Blood neutrophil genetics highlight the role of neutrophils in early childhood asthma and viral respiratory illnesses.

Abstract

Neutrophils are key in eliminating bacterial and fungal pathogens, but they are less effective against viruses. Excessive neutrophil activity may indicate dysregulated immunity preceding childhood asthma and viral respiratory illnesses. We investigated if genetic predisposition to an excessive neutrophil activation is linked to childhood asthma and viral respiratory illnesses. 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 (COPSAC₂₀₁₀) cohort and 2 registry-based cohorts hospitalized for asthma by age 6 years (iPSYCH and COPSAC_severe). Mendelian randomization was used to test whether genetically predicted neutrophil counts causally influence childhood asthma risk. In COPSAC₂₀₁₀, blood cytokines were measured at 18 months on ex vivo stimulation with virus-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 analyzed for pathogenic viruses and bacteria. The neutrophil PRS was associated with an increased risk of hospitalization for asthma (odds ratio = 1.09; 95% confidence interval, 1.05-1.13; P = 8.7e-6). Mendelian randomization suggested causality. In COPSAC₂₀₁₀, 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 3 and asthma by age 6. 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.