PT - JOURNAL ARTICLE AU - Anna Guyatt AU - Catherine John AU - Alexander T Williams AU - Nick Shrine AU - Nicola F Reeve AU - SpiroMeta consortium AU - Ian Sayers AU - Ian Hall AU - Louise V Wain AU - Nuala Sheehan AU - Frank Dudbridge AU - Martin D Tobin TI - Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease AID - 10.1136/thoraxjnl-2021-217993 DP - 2022 May 10 TA - Thorax PG - thoraxjnl-2021-217993 4099 - http://thorax.bmj.com/content/early/2022/05/10/thoraxjnl-2021-217993.short 4100 - http://thorax.bmj.com/content/early/2022/05/10/thoraxjnl-2021-217993.full AB - 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 https://www.ebi.ac.uk/gwas/.