高 IL-6 水平与癌症、自身免疫性疾病和感染等疾病相关。用于治疗类风湿关节炎和 COVID-19 的 IL-6 受体抑制剂 (IL-6Ri) 可能有更广泛的用途。我们应用药物靶标孟德尔随机化 (MR) 来研究 IL-6Ri 的效应。为了模拟基因阻断 IL-6R 的效应，我们选择了 IL6R 基因内或附近的单核苷酸多态性 (SNP)，这些单核苷酸多态性 (SNP) 显示出显着的全基因组关联与C反应蛋白。使用类风湿性关节炎和 COVID-19 作为阳性对照，我们的主要研究成果包括哮喘、哮喘性肺炎、肺心病、非小细胞肺癌、小细胞肺癌、帕金森病、阿尔茨海默病、溃疡性结肠炎、克罗恩病的风险、系统性红斑狼疮、1 型糖尿病和 2 型糖尿病。逆方差加权 (IVW) 方法是我们的​​主要分析方法，通过敏感性和共定位分析来评估 MR 的假设。此外，我们还进行了贝叶斯孟德尔随机化分析，以最大程度地减少混杂因素并扭转因果偏差。IL-6抑制剂显着降低了特发性肺纤维化的风险（OR= 0.278，95% [CI]，0.138-0.558；P < 0.001）、帕金森病（OR = 0.354，95% CI，0.215-0.582；P <0.001），并对与 2 型糖尿病的因果关系产生积极影响（OR = 0.759，95% CI，0.637-0.905；P = 0.002） 。然而，这些抑制剂增加了哮喘（OR = 1.327，95% CI，1.118-1.576；P = 0.001）和哮喘性肺炎（OR = 1.823，95% CI，1.246-2.666；P = 0.002）的风险。通过 BWMR 方法获得的因果效应估计与基于 IVW 方法获得的因果效应估计一致。同样，sIL-6R也对这些疾病产生显着影响。阿尔茨海默病、克罗恩病、肺心病、系统性红斑狼疮、1型糖尿病、非小细胞肺癌和溃疡性结肠炎等疾病显示出非显着关联（ p > 0.05）并被排除在进一步分析之外。同样，由于结果不一致，小细胞肺癌也被排除在外。值得注意的是，哮喘性肺炎的共定位证据 (coloc.abf-PPH4 = 0.811) 强有力地支持其与 CRP 的关联。帕金森病的共定位证据 (coloc.abf-PPH4 = 0.725) 适度支持其与 CRP 的关联。IL-6Ri 可能代表特发性肺纤维化、帕金森病和 2 型糖尿病的一种有前景的治疗途径。版权所有 © 2024 Fu, Wang和蔡。

High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects.To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible.IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP.IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.Copyright © 2024 Fu, Wang and Cai.