Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Huazhong University of Science and Technology, Tongji Medical College, School of Medicine and Health Management, Wuhan 430022, China.
Cytokine. 2024 Nov;183:156736. doi: 10.1016/j.cyto.2024.156736. Epub 2024 Aug 21.
Although existing studies have indicated a connection between chronic low-grade inflammation and the onset of frozen shoulder (FS), the precise causal relationship between distinct circulating inflammatory factors and FS has yet to be thoroughly evaluated. In this study, we employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between systemic cytokines and FS.
A genome-wide association dataset comprising 41 serum cytokines from 8,293 individuals of Finnish descent was utilized, along with FS data from the UK Biobank included 10,104 FS cases and 451,099 controls. The primary MR method was the inverse variance weighted approach, and four additional MR techniques (MR-Egger, weighted median, simple mode, and weighted mode) were also employed to support and validate the findings. Heterogeneity and horizontal pleiotropy assessments were assessed using Cochrane's Q and MR-Egger intercept tests. Moreover, a series of sensitivity analyses were conducted to strengthen the accuracy and credibility of these findings.
Based on the IVW method, genetically predicted increasing levels of growth regulated oncogene alpha (GROa) (OR=1.08, 95 % CI 1.02-1.13, P=0.005), interferon gamma-induced protein 10 (IP-10) (OR=1.09, 95 % CI 1.02-1.17, P=0.010), regulated on activation, C-C Motif Chemokine Ligand 5 (CCL5) (OR=1.11, 95 % CI 1.03-1.20, P=0.007) were suggestively associated with an increased risk of FS. Reverse MR analysis revealed no significant causal effect of FS on the 41 systemic inflammatory factors. No heterogeneity or horizontal pleiotropy was observed in our analysis.
This study established a causal association between 41 systemic inflammatory factors and FS, indicating that elevated levels of GROa, IP-10 and CCL5 were associated with a higher risk of FS. Further research is warranted to explore the potential of these biomarkers as early predictors and therapeutic targets for FS.
虽然现有研究表明慢性低度炎症与冻结肩（FS）的发生之间存在关联，但不同循环炎症因子与 FS 的确切因果关系尚未得到彻底评估。在这项研究中，我们采用双向两样本孟德尔随机化（MR）分析来研究系统性细胞因子与 FS 之间的潜在因果关系。
我们利用了包含 8293 名芬兰血统个体的 41 种血清细胞因子的全基因组关联数据集，以及包含 10104 例 FS 病例和 451099 名对照的英国生物库 FS 数据。主要的 MR 方法是逆方差加权法，还使用了另外四种 MR 技术（MR-Egger、加权中位数、简单模式和加权模式）来支持和验证研究结果。采用 Cochrane's Q 和 MR-Egger 截距检验评估异质性和水平多效性。此外，还进行了一系列敏感性分析，以增强这些发现的准确性和可信度。
根据 IVW 方法，遗传预测的生长调节癌基因α（GROa）水平升高（OR=1.08，95%CI 1.02-1.13，P=0.005）、干扰素γ诱导蛋白 10（IP-10）（OR=1.09，95%CI 1.02-1.17，P=0.010）、激活调节的 C-C 基序趋化因子配体 5（CCL5）（OR=1.11，95%CI 1.03-1.20，P=0.007）与 FS 风险增加有提示性关联。反向 MR 分析显示 FS 对 41 种系统性炎症因子没有显著的因果影响。我们的分析未观察到异质性或水平多效性。
本研究建立了 41 种系统性炎症因子与 FS 之间的因果关联，表明 GROa、IP-10 和 CCL5 水平升高与 FS 风险增加相关。需要进一步研究以探索这些生物标志物作为 FS 早期预测因子和治疗靶点的潜力。
