组织蛋白酶与自身免疫性甲状腺疾病的因果关联：来自孟德尔随机化研究的探索

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【中图分类号】R581 【文献标识码】A

【Abstract】 Objective To explore the causal relationship between cathepsins and autoimmune thyroid diseases （AITDs） using Mendelian randomization （MR） study， and to provide genetic evidence for the association between cathepsins and the risk of AITDs. Methods The pooled datasets of nine cathepsins （B，E，F G，H，L2，O，Sand Z）and four AITDs were selected from a publicly available genome-wide assciation study （GWAS） website.The generalized summary data-based MR （GSMR），univariate bidirectional MR，and multivariate MR （MVMR）were used to analyze the causal relationship between them and the independent effcts of specific risk factors. Plasma protein quantitative trait loci （pQTL） genetic instrumental variables were obtained from the Ferkingstad study to verifycausality at the protein level.The inverse variance weighted method （IVW）was used as the primary analytical approach of univariate bidirectional MR Analysis， supplemented by MR-Eger， weighted median method，simple model， and weighted model methods. Horizontal pleiotropyand heterogeneity were evaluated，and sensitivity analysis was performed to ensure the robustness of the results. Results GSMR and forward MR analysis showed that cathepsin F（CTSF） significantly reduced the risk of Graves disease （GD）.Reverse MR Analysis showed no reverse causality between the GDand CTSF.After adjusting for the effcts of other cathepsins，MVMR analysis confrmed that the correlation between CTSF and GD was stillsignificant.Furthermore，the causal effct between CTSF and GD was verified by cis-QTL MR. Conclusion There is a causal relationship between CTSF and the reduced risk of GD，and CTSF is a potential protective factor against GD.

【Keywords】Cathepsins; Autoimmune thyroid diseases; Mendelian randomization; Causal relationship

自身免疫性甲状腺疾病（autoimmune thyroiddiseases，AITDs）是最常见的器官特异性自身免疫性疾病，影响约 2%～5% 的普通人群，其中女性（ 5%～15% ）患病率显著高于男性（ 1%～5% ）[1-2]最常见的AITDs是格雷夫斯病（Gravesdisease，GD）和自身免疫性甲状腺炎（autoimmunethyroiditis，AIT），两者以甲状腺实质淋巴细胞浸润为共同病理特征，临床特征分别是甲状腺功能亢进症和甲状腺功能减退症[3]。（剩余11069字）