Altered HIF-1α, Netrin-1, and Netrin-4 Levels in Obstructive Sleep Apnea: Associations with Intermittent Hypoxia and...

Background and Objectives: Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse, leading to intermittent hypoxia, oxidative stress, and systemic inflammation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in cellular adaptation to hypoxia, whereas Netrin family members have emerged as regulators of inflammatory and endothelial responses. However, the roles of Netrin-1 and Netrin-4 in OSA-related intermittent hypoxia remain unclear. This study aimed to investigate circulating HIF-1α, Netrin-1, and Netrin-4 levels in patients with OSA and to evaluate their associations with disease severity and hypoxic burden. Materials and Methods: This study included 52 patients with newly diagnosed OSA and 26 healthy controls. Participants were classified as severe OSA, mild-moderate OSA, or control according to apnea-hypopnea index (AHI) values. All participants underwent overnight polysomnography. Serum HIF-1α, Netrin-1, and Netrin-4 levels were measured using ELISA. ROC curve analyses were performed to assess the ability of the investigated biomarkers to distinguish patients with OSA from controls. Correlation analyses evaluated associations between biomarkers and polysomnographic parameters, while multiple linear regression analyses adjusted for BMI, age, gender, CRP, and LDL levels were used to identify independent associations. Results: Serum HIF-1α, Netrin-1, and Netrin-4 levels differed significantly among the groups (p < 0.0001) and progressively increased from controls to mild-moderate and severe OSA groups. ROC curve analyses demonstrated excellent discriminative performance for HIF-1α (AUC = 0.9072) and Netrin-1 (AUC = 0.8928), while Netrin-4 also showed good discriminative ability (AUC = 0.8284). HIF-1α levels were positively correlated with both AHI, reflecting disease severity, and T90, reflecting nocturnal hypoxic burden (p < 0.0001). Similar positive correlations were observed between Netrin-1, Netrin-4, and both AHI and T90 (p < 0.0001). In multiple linear regression analyses, AHI remained independently associated with HIF-1α, Netrin-1, and Netrin-4 after adjustment for BMI, age, gender, CRP, and LDL levels (p < 0.0001). In contrast, BMI, age, gender, CRP, and LDL were not significantly associated with any of these biomarker levels in the adjusted models. Conclusions: Circulating HIF-1α, Netrin-1, and Netrin-4 levels are significantly elevated in patients with OSA and are positively associated with disease severity and hypoxic burden. The independent relationship between AHI and these biomarkers suggests that intermittent hypoxia may contribute to activation of HIF-1α-related and Netrin-associated pathways in OSA. These findings indicate that Netrin family members may have potential relevance as biomarkers of hypoxia-associated inflammatory and endothelial alterations in OSA.