The Relationship Between HIF1α and Clock Gene Expression in Patients with Obstructive Sleep Apnea

Abstract

Purpose: In this study, we aimed to investigate the precise relationship between hypoxia-inducible factor 1α (HIF1α), circadian clock genes, and OSA. Methods: We recruited 21 patients with OSA and 22 age-matched controls who underwent polysomnography and had their peripheral blood collected on the evening before and the morning after sleep. OSA was defined as an apnea hypopnea index (AHI) ≥ 15 events/h. Patients in which T90 > 0 were defined as having nocturnal hypoxemia (NH) and were referred to as the NH group. The mRNA levels of HIF1α, HIF1β and several clock genes ( Timeles s, Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, Ck1δ, Rorα, NR1D1 , and NPAS2) were determined by RT-qPCR. The percentage difference in gene expression levels when compared between the morning and evening was then determined as referred to as morning-evening variation (MEV). Results: The MEV for HIF1α mRNA expression in OSA patients increased significantly by 23% ( P = 0.008) when compared to patients without OSA. The gene expression levels of Timeless ( P = 0.038) and Cry2 ( P = 0.012) decreased with AHI. The MEV of Bmal1, Rorα , and HIF1α mRNA levels were upregulated by 16% ( P = 0.006), 14% ( P = 0.027), and 25% ( P = 0.005), respectively, in participants with NH when compared to those without NH. Furthermore, the MEV for HIF1α mRNA levels was positively correlated with the MEV of Bmal1, Cry1 , and CK1δ mRNA levels ( R = 0.638, P < 0.001; R = 0.327, P = 0.002; R = 0.332, P = 0.001, respectively) and negatively correlated with LSpO 2 ( R = − 0.464, P =0.009) and Mean SpO 2 ( R = − 0.500, P = 0.003). Conclusion: Our data suggest that patients with OSA or NH tend to develop circadian rhythm disorders that may be induced by the hypoxia-mediated augmentation of HIF1α gene expression in OSA. Keywords: obstructive sleep apnea, hypoxia-inducible factor, circadian rhythm, apnea hypopnea index

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