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

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 (Timeless, 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 LSpO₂ (R = -0.464, P =0.009) and Mean SpO₂ (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.