RATIONALE: The identification of novel molecules associated with asthma may provide insights into mechanisms of disease and their potential clinical implications.
OBJECTIVES: To conduct a screening of circulating proteins in childhood asthma and to study proteins emerged from human studies in a mouse model of asthma.
METHODS: We included 2,264 children from eight birth cohorts from the MeDALL project and the Tucson TCRS Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As creatine kinase (CK) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma (n=249) and used a house dust mite (HDM) challenged mouse model to gain insights into CK lung expression and its role in resolution of asthma phenotypes.
MEASUREMENTS AND MAIN RESULTS: As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjOR: 0.31, 0.15-0.65; p=0.002), validation (0.63, 0.42-0.95; p=0.03), and replication (0.40, 0.16-0.97; p = 0.04) stages. Both cytosolic CK forms (CKM, CKB) were under-expressed in blood from asthmatics compared to controls (p=0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced and, following HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness (AHR) and reduction of airway mucin.
CONCLUSIONS: Circulating levels and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of AHR and reduction of airway mucin.
