## 4 Discussion
Although numerous studies suggest that inflammatory cytokines and their genetic polymorphisms might play an essential role in the pathogenesis of atherosclerosis and CA stenosis, the results remain controversial. The harmful effect of GCs on peripheral tissues metabolism is well understood and has been the subject of intensive research for many years. The connection between GC sensitivity and increased risk of CVDs has been suggested in various studies [35; 36; 37]. It has been reported that GCs may trigger or modulate atherosclerosis, i.e., through regulating lipid metabolism [4]. GCs exert effects on the vasculature by GR regulation of various signaling pathways. The well-characterized impact of GCs on the vascular system include those mediated by GR modulation of NO biosynthesis [38]. Hence, variants of the _NR3C1_ gene may affect the development and progression of CA atherosclerosis [4]. So far, several _NR3C1_ gene polymorphisms have been described to affect the variable sensitivity of GCs and changes in the metabolic parameters [4]. The increased sensitivity to GCs leads to the chronic hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which harmfully affects the vascular system. It may contribute to atherosclerosis [39]. The most widely studied polymorphisms are ER22/23 EK, BclI, GR-9/B, N363S, and Th1111. In our study, no associations between traditional risk factors for cardiovascular diseases such as plasma lipid levels, DM, HT, or BMI and Th1111, N363S, or ER22/23 EK-_NR3C1_ gene polymorphisms were found. Our results remain in accordance with other studies. [PERSON] et al. did not show any connection between 363S allele and BMI, plasma lipid levels or glucose tolerance status in the Caucasian population [17]. [PERSON] et al., in a population with familial hypercholesterolemia that presented very high risk of CVD, observed no significant association with ER22/23 EK polymorphism as well [40]. Moreover, another study conducted in the Dutch and British populations demonstrated a lack of association between _NR3C1_ gene polymorphisms and risk factors such as HT, DM, or plasma insulin and cholesterol levels [17; 41]. However, it should be noted that the traditional risk factors presented in these studies were not as strongly expressed as in the current study. Contrarwise, it has been reported that Th1111, N363S, or ER22/23 EK-_NR3C1_ gene polymorphisms are correlated with the development of CAD, atherosclerosis, and altered metabolic profile [21; 42]. In the Turkish population, the N363S polymorphism of the GR gene was associated with obesity and higher weight and BMI in patients with DM type 2 (DM2) [43]. There is evidence of linkage between Th1111 and ER22/23 EK polymorphisms with decreased GC sensitivity, lower LDL-\(c\), and lower fasting insulin levels [44]. Moreover, [PERSON] et al. proved that the ER22/23 EK polymorphism (heterozygous for the 22/23 EK) is associated with a better metabolic profile (lower LDL-\(c\), insulin, and fasting glucose levels), leading to lowering the risk of DM2 and CVD. The effect in this case may be due to the reduced GC sensitivity [19]. In another large study, the BclI polymorphism of the GR gene relates to significantly greater total body fat, contributing to increased insulin resistance. The authors support the hypothesis that even slight genetic changes in the GR gene, which are known to alter the sensitivity of GCs, may have subtle metabolic implications [45]. The discrepancy between results of studies on the aforementioned polymorphisms' influence on metabolic findings might be explained by the age differences or type 1 error that is a false-positive finding. However, it seems that these subtle changes may be mitigated when heavily influenced by environmental factors and dependent on the population. In our previous study, an association between homozygous Th1111 and multiessel CAD was found for the first time to the best of our knowledge [46].