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BACKGROUND: Neutrophils are key in eliminating bacterial and fungal pathogens, but are less effective against viruses. Excessive neutrophil activity may indicate dysregulated immunity preceding childhood asthma and viral respiratory illnesses.OBJECTIVE: To investigate if genetic predisposition to an excessive neutrophil activation is linked to childhood asthma and viral respiratory illnesses.METHODS: Polygenic Risk Scores (PRS)-calculated as the weighted sum of genetic variants associated with blood neutrophil counts-were derived for children in the COpenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC) cohort and two registry-based cohorts hospitalized for asthma by age 6 years (iPSYCH and COPSAC). Mendelian randomization (MR) was used to test whether genetically predicted neutrophil counts causally influence childhood asthma risk. In COPSAC, blood cytokines were measured at 18 months upon ex vivo stimulation with viral-mimicking ligands (R848 and Poly(I:C)) and then combined into neutrophil PRS-associated immune signature scores representing genetically linked variation in innate immune responsiveness. Nasopharyngeal samples from children during acute illness were analysed for pathogenic viruses and bacteria.RESULTS: The neutrophil PRS was associated with an increased risk of hospitalization for asthma (Odds Ratio [OR] 1.09, 95% Confidence Interval [CI]: 1.05-1.13, p = 8.7e-6). MR suggested causality. In COPSAC, neutrophil PRS was associated with an increased Type 17 immune response to viral stimulation, notably CXCL8, IL-6, and IL-18. The neutrophil PRS-associated cytokine signature scores were associated with increased risk of viral respiratory illnesses by age three and asthma by age six.CONCLUSION: Genetic predisposition to elevated neutrophils may drive early-life antiviral immune dysregulation, increasing the risk of respiratory illness and childhood asthma. This supports neutrophil pathways as potential preventive or therapeutic targets.