Abstract
PURPOSE: While elevated blood eosinophil counts (BECs) are established biomarkers in asthma and chronic obstructive pulmonary disease, their impact on lung function in general populations remains less defined. This multi-ethnicity study examined BEC-lung function associations across diverse populations and employed Mendelian randomization (MR) to explore causal mechanisms. PATIENTS AND METHODS: Integrated cross-sectional analyses involved three cohorts: Hongtong (n=13,868), NHANES (n=11,833), UK Biobank (UKB; n=428,610). Longitudinal assessment used UKB data (n=38,532). Multivariable regression assessed BEC associations with FEV(1), FVC, FEV(1)/FVC, and PEF. Linear mixed-effects models estimated longitudinal changes by baseline BEC. Two-sample MR used European/Asian genetic instruments. Subgroup analyses assessed age, sex, disease status, and smoking effects. RESULTS: BECs consistently showed inverse associations with FEV(1) across cohorts, strongest in UKB (266.22 mL and 171.95 mL FEV(1) reduction per 1×10(9) cells/L BEC increase in males and females, respectively). Associations with FVC, FEV(1)/FVC, and PEF were most pronounced in UKB, whereas significant associations were absent for FVC in Hongtong and NHANES males. Longitudinally, higher baseline BECs predicted accelerated lung function decline, especially in males. Subgroup analyses revealed intensified negative associations in smokers and individuals >45 years. Importantly, these inverse associations persisted in sensitivity analyses excluding individuals with respiratory diseases. MR showed significant association in all traits in Europeans (P<0.05) but only for FEV(1)/FVC in Asians. CONCLUSION: BECs show a significant and independent association with lung function impairment at the population level. MR analyses provide supportive evidence for a potential causal role, identifying distinct patterns of airway obstruction in Asian populations versus broader lung function deficits in Europeans. Variations by sex, ancestry, age, and smoking underscore demographic considerations in eosinophil-related respiratory health. These findings suggest the potential utility of monitoring BECs in asymptomatic individuals and warrant further investigation into personalized prevention strategies.