Circadian rhythms and asthma: exploring the impact of circadian clock proteins on childhood asthma management

Main Article Content

Adem Yaşar https://orcid.org/0000-0002-1045-0211
Feyza Kelleci Çelik
Tahir Aydın
Derya Büyükkayhan

Keywords

airway inflammation, chronotherapy biomarkers, circadian rhythms, pediatric asthma

Abstract

Background: Asthma is a chronic inflammatory disorder characterized by airway inflammation and hyperresponsiveness, significantly impacting children’s quality of life. Despite optimal treatment, some children experience poor asthma control, partly attributed to circadian rhythm disturbances.


Objectives: This study aimed to evaluate circadian clock protein levels and their relationship with asthma control and sleep quality in children.


Methods: Patients with asthma aged 8–17 years and age-matched healthy controls were enrolled. Pulmonary function was assessed using spirometry, asthma control via the Asthma Control Test (ACT), and sleep quality using the Children’s Sleep Habits Questionnaire (CSHQ). Serum circadian protein levels (BMAL1, CLOCK, CRY1, CRY2, PER1, and PER2) were quantified and compared between groups.


Results: Asthmatic children had significantly elevated levels of BMAL1, CLOCK, CRY1, PER1, and PER2 compared to controls (p<0.01); however, CRY2 was not significantly different. Poor sleep quality was associated with higher levels of BMAL1, PER1, and PER2 (p<0.01). Elevated circadian protein levels correlated with poorer asthma control and reduced pulmonary function (FEV1, FEV1/FVC, PEF; p<0.05). Individually, PER2 and BMAL1 showed the highest AUCs (~0.75), while a combined model of all proteins yielded an AUC of ~0.76, indicating complementary rather than singularly dominant contributions.


Conclusion: These exploratory findings support further evaluation of circadian proteins as biomarkers in pediatric asthma and warrant investigation of chronotherapy in appropriately designed trials, rather than justifying a specific dosing time at present. Circadian proteins, particularly PER2 and BMAL1, may serve as potential biomarkers and support precision-based chronotherapy in pediatric asthma management.

Abstract 107 | PDF Downloads 76 HTML Downloads 0 XML Downloads 6

References

1 Global Initiative for Asthma. 2024 GINA Main Report. Global strategy for asthma management and prevention. Accessed on Apr 12, 2025. Available from: https://ginasthma.org/2024-report/

2 Martinez FD, Vercelli D. Asthma. The Lancet. 2013;382(9901):1360–72.

3 Smolensky MH, Peppas NA. Chronobiology, drug delivery, and chronotherapeutics. Adv Drug Deliv Rev. 2007;59(9–10):828–51. 10.1016/j.addr.2007.07.001

4 Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017;18(3):164–79. 10.1038/nrg.2016.150

5 Durrington HJ, Farrow SN, Loudon AS, Ray DW. The circadian clock and asthma. Thorax. 2014;69(1):90–2.

6 Haspel JA, Chettimada S, Shaik RS, Chu JH, Raby BA, Cernadas M, et al. Circadian rhythm reprogramming during lung inflammation. Nat Commun. 2014;5:4753. 10.1038/ncomms5753

7 Busse WW, Lemanske RF. Asthma. New England Journal of Medicine. 2001;344(5):350–62.

8 Giri A, Wang Q, Rahman I, Sundar IK. Circadian molecular clock disruption in chronic pulmonary diseases. Trends Mol Med. 2022;28(6):513–27.

9 Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, et al. After asthma: redefining airways diseases. Lancet. 2018;391(10118):350–400.

10 Sutherland ER. Nocturnal asthma: underlying mechanisms and treatment. Curr Allergy Asthma Rep. 2005 Mar;5(2):161–7.

11 Zasłona Z, Case S, Early JO, Lalor SJ, McLoughlin RM, Curtis AM, et al. The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma. Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L855–60.

12 Zeng Y, Guo Z, Wu M, Chen F, Chen L. Circadian rhythm regulates the function of immune cells and participates in the development of tumors. Cell Death Discov. 2024 Apr 27;10(1):199. 10.1038/s41420-024-01960-1

13 Oyama Y, Shuff SR, Burns N, Vohwinkel CU, Eckle T. Intense light-elicited alveolar type 2-specific circadian PER2 protects from bacterial lung injury via BPIFB1. Am J Physiol Lung Cell Mol Physiol. 2022;322(5):L647–61.

14 Scheer FAJL, Hilton MF, Evoniuk HL, Shiels SA, Malhotra A, Sugarbaker R, et al. The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles. Proc Natl Acad Sci USA. 2021;118(37).

15 Chen HC, Chen YC, Wang TN, Fang WF, Chang YC, Chen YM, et al. Disrupted Expression of Circadian Clock Genes in Patients with Bronchial Asthma. J Asthma Allergy. 2021;14:371–80. 10.2147/JAA.S302508

16 Tran NQV, Le MK, Nakamura Y, Nakao A. Severe asthmatic airways have distinct circadian clock gene expression pattern associated with WNT signaling. Clin Transl Allergy. 2024;14(7):e12379. 10.1002/clt2.12379

17 Powell WT, Clark L V, Rich LM, Vanderwall ER, Gates C, White MP, et al. Altered circadian gene expression in primary human airway epithelial cells in asthma. ERJ Open Res. 2024;10(4).

18 Spengler CM, Shea SA. Endogenous Circadian Rhythm of Pulmonary Function in Healthy Humans. Am J Respir Crit Care Med. 2000;162(3):1038–46. 10.1164/ajrccm.162.3.9911107

19 Medarov BI, Pavlov VA, Rossoff L. Diurnal variations in human pulmonary function. Int J Clin Exp Med. 2008;1(3):267–73.

20 Barnes PJ. Corticosteroids: the drugs to beat. Eur J Pharmacol. 2006;533(1–3):2–14. 10.1016/j.ejphar.2005.12.052

21 Stanojevic S, Kaminsky DA, Miller MR, Thompson B, Aliverti A, Barjaktarevic I, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 2022;60(1). 10.1183/13993003.01499-2021

22 Uysal MA, Mungan D, Yorgancioglu A, Yildiz F, Akgun M, Gemicioglu B, et al. The validation of the Turkish version of Asthma Control Test. Qual Life Res. 2013;22(7):1773–9. 10.1007/s11136-012-0309-1

23 Perdahlı Fiş N, Arman A, Ay P, Topuzoğlu A, Güler AS, İmren SG, Ersu R, Berkem M. The validity and the reliability of Turkish Version of Children’s Sleep Habits Questionnaire. Alpha Psychiatry 2010, 11(2), 151–160.

24 Nilsonne G, Lekander M, Åkerstedt T, Axelsson J, Ingre M. Diurnal Variation of Circulating Interleukin-6 in Humans: A Meta-Analysis. PLoS One. 2016;11(11):e0165799. 10.1371/journal.pone.0165799

25 Janssens J, Atmosoerodjo SD, Vermeiren Y, Absalom AR, den Daas I, De Deyn PP. Sampling issues of cerebrospinal fluid and plasma monoamines: Investigation of the circadian rhythm and rostrocaudal concentration gradient. Neurochem Int. 2019;128:154–62. 10.1016/j.neuint.2019.04.015

26 Kelleci Çelik F, Charehsaz M, Aydin A. Toxicological evaluation of the interaction between circadian rhythm activator; KL001 and general anesthetic; isoflurane. Biol Rhythm Res. 2022;53(5):725–41. 10.1080/09291016.2019.1698808

27 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75. 10.1016/S0021-9258(19)52451-6

28 Sundar IK, Yao H, Sellix MT, Rahman I. Circadian molecular clock in lung pathophysiology. Am J Physiol Lung Cell Mol Physiol. 2015;309(10):L1056-75. 10.1152/ajplung.00152.2015

29 Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, et al. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc Natl Acad Sci U S A. 2012;109(2):582–7. 10.1073/pnas.1106750109

30 Scheiermann C, Gibbs J, Ince L, Loudon A. Clocking in to immunity. Nat Rev Immunol. 2018;18(7):423–37. 10.1038/s41577-018-0008-4

31 Krakowiak K, Maidstone RJ, Chakraborty A, Kendall AC, Nicolaou A, Downton P, et al. Identification of diurnal rhythmic blood markers in bronchial asthma. ERJ Open Res. 2023;9(4). 10.1183/23120541.00161-2023

32 Ehlers A, Xie W, Agapov E, Brown S, Steinberg D, Tidwell R, et al. BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes. Mucosal Immunol. 2018;11(1):97–111. 10.1038/mi.2017.24

33 Lee Y, Field JM, Sehgal A. Circadian Rhythms, Disease and Chronotherapy. J Biol Rhythms. 2021;36(6):503–31. 10.1177/07487304211044301

34 Song JU, Park HK, Lee J. Impact of dosage timing of once-daily inhaled corticosteroids in asthma: A systematic review and meta-analysis. Ann Allergy Asthma Immunol. 2018;120(5):512–9. 10.1016/j.anai.2017.12.021

35 Pincus DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1995;95(6):1172–8. 10.1016/S0091-6749(95)70073-0.

36 Wang R, Maidstone R, Singh D, Ray D, Loudon AS, Simpson A, et al. The impact of dosage timing for inhaled corticosteroids in asthma: a randomised three-way crossover trial. Thorax. 2025;80(8):504–11. 10.1136/thorax-2024-222073