Assessment of causal relationships between eosinophils and respiratory disease using Mendelian randomization

Eosinophils are involved in airway inflammation in respiratory disease, but whether eosinophils play a causal role in pathogenesis is not fully understood. We investigated whether there was a causal relationship between eosinophils and: lung function, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), moderate-to-severe asthma, and respiratory infections. We performed Mendelian randomization 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 for traits where there was possible evidence of causation by eosinophils. Causal estimates derived from individual variants were highly heterogeneous. This may arise from pleiotropy, i.e. one variant/gene influencing multiple biological pathways. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils 1.44 [95%CI 1.19,1.74]), and moderate-severe asthma (weighted median OR 1.50 [95%CI 1.23,1.83]), and to reduce FEV₁/FVC and FEV₁ (weighted median estimator, SD FEV₁/FVC: -0.054 [95%CI -0.078,-0.029]. Effects on lung function were more prominent in those with asthma. Broad consistency between methods suggests eosinophils have a causal effect, though of uncertain magnitude. However, given heterogeneity in our results, the genetic variants examined may impair respiratory health through mechanisms other than eosinophils. Anti-IL5 agents may have utility in conditions other than asthma, and further investigation of potential mechanisms of action would be valuable.