The relationship between inflammatory cytokines and frozen shoulder: a large-sample analysis of the European population based on the FinnGen GWAS database

Abstract

BACKGROUND: Frozen shoulder is a common disease in orthopedics, but there is no specific clinical indicator for diagnosis. There is a significant association between inflammatory cytokines and frozen shoulder, but the specific causal relationship is not yet clear. This study used summary statistical data from genome-wide association studies (GWAS) for Mendelian randomization analysis. GWAS data are based on large-sample genetic variation information, which can reduce environmental confounding factors and more reliably infer the causal relationship between inflammatory cytokines and frozen shoulder, making up for the limitation that traditional observational studies cannot determine causal associations. OBJECTIVE: To explore the causal relationship between inflammatory cytokines and the onset of frozen shoulder using bidirectional two-sample Mendelian randomization. METHODS: Using summary statistics from GWAS in the FinnGen database, we analyzed the causal relationship between 41 inflammatory cytokines and frozen shoulder. The FinnGen database, jointly initiated by the Finnish National Institute for Health and Welfare (THL), the University of Helsinki, and other Finnish research institutions, includes 2,942 cases and 167,641 European-ancestry controls, integrating genomic, clinical phenotype, and biochemical indicator data from hundreds of thousands to millions of individuals, supporting genetic association studies of diseases. This study is based on publicly available summary statistics databases and does not require ethical approval. Bidirectional Mendelian randomization analyses were performed using inverse variance weighting, weighted median, weighted model, simple model, MR-Egger regression, and sensitivity analyses (including MR-Egger, MR-PRESSO, Cochran's Q test). RESULTS AND CONCLUSION: Monocyte chemoattractant protein-3 (MCP-3) showed significant causal effects in both directions. In the forward analysis, MCP-3 was positively associated with frozen shoulder risk (OR=1.176, 95%CI: 1.034-1.338, P=0.014); in the reverse analysis, frozen shoulder was negatively associated with MCP-3 levels (OR=0.782, 95%CI: 0.625-0.979, P=0.032). Additionally, a significant association was found between tumor necrosis factor beta (TNF-β) and frozen shoulder risk (OR=1.126, 95%CI: 1.002-1.264, P=0.046); in the reverse analysis, stromal cell-derived factor 1 alpha (SDF-1α) was also significantly associated with frozen shoulder risk (OR=1.1, 95%CI: 1.011-1.196, P=0.028), indicating reliable correlations of TNF-β and SDF-1α with frozen shoulder. This bidirectional Mendelian randomization study reveals a complex interaction between MCP-3 and frozen shoulder, suggesting that MCP-3 may serve as a potential therapeutic target. Furthermore, the study indicates that TNF-β is associated with frozen shoulder risk and may be a potential risk factor; while frozen shoulder is also associated with elevated SDF-1α levels, and SDF-1α has the potential to become a diagnostic marker for frozen shoulder. However, further research is needed to elucidate the biological mechanisms underlying these causal relationships. Additionally, the analysis of international databases provides candidate molecules and causal inference paradigms for Chinese research, but it needs to be combined with local data for precise translation.

1. Introduction

Frozen shoulder is one of the common diseases in orthopedics, characterized by gradual stiffness and pain in the shoulder joint, typically presenting as gradual onset of pain, followed by limited range of motion, and ultimately reaching a 'frozen' state [1]. The incidence of frozen shoulder increases with age, commonly affecting individuals aged 40-60 years [2], hence it is also known as 'fifty shoulder'. Although the exact etiology of frozen shoulder remains unclear, several risk factors have been identified, including diabetes, thyroid disease, hypothyroidism, prolonged immobilization, and a history of shoulder trauma [3-4]. To further treat and prevent frozen shoulder, more attention should be paid to other potentially modifiable risk factors.

Recent studies suggest a potential role of inflammation in the progression of frozen shoulder [5-6]. Compared with healthy controls, patients with frozen shoulder have elevated levels of inflammatory cytokines (such as interleukin-6, interleukin-1) in serum and synovial fluid, indicating that inflammation may contribute to the pathogenesis of the condition. However, the causal relationship between specific inflammatory cytokines and frozen shoulder remains unclear. Traditional observational studies are susceptible to confounding factors and reverse causation, limiting the ability to establish causality. To address this, the present study employs a bidirectional two-sample Mendelian randomization approach using summary statistics from genome-wide association studies (GWAS) to investigate the causal effects of 41 inflammatory cytokines on frozen shoulder risk. This method leverages genetic variants as instrumental variables, which are randomly assigned at conception, thereby reducing confounding and reverse causation, and providing more reliable evidence for causal inference.