分，以确定中央和肌肉脂肪以及大腿肌肉组织大小和组织密度。通过质谱法测量血浆酰基肉碱、氨基酸和有机酸代谢物。通过核磁共振（NMR）光谱法测量血浆脂蛋白。使用 Spearman 相关分析评估 microRNA 与炎症和心血管代谢指标的关系。使用 Fisher 变换比较 RA 患者和对照组的关联。 在 RA 患者中，血浆 miR-143 与血浆 IL-6 和 IL-8 呈正相关。没有其他 RA microRNA 与疾病活动或炎症标志物呈正相关。在 RA 中，microRNA 表达与肥胖有关，包括内脏肥胖（miR-146a、miR-21、miR-23b 和 miR-27a）和大腿内肌脂肪（miR-146a 和 miR-223）。RA miR-146a 与心血管代谢风险标志物（血浆短链二羧酸/羟基酰基肉碱、甘油三酯、大 VLDL 颗粒和小 HDL 颗粒）浓度较高和肌肉能量底物（长链酰基肉碱和丙酮酸）浓度较低有关。尽管 RA 和对照组的 microRNA 水平相似，但 RA 和对照组之间的几个与细胞因子和血浆及骨骼肌代谢中间产物的关联在程度和方向上存在差异。 大多数被认为与 RA 疾病活动和炎症相关的 microRNAs 更能反映 RA 的肥胖和代谢受损。这些关联表明，RA 中的 microRNAs 可能是 RA 炎症与心血管代谢合并症之间的表观遗传联系。
