ANGPTL3, ANGPTL4, APOA5, APOB, APOC2, APOC3, LDLR, PCSK9, LPL gene variants and coronary artery disease risk

Aim. To study the contribution of rare and low-frequency variants of ANGPTL3, ANGPTL4, APOA5, APOB, APOC2, APOC3, LDLR, PCSK9, LPL genes in assessing the risk of coronary artery disease (CAD) in a cohort of Russian patients with various cardiovascular risks.Material and methods. The study was conducted on a sample of participants in cohort and epidemiological studies (n=2405). Targeted enrichment of coding sequences and exon-intron regions of nine genes (ANGPTL3, ANGPTL4, APOA5, APOB, APOC2, APOC3, LDLR, PCSK9, LPL) was performed. Genetic diagnostics was carried out by next generation sequencing.Results. CAD was confirmed in 267 patients (11%). After genetic diagnosis, all patients were divided into three following groups: individuals with previously described genetic variants associated with elevated levels of low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TGs); individuals with genetic variants associated with reduced levels of LDL-C and/or TGs; individuals without genetic variants associated with LDL-C and/or TG levels, or with two or more variants with opposite effects on LDL-C and/or TG levels. Kaplan-Meier method revealed that the groups significantly differ in cumulative risk of CAD (p<0,001 for the log-rank test), the maximum risk was in group 1, and the minimum risk in group 2. When conducting the Cox regression, we found that in persons from group 1, the hazard ratio (HR) for CAD is 2,63 times higher (HR =2,63, 95% confidence interval (CI), 1,6-4,34; p><0,001), and in persons from group 2 lower by 1,88 times (HR =0,53, 95% CI, 0,3-0,98; p=0,042) compared with persons from group 3, adjusted for other CAD risk factors: sex, age, smoking, LDL-C and hypertension. Conclusion. Genetic testing in young patients makes it possible to identify individuals with an increased genetic risk of CAD and to focus preventive and therapeutic measures primarily for this category of patients. Keywords: coronary artery disease, cardiovascular diseases, low-density lipoprotein cholesterol, genetic testing. Relationships and Activities: none. 1National Medical Research Center for Therapy and Preventive Medicine, Moscow; 2Pirogov Russian National Research Medical University, Moscow; 3E. I. Chazov National Medical Research Center of Cardiology, Moscow; 4Lomonosov Moscow State University, Moscow; 5Moscow Institute of Physics and Technology, Dolgoprudny, Russia.><0,001 for the log-rank test), the maximum risk was in group 1, and the minimum risk in group 2. When conducting the Cox regression, we found that in persons from group 1, the hazard ratio (HR) for CAD is 2,63 times higher (HR =2,63, 95% confidence interval (CI), 1,6-4,34; p<0,001), and in persons from group 2 lower by 1,88 times (HR =0,53, 95% CI, 0,3-0,98; p=0,042) compared with persons from group 3, adjusted for other CAD risk factors: sex, age, smoking, LDL-C and hypertension.Conclusion. Genetic testing in young patients makes it possible to identify individuals with an increased genetic risk of CAD and to focus preventive and therapeutic measures primarily for this category of patients

The role of peptide hormones (adiponectin, leptin, insulin) in the pathogenesis of atherosclerosis

Currently, cardiovascular diseases (CVD) remain the main problem in the world and in Russia in particular. The study of the causes and progression of atherosclerosis is a critical moment in the fight against CVD. Adipose tissue and processes that occur in it attracts attention in recent years. The important role of adipose tissue as an endocrine and immune organ is revealed as well as its participation in the development of the inflammatory process. This leads to the development of initial manifestations of atherosclerosis a precursor of many metabolic disorders and CVD. Particular attention causes adipokines regulatory peptide hormones in the adipose tissue, as well as insulin, due to its close relationship with the adipose tissue and especially with adiponectin and leptin. Recent data on the role of adiponectin, leptin and insulin in the pathogenesis of atherosclerosis in order to identify new potential targets among peptide hormones for the treatment of atherosclerosis are presented. </p

THE EFFECTIVENESS OF OUTPATIENT AND HOSPITAL LIPID-LOWERING THERAPY IN PATIENTS WITH HIGH AND VERY HIGH CARDIOVASCULAR RISK DURING 2011-2015

Aim. To estimate the effectiveness of lipid-lowering therapy (LLT) at outpatient and hospital treatment stages in patients at high and very high cardiovascular risk during 2011-2015.Material and methods. In a cross-sectional epidemiological study we analyzed LLT in hospital patients for the period April-May 2011, 2012 and 2015. All data were obtained from randomly selected case-records of patients (n=548; 20% of all hospital patients over the study period). Risk categories of patients as well as target levels of low density lipoprotein (LDL) cholesterol were determined according to the current clinical guidelines for the respective year. Outpatient LLT was administered in local out-patient clinics and hospital one – in the clinic of State Research Centre for Preventive Medicine.Results. The most commonly prescribed group of lipid-lowering drugs was statins, while combined treatment or monotherapy with other lipid-lowering agents were used only in rare cases. From 2011 to 2015 the proportion of patients taking statins before admission increased from 20% to 49.8% (from 23.1% up to 29.6% of patients at high cardiovascular risk and from 28% up to 68.5% of patients at very high cardiovascular risk, respectively). During hospitalization the proportion of individuals receiving statins increased from 49.8% to 72.9%, from 29.6% to 74% and from 68.5% to 95.3% in general group, among patients at high and very high cardiovascular risk, respectively. In 2015 LDL cholesterol target levels were achieved in 14.8% and 7.1% of patients at high and very high risk, respectively. In-hospital rate of simvastatin administration reduced from 33.6% to 0.5%, whereas prescription of atorvastatin and rosuvastatin increased from 31.4% to 64.5% and from 3.6% to 9.9%, respectively. Average dose of statins (in conversion to atorvastatin) increased from 10 mg to 20 mg in high-risk patients and from 10 mg to 40 mg – in very high risk group.Conclusion. Positive trend in frequency of LLT prescription was demonstrated in patients at high and very high cardiovascular risk during 2011-2015. Nevertheless, significant number of patients in out-patient clinics still remains under non-optimal treatment

ASSOCIATION OF THE VARIANTS OF NUCLEOTIDE SEQUENCE OF THE GENE ADIPOQ WITH PLASMATIC LEVEL OF ADIPONECTIN, THE GRADE OF CORONARY ATHEROSCLEROSIS SEVERITY AND RATE OF CARDIOVASCULAR DISEASES

Aim. The search for genetic markers of ADIPOQ, associated with the level of adiponectin and development of coronary atherosclerosis.Material and methods. To the study, patients included, who had undergone diagnostic coronary arteriography in 2011-2012 in the NMRCPM with assessment of the severity of coronary atherosclerosis. The level of adiponectin was measured in plasma with the test-system based on the immune enzyme analysis. Genetic variants rs17300539, rs182052 and rs266729 gene ADIPOQ were measured realtime (Applied Biosystems, 7500 Real Time PCR System). Alleles of the studied variants were summarized by a unified score of genetic risk (SGR).Results. To the study, 447 patients included, of those 319 males (70,7%). Median of age was 61 [55-69] y.o. All patients were selected to 2 groups by SGR (≤2 and &gt;2, respectively). Groups differed by the level of adiponectin 7,64 vs 8,29 mcg/mL (р=0,01), total cholesterol 4,60 vs 5,00 mM/L (p=0,03), cholesterol of low density lipoproteides 2,8 vs 3,09 mM/L (p=0,03), and the rate of unstable angina development 2,15% vs 6,8% (р=0,02) and type 2 diabetes 11,8% vs 21,1% (р=0,01), respectively. There was no difference in the groups by Syntax and Gensini score.Conclusion. Genetic score based on the three variants of ADIPOQ does determine the plasmatic level of adiponectin and risk of unstable angina and diabetes, but not the grade of coronary atherosclerosis

CONTRIBUTION OF GENETIC MARKERS AND PRODUCTION FACTORS IN THE DEVELOPMENT OF ARTERIAL HYPERTENSION IN MEN IN AN ORGANIzED WORKERS COHORT OF MACHINE-BUILDING PLANT

Aim. The aim of the present study was to evaluate  the contribution of 11 singlenucleotide  polymorphisms  (SNPs) and  production  factors  to the development  of arterial  hypertension  (AH) in men  in an  organized  workers  cohort  of machinebuilding plant.Material  and  methods. The study  included  men  aged  20-65  years  who had contact  with production  factors  (PF) during  at  least  50%  of the  working time. Genotyping of 11 SNPs was performed using TaqMan  real-time PCR. Data statistical analysis was carried out using statistica 8.0 and SAS, v. 6.12 software.Results. 583 men were included in the study, 205 of those had AH, 378 did not. The groups differed significantly in age, presence of higher education,  the frequency of combination of two or more components of the metabolic syndrome and the severity of its individual components: weight, waist circumference, level of total cholesterol, triglycerides, low density lipoprotein cholesterol, glucose. As a result of genotyping, it was found that the frequency distribution of genotypes between groups with and without AH significantly differed  for two SNPs  — rs2932538  (p=0,0414)  in the MOV10 gene   and  rs4373814   (p=0,0344)   in  the  CACNB2 gene.   Combining information on several SNPs in the genetic  risk SCORE  (GRS) it was shown that the mean value of the total GRS in the groups  with and without AH was 0,0382±0,119 and  0,0195±0,111, correspondingly. The differences   between  the  groups  were significant (p=0,032). Based on the results of multivariate analysis, it was shown that the independent factors associated with the presence of AH in participants were age (OR=1,057 (1,037-1,076), p=0,0001), the presence of two or more components of the metabolic syndrome  (OR=2,519 (1,621-3,914), p=0,0001)  and the total GRS, consisting  of 11 SNP (OR=1,479 (1,02-2,143), p=0,04).  PF adjusting for the age were not associated with the presence of AH.Conclusion. In men, who had direct contact with PF at machine-building plant, GRS consisting of 11 SNPs was an independent factor influencing the presence of AH. The results  show the necessity  of practical  USAge  of genetic  tests  together  with traditional risk factors  assessment with the aim for increase of AH risk estimation precision and for carrying out individual prevention