Creatine Kinase Is Decreased in Childhood Asthma.

Abstract

<b>Rationale:</b> The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. <b>Objectives:</b> To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. <b>Methods:</b> We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory 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 CK (creatine kinase) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma (<i>n</i> = 249) and used a house dust mite (HDM)-challenged mouse model to gain insights into CK lung expression and its role in the resolution of asthma phenotypes. <b>Measurements and Main Results:</b> As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjusted odds ratio, 95% confidence interval: 0.31; 0.15-0.65; <i>P</i> = 0.002), validation (0.63; 0.42-0.95; <i>P</i> = 0.03), and replication (0.40; 0.16-0.97; <i>P</i> = 0.04) stages. Both cytosolic CK forms (<i>CKM</i> and <i>CKB</i>) were underexpressed in blood from asthmatics compared with control subjects (<i>P</i> = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, <i>Ckb</i> expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. <b>Conclusions:</b> Circulating concentrations 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 airway hyperresponsiveness and reduction of airway mucin.