Creatine Kinase Is Decreased in Childhood Asthma

• Published in: American journal of respiratory and critical care medicine Vol. 207; no. 5; pp. 544 - 552
• Main Authors: Guerra, Stefano, Ledford, Julie G, Melén, Erik, Lavi, Iris, Carsin, Anne-Elie, Stern, Debra A, Zhai, Jing, Vidal, Marta, Bustamante, Mariona, Addison, Kenneth J, Vallecillo, Renata G, Billheimer, Dean, Koppelman, Gerard H, Garcia-Aymerich, Judith, Lemonnier, Nathanaël, Fitó, Montserrat, Dobaño, Carlota, Kebede Merid, Simon, Kull, Inger, McEachan, Rosemary R C, Wright, John, Chatzi, Leda, Kogevinas, Manolis, Porta, Daniela, Narduzzi, Silvia, Ballester, Ferran, Esplugues, Ana, Zabaleta, Carlos, Irizar, Amaia, Sunyer, Jordi, Halonen, Marilyn, Bousquet, Jean, Martinez, Fernando D, Anto, Josep M
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.03.2023
• Subjects: Animals; Asthma; Asthma - metabolism; Child; Childrens health; Creatine Kinase - metabolism; Cross-Sectional Studies; Disease Models, Animal; Humans; Kinases; Life Sciences; Lung - metabolism; Medicin och hälsovetenskap; Mice; Mucins - metabolism; Original; Pathophysiology; Pediatrics; Proteins; Pyroglyphidae; Respiratory Hypersensitivity - complications; biomarkers; asthma; creatine kinase; asthma; biomarkers; creatine kinase
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202010-3746OC

The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. 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. 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 (  = 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. 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;  = 0.002), validation (0.63; 0.42-0.95;  = 0.03), and replication (0.40; 0.16-0.97;  = 0.04) stages. Both cytosolic CK forms ( and ) were underexpressed in blood from asthmatics compared with control subjects (  = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. 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.