关键词: 胰岛素样生长因子, 炎症性关节炎, 强直性脊柱炎, 类风湿性关节炎, 银屑病关节炎, 孟德尔随机化, 因果关系

Abstract: BACKGROUND: Studies have shown a significant association between members of the insulin-like growth factor family and the occurrence of inflammatory arthritis, but the causal relationship has not been accurately characterized. 
OBJECTIVE: To explore the potential association between members of the insulin-like growth factor family and the occurrence and development of ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis.
METHODS: Genetic instrumental variables associated with 14 discrete members of the insulin-like growth factor family, primarily derived from the expansive genomic database of a genome-wide association study, were used. The pertinent summary statistics for ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis were meticulously procured from the FinnGen Consortium’s extensive dataset. Our primary analytical methodology was anchored in the inverse-variance weighted approach, which is recognized for its robustness in Mendelian randomization studies. To augment the credibility and broader applicability of the findings, an array of complementary analyses were performed. These encompassed the weighted-median method, which mitigates the influence of potential outliers; the MR-Egger regression, a tool for assessing directional pleiotropy; the weighted mode and simple mode approaches, which provide alternative estimates of the causal effect; the MR pleiotropy residual sum and outlier test, designed to identify and correct for horizontal pleiotropy; Cochran’s Q statistic test, which evaluates the heterogeneity of the effect estimates; and the MR-Egger intercept analysis, a diagnostic for detecting and adjusting the impact of pleiotropic relationships. 
RESULTS AND CONCLUSION: We identified four distinct causal associations: CYR61 protein was negatively correlated with ankylosing spondylitis (odd ratios [OR]: 0.919, 95% confidence interval [CI]: 0.848-0.997, P=0.042) and rheumatoid arthritis (OR: 0.946, 95% CI: 0.908-0.987, P=0.011); IGF-II receptor was negatively correlated with ankylosing spondylitis (OR: 0.909, 95% CI: 0.835-0.990, P=0.029); IGFBP-7 was positively correlated with psoriatic arthritis (OR: 1.104, 95% CI: 1.002-1.218, P=0.046). The results of sensitivity analyses were consistent (P < 0.05). This rigorous analytical approach has yielded evidence suggestive of a potential causal nexus between a constellation of insulin growth factor family members and the risk of inflammatory arthritis. These findings underscore the necessity for further research to delineate the precise mechanisms by which insulin-like growth factor family members influence the developmental trajectories of ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis, thereby providing evidence for developing targeted interventions. In addition, by drawing on international research experience, future biomedical research in China should further focus on the genetic mechanisms of inflammatory and immune-related diseases, promote clinical translation and the development of precision medicine, and provide more efficient and personalized treatment plans for Chinese patients.

Key words: insulin-like growth factor, inflammatory arthritis, ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, Mendelian randomization, causal relationship