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Publications

Journal Article Ahead of print

PubMed: 41956381 DOI: 10.1016/j.jaci.2026.03.019

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

J Allergy Clin Immunol

Authors: Yang Luo, Anders Ulrik Eliasen, Kasper Fischer-Rasmussen, Jonathan Thorsen, Nicklas Brustad, Signe Kjeldgaard Jensen, Liang Chen, Tamo Sultan, Anna Hammerich Thysen, Allan Linneberg, Thomas Werge, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Susanne Brix, Jakob Stokholm, Bo Chawes, Casper-Emil Tingskov Pedersen, Klaus Bønnelykke

Affiliations

  • COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.
  • COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark; Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA; Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
  • COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark; Department of Pediatrics, Copenhagen University Hospital - Naestved, Slagelse and Ringsted, Slagelse, Denmark.
  • Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
  • Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research; Center for Genomics and Personalized Medicine, Aarhus, Central Region Denmark, Denmark; Institute of Biological Psychiatry, Copenhagen Mental Health Services, Copenhagen, Denmark.
  • Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
  • COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark; Section of Microbiology and Fermentation, Department of Food Science, University of Copenhagen, Denmark.
  • COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.

Abstract

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 2010) cohort and two registry-based cohorts hospitalized for asthma by age 6 years (iPSYCH and COPSAC severe). Mendelian randomization (MR) was used to test whether genetically predicted neutrophil counts causally influence childhood asthma risk. In COPSAC 2010, 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 2010, 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.

MeSH

Cytokines, Blood, Genetics, Neutrophils, Viruses, Immunity, Asthma, Bacteria, Child