Abstract
<jats:p>COVID-19 not only affects the respiratory system but also increases the risk of cerebrovascular complications, including ischemic stroke. Experimental and clinical data suggest that cytokine dysregulation and polymorphisms of thrombophilia-related genes (MTHFR, MTR, and MTRR) may jointly promote hypercoagulation, endothelial dysfunction, and thromboinflammation, thereby contributing to post-COVID ischemic stroke. This study included 160 patients treated at Zangiota Infectious Diseases Hospitals (2021–2023): 60 patients with ischemic stroke in the acute or post-COVID period (experiment group), 50 COVID-19 patients without ischemic stroke (comparison group), and 50 ischemic stroke patients without COVID-19 (control group). Clinical–neurological and immunological parameters were assessed, and polymorphisms in thrombophilia/folate cycle genes (MTHFR C677T, MTR, and MTRR) were genotyped by PCR/real-time PCR. Statistical analysis included χ2 tests, t-tests, logistic regression with odds ratios (OR) and 95% confidence intervals (CI); Hardy–Weinberg equilibrium was verified. A strong association was identified between the MTHFR C677T polymorphism and ischemic stroke on the background of COVID-19 (OR = 5.4; 95% CI: 2.1–13.8; p < 0.001). The TNF-α rs1800629 polymorphism was also significantly associated with COVID-19-related cerebrovascular events (OR = 3.27; 95% CI: 1.4–7.6; p = 0.006). Carriage of two or more minor alleles produced a synergistic effect, markedly increasing the risk of post-COVID ischemic stroke (OR = 5.59; 95% CI: 2.3–13.6; p < 0.001). These polymorphisms were linked to hyperhomocysteinemia, endothelial dysfunction, and mechanisms contributing to multifactorial arterial ischemic events. The combined assessment of thrombophilia and folate cycle-related genotypes and clinical indicators may provide a potential framework for improved risk stratification. Polymorphisms in MTHFR may appear to represent important genetic determinants of ischemic stroke following COVID-19, particularly in the context of arterial ischemic mechanisms.</jats:p>