■高白细胞介素-6水平与癌症等疾病相关,自身免疫性疾病,和感染。IL-6受体抑制剂(IL-6Ri),用于类风湿性关节炎和COVID-19,可能有更广泛的用途。我们应用药物靶向孟德尔随机化(MR)研究IL-6Ri的作用。
■为了模拟基因阻断IL-6R的影响,我们选择了IL6R基因内或附近的单核苷酸多态性(SNPs),这些多态性在全基因组范围内与C反应蛋白有显著关联.使用类风湿性关节炎和COVID-19作为阳性对照,我们的主要研究结果包括哮喘的风险,喘息性肺炎,肺心病,非小细胞肺癌,小细胞肺癌,帕金森病,老年痴呆症,溃疡性结肠炎,克罗恩病,系统性红斑狼疮,1型糖尿病,和2型糖尿病。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评估MR的假设。此外,我们进行了贝叶斯孟德尔随机化分析,以最大程度地减少混淆和反向因果关系偏差.
■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),与2型糖尿病的因果关系呈正相关(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方法的因果效应估计一致。同样,sIL-6R对这些疾病也有显著影响。疾病如阿尔茨海默病,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显示无显著相关性(p>0.05),并排除在进一步分析之外。同样,由于结果不一致,小细胞肺癌被排除。值得注意的是,哮喘性肺炎的共同定位证据(coloc.abf-PPH4=0.811)有力地支持其与CRP的关联。帕金森病的共同定位证据(coloc。abf-PPH4=0.725)适度支持其与CRP的关联。
■IL-6Ri可能代表了特发性肺纤维化的一种有希望的治疗途径,帕金森病,2型糖尿病。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson\'s disease, and Type 2 diabetes.