GENETIC MARKERS OF ENDOTHELIAL AND HYPOXIC DYSREGULATION IN CHRONIC CEREBRAL ISCHEMIA OF VARYING SEVERITY
Keywords:
chronic cerebral ischemia, endothelial dysfunction, NOS3, ACE, HIF1A, genetic polymorphism, hypoxia, cerebrovascular riskAbstract
The study aimed to assess the distribution and associations of NOS3 -786T>C (rs2070744), ACE Ins/Del (rs4646994), and HIF1A C/T (rs11549465) polymorphisms, reflecting endothelial regulation, renin-angiotensin system activity, and cellular adaptation to hypoxia, in patients with chronic cerebral ischemia (CCI) of varying severity. Genotyping results were analyzed in 111 patients with CCI, stratified into three clinical groups corresponding to stage I (n=31), stage II (n=43), and stage III (n=37), as well as in 105 control subjects. Genotyping was performed using real-time PCR. Allele and genotype frequencies, odds ratios (ORs) with 95% confidence intervals (CIs), Fisher's exact test/χ² test, and conformity of genotype distributions to Hardy-Weinberg equilibrium were analyzed. For NOS3, no overall difference was found between all patients and controls; however, the frequency of the C allele increased from 4.84% at stage I to 18.60% at stage II and 22.97% at stage III, and a linear trend across stages was identified for C-allele carriage (p=0.024). At stage III, the C allele was more frequent than in controls (OR 2.31; 95% CI 1.16-4.60; p=0.021). For ACE, the Del allele was significantly more frequent in the patient group than in controls (40.99% vs 24.76%; OR 2.11; 95% CI 1.40-3.19; p<0.001), and Del-allele carriage was also increased (OR 2.28; 95% CI 1.32-3.93; p=0.004). The strongest association was observed at stages I-II. For HIF1A, the T allele was more frequent in patients than in controls (12.16% vs 5.24%; OR 2.50; 95% CI 1.21-5.19; p=0.016); T-allele carriage increased the odds of belonging to the CCI group (OR 2.36; 95% CI 1.09-5.10; p=0.028), with the greatest difference observed at stage I. The investigated loci demonstrated different patterns of association with CCI. NOS3 was characterized by a stage-related gradient, ACE by a consistent association with CCI predominantly at stages I-II, and HIF1A by an increased prevalence of the T allele without a monotonic increase with disease progression. These findings support the use of these markers as components of comprehensive genetic stratification, but not as standalone diagnostic tests.
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