TY - JOUR
T1 - Creatine Kinase Is Decreased in Childhood Asthma
AU - Guerra, Stefano
AU - Ledford, Julie G.
AU - Melén, Erik
AU - Lavi, Iris
AU - Carsin, Anne Elie
AU - Stern, Debra A.
AU - Zhai, Jing
AU - Vidal, Marta
AU - Bustamante, Mariona
AU - Addison, Kenneth J.
AU - Vallecillo, Renata G.
AU - Billheimer, Dean
AU - Koppelman, Gerard H.
AU - Garcia-Aymerich, Judith
AU - Lemonnier, Nathanaël
AU - Fitó, Montserrat
AU - Dobaño, Carlota
AU - Kebede Merid, Simon
AU - Kull, Inger
AU - McEachan, Rosemary R.C.
AU - Wright, John
AU - Chatzi, Leda
AU - Kogevinas, Manolis
AU - Porta, Daniela
AU - Narduzzi, Silvia
AU - Ballester, Ferran
AU - Esplugues, Ana
AU - Zabaleta, Carlos
AU - Irizar, Amaia
AU - Sunyer, Jordi
AU - Halonen, Marilyn
AU - Bousquet, Jean
AU - Martinez, Fernando D.
AU - Anto, Josep M.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: 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. Methods: 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 (n = 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. Measurements and Main Results: 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; 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 and CKB) were underexpressed in blood from asthmatics compared with control subjects (P = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: 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.
AB - Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: 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. Methods: 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 (n = 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. Measurements and Main Results: 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; 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 and CKB) were underexpressed in blood from asthmatics compared with control subjects (P = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: 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.
KW - asthma
KW - biomarkers
KW - creatine kinase
UR - http://www.scopus.com/inward/record.url?scp=85149174891&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85149174891&partnerID=8YFLogxK
U2 - 10.1164/rccm.202010-3746OC
DO - 10.1164/rccm.202010-3746OC
M3 - Article
C2 - 35876143
AN - SCOPUS:85149174891
SN - 1073-449X
VL - 207
SP - 544
EP - 552
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 5
ER -