Rationale Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. Objectives We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. Methods We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. Measurements and main results Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 (weighted median estimator, SD FEV1/FVC: −0.054 (95% CI −0.078 to −0.029), effect only prominent in individuals with asthma). Conclusions Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD. Code used in the analysis for this paper is available on request. Summary-level statistics for the IVs used in this paper are available in the relevant published papers, or are available on request where not already published. Summary-level lung function GWAS and blood cell GWAS data are available from .

中文翻译：

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与肺功能和疾病相关的嗜酸性粒细胞和其他细胞类型的孟德尔随机化

基本原理 嗜酸性粒细胞与呼吸道疾病中的气道炎症有关。嗜酸性粒细胞的产生和存活部分由白细胞介素 5 控制：抗白细胞介素 5 药物可减少哮喘，且反应与基线嗜酸性粒细胞计数相关。然而，嗜酸性粒细胞升高是否与慢性阻塞性肺疾病（COPD）和其他呼吸道表型有因果关系尚不清楚。目的 我们研究了嗜酸性粒细胞与以下因素之间的因果关系：肺功能、COPD 急性加重、哮喘-COPD 重叠 (ACO)、中度至重度哮喘和呼吸道感染。方法 我们使用英国生物库/INTERVAL 中血液嗜酸性粒细胞全基因组关联研究的 151 个变异以及英国生物库/SpiroMeta 中呼吸特征的 151 个变异进行孟德尔随机化 (MR)，使用依赖于不同有效性假设的方法。我们使用八种细胞类型进行了多变量分析，其中可能存在嗜酸性粒细胞因果关系的证据。测量和主要结果 来自个体变异的因果估计具有高度异质性，这可能源于多效性。增加嗜酸性粒细胞的平均效应是增加 ACO（每个 SD 嗜酸性粒细胞的加权中位 OR，1.44（95%CI 1.19 至 1.74））和中重度哮喘（加权中位 OR 1.50（95%CI 1.23 至 1.83））的风险，并减少 1 秒用力呼气量 (FEV1)/用力肺活量 (FVC) 和 FEV1（加权中值估计值，SD FEV1/FVC：-0.054（95% CI -0.078 至 -0.029），仅在个体中效果显着患有哮喘）。结论 MR 方法的广泛一致性可能表明嗜酸性粒细胞是因果关系（尽管程度不确定），但异质性需要谨慎：其他重要机制可能是这些嗜酸性粒细胞升高变异损害呼吸系统健康的原因。这些结果可能表明，抗 IL5 药物（旨在降低嗜酸性粒细胞）可能对治疗其他呼吸系统疾病很有价值，包括具有哮喘和慢性阻塞性肺病重叠特征的患者。本文分析中使用的代码可根据要求提供。本文中使用的 IV 的摘要级统计数据可在相关已发表的论文中找到，或者在尚未发表的情况下根据要求提供。摘要级肺功能 GWAS 和血细胞 GWAS 数据可从。