Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Medicine (Baltimore). 2024 Oct 25;103(43):e40268. doi: 10.1097/MD.0000000000040268.
Cysteine cathepsins are proteolytic enzymes crucial in various physiological and pathological processes, primarily operating within lysosomes. Their functions include protein degradation, immune system regulation, and involvement in various diseases. While some cysteine cathepsins play important roles in the immune system, their connection to autoimmune diseases remains unclear. This study proposes using Mendelian randomization to explore the causal relationship between cysteine cathepsins and autoimmune diseases. Single nucleotide polymorphisms (SNPs) for cysteine cathepsins were obtained from a publicly available genome-wide association study (GWAS) dataset, while outcome SNP data were sourced from 10 separate GWAS datasets. Mendelian randomization (MR) analysis employed the Wald ratio (WR) and inverse variance weighted (IVW) approach as primary methods, supplemented by the weighted median and MR-Egger methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analysis was conducted using the MR-PRESSO method. The association strength between exposure and outcome was evaluated using odds ratios (OR) with 95% confidence intervals (CI). The study identified a potential positive correlation between elevated cathepsin B and psoriasis (Wald ratio OR = 1.449, 95% CI: 1.053-1.993, P = .0227). Elevated cathepsin F was potentially linked to ulcerative colitis (WR OR = 1.073, 95% CI: 1.021-1.127, P = .0056), ankylosing spondylitis (WR OR = 1.258, 95% CI: 1.082-1.463, P = .0029), and primary biliary cholangitis(PBC) (WR OR = 1.958, 95% CI: 1.326-2.889, P = .0007). Conversely, cathepsin H appeared protective against celiac disease (WR OR = 0.881, 95% CI: 0.838-0.926, P = 6.5e-7), though elevated levels may increase the risk of type 1 diabetes (IVW OR = 1.121, 95% CI: 1.053-1.194, P = .0003) and PBC (WR OR = 1.792, 95% CI: 1.062-3.024, P = .0288). Cathepsin Z was also associated with an increased risk of type 1 diabetes (IVW OR = 1.090, 95% CI: 1.006-1.181, P = .0349). The MR analysis suggests potential risks of cathepsin B with psoriasis, cathepsin F with ulcerative colitis, ankylosing spondylitis, and PBC, and cathepsin Z with type 1 diabetes. Conversely, cathepsin H may protect against celiac disease but could increase the risk of type 1 diabetes and PBC.
半胱氨酸组织蛋白酶是在各种生理和病理过程中至关重要的蛋白水解酶，主要在溶酶体中发挥作用。它们的功能包括蛋白质降解、免疫系统调节以及参与各种疾病。虽然一些半胱氨酸组织蛋白酶在免疫系统中发挥重要作用，但它们与自身免疫性疾病的联系仍不清楚。本研究提出使用孟德尔随机化来探讨半胱氨酸组织蛋白酶与自身免疫性疾病之间的因果关系。半胱氨酸组织蛋白酶的单核苷酸多态性（SNP）从公开的全基因组关联研究（GWAS）数据集获得，而结果 SNP 数据来自 10 个单独的 GWAS 数据集。孟德尔随机化（MR）分析采用 Wald 比（WR）和逆方差加权（IVW）方法作为主要方法，加权中位数和 MR-Egger 方法作为补充。异质性采用 Cochran Q 检验进行评估，敏感性分析采用 MR-PRESSO 方法进行。暴露与结局之间的关联强度采用比值比（OR）及其 95%置信区间（CI）进行评估。研究发现，半胱氨酸组织蛋白酶 B 水平升高与银屑病之间存在潜在的正相关（Wald 比 OR=1.449，95%CI：1.053-1.993，P=0.0227）。半胱氨酸组织蛋白酶 F 水平升高可能与溃疡性结肠炎（WR OR=1.073，95%CI：1.021-1.127，P=0.0056）、强直性脊柱炎（WR OR=1.258，95%CI：1.082-1.463，P=0.0029）和原发性胆汁性胆管炎（PBC）（WR OR=1.958，95%CI：1.326-2.889，P=0.0007）有关。相反，半胱氨酸组织蛋白酶 H 似乎可以预防乳糜泻（WR OR=0.881，95%CI：0.838-0.926，P=6.5e-7），但高水平可能会增加 1 型糖尿病（IVW OR=1.121，95%CI：1.053-1.194，P=0.0003）和 PBC（WR OR=1.792，95%CI：1.062-3.024，P=0.0288）的风险。半胱氨酸组织蛋白酶 Z 也与 1 型糖尿病的风险增加有关（IVW OR=1.090，95%CI：1.006-1.181，P=0.0349）。MR 分析表明，半胱氨酸组织蛋白酶 B 与银屑病、半胱氨酸组织蛋白酶 F 与溃疡性结肠炎、强直性脊柱炎和 PBC、半胱氨酸组织蛋白酶 Z 与 1 型糖尿病之间存在潜在风险。相反，半胱氨酸组织蛋白酶 H 可能对乳糜泻有保护作用，但可能会增加 1 型糖尿病和 PBC 的风险。
