Blood leukocyte counts (e.g., eosinophil count) are important
biomarkers for the onset, classification, and exacerbation of
chronic obstructive pulmonary disease (
COPD). The causal relationships between them are necessary for the development of
COPD treatment strategy, but remain unclear. Here, we implement two-sample bi-directional univariable Mendelian Randomization (MR) and multivariable MR to investigate the causal relationships. Univariable MR find that elevated blood eosinophil count significantly increases the risk of
COPD (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14-1.30, P = 1.54 × 10-09) and
COPD-related hospitalization (OR = 1.44, 95% CI: 1.15-1.80, P = 1.36 × 10-03). Besides, it also significantly decreases the ratio of forced expiratory volume in the first second over forced vital capacity (FEV1/FVC ratio) (OR = 0.942, 95% CI: 0.914-0.971, P = 1.02 × 10-04). These findings are fully supported by multivariate MR results. Interestingly, univariable MR reveals a weak causal relationship between elevated blood eosinophil count and
COPD risk in younger people (<65 years) (OR = 1.39, 95% CI: 1.10-1.75, P = 5.52 × 10-03), but not older individuals (OR = 1.20, 95% CI: 0.926-1.55, P = 0.17). Finally, reverse univariable MR reveals the onset of
COPD and the decreased FEV1/FVC ratio both lead to increased blood neutrophil count (OR = 1.03, 95% CI: 1.01-1.05, P = 3.40 × 10-03 and OR = 0.947, 95% CI: 0.91-0.986, P = 8.75 × 10-03 respectively). In summary, this MR study demonstrates that high blood eosinophil count is an independent causal mediator of
COPD risk, FEV1/FVC decline, and
COPD-related hospitalization. The increase in neutrophil count is induced by
COPD onset or FEV1/FVC decline. This suggests eosinophil, but not neutrophil, may be used as a therapeutic target for preventing the onset and exacerbation of
COPD and FEV1/FVC decline. Therefore, a non-neutrophil-targeted therapeutic strategy for neutrophilic
COPD is required in the future.