Genotypic stratification of risk of acute cerebral circulation disorder

Aim. To study the association of rs662799 gene APOA5 with the development of Acute Cerebrovascular Event in patients with cardiovascular diseases (CVD) and their risk factors.

Material and methods. 260 Acute Cerebrovascular Event patients (main group) and 272 control group patients were examined. The age range of patients of the main group is defined from 32 to 69 years [57.0; 51.0–62.0], individuals in the control group were 37 to 68 years old [55.0; 51.0–62.0]. The distribution by sex of the main group was as follows: 157 men (age [56.5; 51.0–62.0]) and 103 women (age [57.0; 51.0–62.0]). The sex and age composition of the control group is comparable to those of the main group: 170 men (age [55.0; 51.0–62.0]) and 102 women (age [55.0; 51.0–62.0]). The main group's research methods were as follows: clinical examination, computed brain tomography, electrocardiography, echocardioscopy, ultrasound duplex scanning extracranial brachiocephalic arteries, daily monitoring of blood pressure and heart rate, blood coagulation system analysis. The control group of our study is a population sample of residents of Novosibirsk, who were examined according to the standard of the international HAPIEE project. Examination of individuals in the control group included: questionnaire (socio-economic living conditions, chronic diseases, level of physical activity, mental health), anthropometry (height, weight, waist volume, hips), survey on smoking, alcohol consumption (frequency and typical dose), blood pressure measurement, lipid profile assessment, stress angina detection (Rose) survey, resting electrocardiogram in 12 leads. All patients of the main and control groups underwent molecular genetic analysis of venous blood. Statistical processing of the material was carried out using the set of applications Statistica for Windows 7.0, Excel and SPSS 22.

Results. 199 patients (123 men and 76 women) of the main group had ischemic stroke, 51 patients (28 men and 23 women) were diagnosed with hemorrhagic stroke, 10 patients (6 men and 4 women) showed a mixed type of Acute Cerebrovascular Event. Of the 260 patients, 19 (13 men and 6 women) had repeated Acute Cerebrovascular Event. None of the patients examined had clinical, anamnestic and instrumental evidence suggesting the presence of CVD. The most common CVD preceding Acute Cerebrovascular Event was arterial hypertension – AH (249 people, 153 of them men and 96 women). Heart rhythm disorders by type of paroxysmal supraventricular tachycardia, including atrial fibrillation, were detected in 31 patients (20 men and 11 women). Among the risk factors for Acute Cerebrovascular Event in the patient group surveyed, dyslipidemia was observed (159 patients, 95 men and 64 women), atherosclerosis of brachiocephalic artery (160 patients, 94 men and 66 women), disorders of the hemostasis system towards hypercoagulation (90 patients, 53 of them men and 37 women), 28 patients (19 men and 9 women) had an aggravated hereditary history according to Acute Cerebrovascular Event. In the control group, AH was diagnosed in 177 patients, of which 98 were men and 79 were women. Other CVD and their risk factors were absent in the control group at the time of the survey. The statistically significant prevalence of rare GG genotype and G allele wearability among Acute Cerebrovascular Event patients compared to healthy patients was verified (4.7% of patients in the main group versus 0.4% in the control group; p=0.001). In addition, a statistically significant decrease in the number of carriers of the advanced AA genotype and allele A compared to the control group (61.8% in the main group versus 61.5% in the control group, p=0.000) was determined in patients with Acute Cerebrovascular Event. In the subgroup of men with Acute Cerebrovascular Event, the common AA genotype was statistically significantly less common (59.9%) than among men in the control groups (82.9%; p=0.000; odds ratio – OR 3.26, 95% confidence interval – CI 1.95–5.46). The AG genotype was significantly predominant in the subgroup of men with Acute Cerebrovascular Event (33.6%), than in the control group of men (17.1%; p=0.001). A rare GG genotype was detected in 6.6% of men with Acute Cerebrovascular Event, and among men in the control group, this genotype was absent (p=0.001). In the subgroup of women with Acute Cerebrovascular Event, the AG genotype was statistically more common (33.3%) than among women in the control group (14.7%; p=0.002). The AA genotype, in contrast, significantly predominated in the control subgroup of women (84.3%) compared to women with Acute Cerebrovascular Event (64.7%; p=0.001; OR 2.93, 95% CI 1.49–5.75). No statistically significant differences were obtained with respect to the GG genotype. Thus, in the subgroup of women with Acute Cerebrovascular Event, the GG genotype of ONV rs662799 (A>G) occurred in 2.0% of patients, in the control subgroup of women – in 1.0% (p=0.56). We analyzed the frequencies of the genotypes and alleles rs662799 (A>G) of the APOA5 gene among patients with AH undergoing Acute Cerebrovascular Event and individuals in the control group without AH and Acute Cerebrovascular Event. The frequency of the AA genotype in the subgroup of AH patients undergoing Acute Cerebrovascular Event was 62.1%, in the control group – 78.9% (p=0.003; OR 2.28, 95% CI 2.13–5.98). The AG genotype was detected in 33.7% of patients with AH and Acute Cerebrovascular Event and in 21.1% of individuals in the control group (p=0.022). The GG genotype in the subgroup of patients with AH and Acute Cerebrovascular Event occurred at a frequency of 4.1%, was absent in the control group (p=0.045). In the subgroup of patients with dyslipidemia and Acute Cerebrovascular Event, a statistically significant predominance of the number of AG genotype carriers (p=0.008) and a decrease in the number of AA genotype carriers (p=0.002; OR 2.11, 95% CI 1.32–3.38) compared to control. With respect to the GG genotype, no statistically significant differences were obtained as in the subgroup of patients with brachiocephalic artery atherosclerosis (p=0.05). The rare G allele was statistically significantly more common among patients with dyslipidemia and Acute Cerebrovascular Event than among the control group (p=0.001; OR 2.01, 95% CI 1.35–3.16). In a subset of patients with impairment in the hemostasis system who underwent Acute Cerebrovascular Event, similar results were obtained. So, among patients with hypercoagulation, the frequency of carrying the AA genotype was 63.8%, the frequency of the AG genotype was 33.0%, and the frequency of the GG genotype was 2.3%. In a subgroup of patients with impaired hemostasis and Acute Cerebrovascular Event, a statistically significant predominance of the number of AH genotype carriers (p=0.001) and a decrease in the number of AA genotype carriers (p=0.000; OR 2.74, 95% CI 1.59–4.72) compared to control. No statistically significant differences were obtained with respect to the GG genotype (p=0.09). The wearing of the rare G allele was statistically significantly more common among patients with hypercoagulation and Acute Cerebrovascular Event than among the control group (p=0.000; OR 2.50, 95% CI 1.54–4.05).

Conclusion. The results of our study suggest the need for further investigation of this polymorphic variant in order to study the possible mechanisms of its influence on the development of CVD and cerebrovascular pathology. We may suggest that the wearing of the AG genotype and the G allele rs662799 (A>G) increase the risk of Acute Cerebrovascular Event in patients regardless of previous CVD and risk factors, including those with AH, supra-ventricular tachyarrhythmias, brachiocephalic artery atherosclerosis, impaired lipid metabolism and hemostasis systems.