The SOD2 Val16Ala (rs4880) Polymorphism Exacerbates Disease Severity in Obstructive Sleep Apnea

Abstract

Background: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH), which induces systemic oxidative stress and inflammation. The mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) is the primary defense against superoxide radicals generated during IH. A common functional polymorphism in the SOD2 gene (rs4880, Val16Ala) impacts the mitochondrial import and efficacy of the enzyme. Objectives: We hypothesized that the valine (Val) allele, associated with reduced antioxidant capacity, exacerbates OSA severity. Methods: A case-control study was conducted with 187 participants stratified into four groups: Controls (n = 41), mild OSA (n = 55), moderate OSA (n = 48), and severe OSA (n = 43). Genotyping for the SOD2 rs4880 variant was performed. Allelic and genotypic frequencies were calculated and compared across groups, assuming Hardy-Weinberg equilibrium. The primary outcome was the association between the Val allele and OSA severity. Results: The frequency of the SOD2 Val allele was significantly higher in the severe OSA group (0.65) compared to all other groups (0.49; P < 0.01), and the genotypic distribution differed significantly across severity groups (P = 0.002). In a multivariate ordinal logistic regression analysis using a dominant genetic model, carriage of at least one Val allele (i.e., Val/Val + Val/alanine (Ala) genotypes) was an independent predictor of increased OSA severity [adjusted odds ratio (aOR) = 2.40, 95% CI: 1.25 - 4.62, P = 0.008], after adjusting for Body Mass Index (BMI), neck circumference, and gender. Conclusions: The SOD2 Val16Ala polymorphism is a significant and independent modifier of OSA severity. The Val allele is associated with an increased risk of severe disease, likely due to inadequate mitigation of mitochondrial oxidative stress during apneic events.