RISK OF ENDOTHELIAL DYSFUNCTION AND CAROTID ARTERIES INTIMA MEDIA THICKNESS DEPENDING ON GUANINE NUCLEOTIDE-BINDING PROTEIN BETA-3 AND ENDOTHELIAL NITRIC OXIDE SYNTHASE GENES’ PO

Abstract

Objective: Endothelial dysfunction (ED) is an initial step to vascular insufficiency, atherosclerosis. The study is aimed to clarify the risk of ED and carotid arteries (CA) intima media thickness (IMT) changes depending on guanine-nucleotide-binding-protein-beta-3 (GNB3, rs5443) and endothelial-nitric-oxide-synthase (NOS3, rs2070744) genes’ polymorphisms in essential arterial hypertension (EAH). Design and method: One-hundred EAH patients with target-organ damage, moderate/high/very high cardiovascular risk were involved in the case-control study: 79.0% females, 21.0% males, mean age 59.87±8.02; disease duration 6-25 years. Control - 48 practically healthy persons . GNB3 (rs5443) and NOS3 (rs2070744) genes’ polymorphisms examined in Real-Time-PCR. Soluble-Vascular-Cell-Adhesion-Molecule (sVCAM-1), total NO-metabolites (NO2-/NO3-), transcriptional activity of NOS3 gene, Endothelium-Dependent-Flow-Mediated-Dilation of the Brachial Artery (FMD BA) and carotid IMT were studied. Results: Severe EAH course (SBP/DBP>160>100 mmHg) is associated with the structural changes of the CA (IMT>0.9 mm) increasing the likelihood more than 3.5 times [OR 95%CI:1.28-10.23; p = 0.012], atherosclerotic plaques on the CA – 4 and 3.5 times as much [OR 95%CI:1.18-13.59; p = 0.018 and 1.23-10.71; p = 0.014], and decreased NOS3 gene transcriptional activity by the mRNA level (<0.5 U) – threefold [OR 95%CI: 1.0-9.66; p = 0.042]). Moderate/severe ED enhance the risk of severe EAH 3-5.5 times [OR 95%CI:1.13-9.34; p = 0.025 and 1.96-14.45; p<0.001]. C-allele of NOS3 (rs2070744) gene elevates the risk of atherosclerotic lesion in CA 3.5 times [OR 95%CI:1.24-11.20; p = 0.019 and 1.22-10.18; p = 0.018], ED – by decrease of total NO metabolites (<25 μmol/l) and sVCAM-1 growth (>1050 ng/ml) almost 12 and 4 times [OR 95%CI: 1.23-112.7; p = 0.023 and 1.24-11.20; p = 0.019]. C-allele of NOS3 gene heighten the probability of low NOS3 gene expression by mRNA level (<0.5 U) 69 times [OR95%CI:17,72-520,0; p<0,001]. Minor T-allele (rs5443) increases the risk of CA changes by IMT (>0,9 mm) threefold [OR 95%CI:1.09-7.74; p = 0.027], CA atherosclerotic plaques – almost 10 and 5 times [OR 95%CI:2.55-38.0; p<0.001 and 1.61-13.27; p = 0.003]. T-allele of GNB3 gene enhances the probability of high sVCAM-1 (>1050 ng/ml) threefold [OR 95%CI:1.06-9.59; p = 0.032]. Conclusions: C-allele of NOS3 (rs2070744) gene contributes more to ED risk elevation. T-allele of GNB3 (rs5443) gene increases the risk of the carotid arteries structural changes.