Protection from asthma in a high-risk birth cohort by attenuated P2X7 function

BackgroundViral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage caused by infection or allergen inhalation increases ATP levels in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X7 can enhance airway leukocyte recruitment to the airways, and P2X7 knockout mice display a reduced asthma-like phenotype.ObjectiveBased on the P2X7 knockout mouse, we hypothesized that children with low P2X7 function would have decreased rates of asthma.MethodsWe used a functional assay to determine P2X7 pore-producing capacity in whole-blood samples in a birth cohort at high risk for asthma development. The P2X7 assay was validated with known loss-of-function alleles in human subjects. P2X7 pore status categorization was used to assess asthma and allergy status in the cohort.ResultsAttenuated P2X7 function was associated with lower asthma rates at ages 6 and 8 years, and the greatest effects were observed in boys. Children with asthma at age 11 years who had low P2X7 capacity had less severe disease in the previous year. Attenuated P2X7 function was also associated with sensitization to fewer aeroallergens.ConclusionP2X7 functional capacity is associated with asthma risk or disease severity, and these relationships appear to be age related.