Disrupted Expression of Circadian Clock Genes in Patients with Bronchial Asthma

Abstract

Hung-Chen Chen,1,2 Yung-Che Chen,1 Tsu-Nai Wang,3 Wen-Feng Fang,1 Ya-Chun Chang,1 Yu-Mu Chen,1 I-Ya Chen,2 Meng-Chih Lin,1 Ming-Yu Yang2,4 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 3Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, TaiwanCorrespondence: Ming-Yu YangGraduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Guishan Dist., Taoyuan City, 33302, TaiwanEmail [email protected] LinDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Road Niaosong Dist., Kaohsiung City, 83301, TaiwanEmail [email protected]: Circadian clock is synchronized to the 24-hour day by the daily light–dark cycle and proper function of circadian rhythm is essential for many physiological processes. Disruption of circadian rhythm can affect disease processes and influence disease severity, treatment responses, and even survivorship. In this retrospective case-controlled study, we tried to explore whether expression of circadian clock genes was disturbed in patients with bronchial asthma.Patients and Methods: We performed real-time quantitative reverse transcriptase-polymerase chain reactions to examine the expression of the nine core circadian clock genes (BMAL1, CK1ϵ, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIM) in total leukocytes of peripheral blood collected at chest clinics from 120 patients with asthma and 60 health individuals.Results: Expression levels of the nine circadian clock genes were significantly different between patients and healthy individuals, but not associated with the asthma control status. We also noted the difference of PER3 expression in asthmatic patients with and without nocturnal symptoms. In well-controlled asthmatics, expression of BMAL1, CK1ϵ, CLOCK, CRY1, CRY2, and PER1 was significantly lower in patients with nocturnal symptoms than those without nocturnal symptoms. However, in not well-controlled asthmatics, expression of only BMAL1, CK1ϵ, PER1, and PER2 was significantly different between patients with and without nocturnal symptoms. Binary logistic regression analysis selected BMAL1, CKIϵ, PER3, and TIM as independent factors for bronchial asthma and ROC curves showed the combined expression of these four genes enhanced the capability of predicting asthma (AUC=0.924; 95% CI=0.875– 0.958; P< 0.001).Conclusion: Our results showed altered expression of circadian clock genes in patients with bronchial asthma and down-regulated PER3 in patients with nocturnal symptoms. Altered expression of circadian clock genes was also observed in asthmatics with or without nocturnal symptoms in well- or not well-controlled subgroups. Combined expression of BMAL1, CKIϵ, PER3, and TIM could be a potential predictor for bronchial asthma.Keywords: bronchial asthma, nocturnal symptom, circadian clock genes, PER3

Keywords

• bronchial asthma
• nocturnal symptom
• circadian clock genes
• per3