Human genome decoding and the development of relatively simple methods of sequencing made it possible to unveil genetic origin of various diseases, including cardiological. Canalopathies, cardiomyopathies, family forms of hyperlipidemia, pulmonary arterial hypertension — these diseases abroad are the indications for more profound genetic test. The article focuses on the indications for routine sequencing of new generation. 

Aim. The study of mononucleotide polymorphisms associations rs20455 gene KIF6, rs7439293 gene PALLD, rs2298566 gene SNX19, rs3900940 gene MYH15, rs1010 gene VAMP8, included into the Riskometer of ischemic heart disease of the Celera Corporation (USA), in sudden cardiac death.

Material and methods. To the study the group of persons included, died from sudden cardiac death, according to the WHO criteria (n=352, mean age — 53,3±8,9 y.), control group from matched by age and gender from DNA bank of HAPIEE, MONICA studies (n=381, mean age — 53,1±8,3 y.), adolescents group (n=296, mean age — 15,6±0,9 y.). DNA extracted via the phenol-chloroform extraction from myocardium of the dyed due to sudden cardiac death, and from venous blood of controls. Genotyping performed with Real-time PCR method using the Taq-Mancatheters technology (Applied Biosystems).

Results. The prevalence of alleles rs7439293 gene PALLD, rs2298566 gene SNX19, rs3900940 gene MYH15 did not statistically significantly differ among the groups. In those died suddenly older than 50 years, there was significant decrease of carriers of GG polymorphism rs20455 gene KIF6 (9,0%) comparing to the controls (17,8%) (р=0,009, OR=0,456, 95% CI 0,256-0,810). In men older 50, died suddenly, there was significant decrease of the carriers of genotype СС (8,0%) (р=0,002, OR=0,328, 95% CI 0,159-0,678) and increase of СТ genotype (49,6%) (р=0,025, OR=1,729, 95% CI 1,084-2,758) polymorphism rs1010 gene VAMP8 comparing to the controls (21,0%, 36,3%, respectively). Conclusion. Polymorphisms rs20455 gene KIF6 and rs1010 gene VAMP8 are associated with sudden cardiac death. 

Aim. The investigation of A1166/166C polymorphisms of the vascular receptor 1 type of angiotensine II gene (AGT2R1) association with the development of coronary and peripheral atherosclerosis in ethnic groups ofAdygheaRepublicinhabitants.

Material and methods. The spread of A1166/166C polymorphic variants of the gene AGT2R1 was studied via the “single nucleotide polymorphism” (SNP) — method with allele-specific primers and electrophoretic results detection (by SPF “Litech”). Gene polymorphisms AGT2R1 (rs5186) with nucleotide replacement of adenine by cytosine (А>C) in the 1166th position of gene AGT2R1 were typified in the samples of donors genomic DNA (n=143) and of those with cardiovascular diseases (n=39) at the age 23-65 y. o. from two ethnic subgroups — Adyghes and Russians. The data was processed via software SPSS Statistics 17.0.

Results. In the group of those with complicated coronary and peripheral atherosclerosis there was statistically significant increase of the prevalence of mutant1166Callele and of pathological monozygous genotype C1166C. The risk of cardiovascular diseases in the carriers of1166Callele increases 3,77 times (c2 =26,07; р=0,00003), and in the case with homozygous “mutant” CC genotype — 10,36 times (c2 =31,20; р=0,00002), that makes it to use the1166Callele and С1166С genotype AGT2R1 as genetic predictors of coronary atherosclerosis and markers of prenosological diagnostics of ischemic heart disease (c2 =42,96; р=0,0000005; OR (95%)=17,37).

Conclusion. The results of this study, together with additional instrumental investigations of cardiovascular system functioning will help to improve the precision of diagnostics of atherosclerosis and its possible complications at earlier stages, that will help to decrease disability rate and mortality in economically active citizens. 

Aim. To assess the specifics of lipid metabolism and efficacy of atorvastatin therapy in Saint-Petersburg citizens, having 2 type diabetes (DM2) — the carriers of various TaqIB gene polymorphisms, the cholesterol ethers transporting protein (CETP).

Material and methods. Totally 382 patients studied, with DM2, native for statins, and 187 almost healthy individuals. All participants underwent blood sampling with lipids test and molecular-genetic testing. Into atorvastatin group we included 164 patients with DM2 and dyslipidemia. Lipid profile parameters were assessed at baseline and in 3 months of atorvastatin therapy.

Results. In almost healthy individuals the carriage of B1B2 genotype of TaqIB polymorphism of CETP gene is associated with higher levels of triglycerides, low density lipoproteides cholesterol, very low density cholesterol and atherogenity coefficient, comparing to these values in B2B2 carriers. DM2 patients had higher triglycerides level if B1B1 comparing to B2B2. In DM2 type, triglycerides level also was higher in B1B1 than in B2B2 (p=0,044); other lipid spectrum parameters did not differ between two groups. While comparing the efficacy of atorvastatin therapy in various genotypes carriers of TaqIB polymorphism gene CETP, there were no differences of the studied parameters within treatment. While evaluating the target levels reach of lipid spectrum on the atrovastatin therapy it was found, that only B1B1 carriers reached target triglycerides level (p=0,017).

Conclusion. In DM2 patients the arrangement of genotypes and alleles of TaqIB polymorphism of CETP gene did not differ of this in healthy individuals; in carriers of different genotypes of this gene lipidogram parameters at baseline and on treatment by atorvastatin for 3 months did not differ; in B1B1 carriers the levels of triglycerides reached target values on atorvastatin.

Aim. To study relation of mononucleotide polymorphism G>A of the gene SCN10A and development of inherited pathology of the heart conduction system.

Material and methods. Totally, 260 persons investigated with primary disorders of cardiac conduction (71 patient with atrioventricular conduction disorder, 84 patients with the Right His bundle branch conduction disorder and 105 — the Left) and 263 persons without any found cardiovascular diseases (controls). All patients underwent standard cardiological investigation, retrospective analysis of previous investigation data (if available), molecular genetic test of DNA.

Results. The obtained results showed statistically significant predominance of the widespread genotype GG gene SCN10A in the control group comparing to atrioventricular disorder patients and Right His bundle branch patients.

Conclusion. Homozygous genotype GG of the gene SCN10A plays protective role against development of idiopathic atrioventricular blocks and Right His bundle branch block.

Aim. To reveal the association of hereditary specifics of inflammatory factors with the adverse risk in atrial fibrillation (AF).

Material and methods. Totally 258 patients studied (68,5±0,67 y. o.) with nonvalvular AF, recording the events as ischemic stroke, myocardial infarction, venous and arterial thromboembolism. Mean follow-up was 455±11,71 days.

Results. Factors that are independently associated with ischemic stroke development in patients not receiving anticoagulants (n=101), were the allele C of polymorphic marker rs2228145(А/С) of gene IL-6 receptor (OR 13,25 CI 1,57112,18, р=0,018), age ?75 y. o. (OR 1,1, CI 1,008-1,2, р=0,032) and EF LV (OR 0,97 CI 0,94-0,99 р=0,027), with a “thrombotic endpoint” development — DM (OR 4,3 CI 1,46-12,45 р=0,008), EF LV (OR 0,96 CI 0,94-0,98, р<0,0001) and carriage of allele C of polymorphic marker rs2228145(А/С) of receptor to IL-6 gene (OR 4,03 CI 1,0715,26, р=0,04). There was no association with adverse outcomes in genes IL-6 polymorphisms as (G(-174)C and G(-572)C), ИЛ-10 (C(-819)T), ФНО (G(-238)A, G(-308)A and ФНО? rs180630). In those receiving adequate anticoagulant therapy (n=157) there was no significant association of IL-6 receptor gene polymorphism with adverse outcomes.

Conclusion. Therefore, the carriage of allele C of polymorphic marker rs2228145(А/С) of the IL-6 receptor gene might be an independent risk marker for adverse outcome in non-valvular AF, potentially, being a selection tool for those patients not having enough high risk according to common scores. 

Aim. To assess genetic issues in the ischemic stroke development in AF and to invent an analytical programmed complex for genetic risk estimation of stroke development in a patient with AF.

Material and methods. Totally 43 patients studied with AF and stroke in anamnesis, 78 — with AF and no stroke. Controls consisted of 188 persons without cardiovascular pathology. The participants underwent ECG, EchoCG, Holter ECG-monitoring, exercise test, TELAS, thyroid gland hormones analysis. For confirmation of the ischemic nature of stroke in participating probands we performed computed tomography of the brain. All participants also underwent molecular genetic testing.

Results. According to the odds ratio, allele A polymorphism -455G>A of gene FGB increases the risk of ischemic stroke development in atrial fibrillation 1,7 times comparing to those patients without the allele; genotypes with the rare T allele in homoand heterozygous state of polymorphism 807С>Т of gene GPI? increases 2,5 times the risk of stroke in AF; presence of allele C polymorphism -5Т>С of gene GPI?? increases 1,9 times the risk of stroke comparing to its absence; presence of the rare genotypes allele C in homoand heterozygous state -5Т>С of gene GPI?? increases 2,3 times stroke risk; allele A of the polymorphism 10976G>A gene FVII decreases the risk of stroke 2,6 times. According to the results, there was a “Clinical-genetic riskometer of the ischemic stroke in AF” developed. Using this informational-analytic complex it is possible to estimate genetic risk of the stroke.

Conclusion. Therefore, the study has shown that homozygous genotype AA of the rare polymorphism 455G>A gene FGB, heterozygous genotype СТ and homozygous genotype ТТ of the rare polymorphism allele 807С>Т gene GPI?, heterozygous genotype TC and homozygous genotype CC by the rare allele polymorphism -5Т>С gene GPI?? are defined as genetic predictors of ischemic stroke development in atrial fibrillation. Allele А of polymorphism 10976G>A gene FVII is protective against ischemic stroke in patients with AF. Knowing the parameters of genetic assessment in AF, it is possible to calculate genetic risk of ischemic stroke development in AF via invented by us a “Clinical-Genetic riskometer of ischemic stroke in AF”.

Aim. To study the relation of mononucleotide polymorphism G?C (rs619203) of ROS1 gene with the risk of ischemic and hemorrhagic stroke development.

Material and methods. Totally 152 patients studied (92 males, 60 females) with acute brain circulation disorder (stroke), of those 124 with ischemic stroke, and 28 with hemorrhagic, and 475 healthy people (320 males, 155 females) of controls. All patients underwent standard neurological, clinical and instrumental investigation in SCC FMBA (Krasnoyarskcity) and molecular-genetic investigation of DNA in SRI of Therapy and Prevention Medicine of SD RAMS (Novosibirskcity). Statistics included standard algorithm of statistical procedures.

Results. The results of the study showed statistical predominance of prevalent genotype GG of ROS1 gene in ischemic stroke patients, comparing to control group.

Conclusion. Homozygous genotype of GG gene of ROS1 is a risk factor for ischemic stroke. 

Aim. Assessment of the impact of genetic polymorphism of rs1799889 gene of PAI-1 inhypofibrinolytic state development, with the inclusion of the protein product amount shifts, in patients with thrombosis of different localizations.

Material and methods. Totally 50 patients studied with thrombosis of different localization and etiology in anamnesis, and 25 controls — almost healthy donors, living on theterritoryofNovosibirskcity and the region. All patients underwent genotyping of polymorphism -675 4G/5G of the PAI-1 gene, and concentration of plasminogen activator inhibitor (PAI1) in blood plasma measurement.

Results. In the groups of patients the prevalence studied of the gene PAI-1 variants -675 4G/5G, and the level of PAI1 measured, the influence of genotypes on the level of protein assessed. Assessment of allele variant 4G and high level of PAI1 is highly informative for the estimation of thrombosis risk.

Conclusion. Genotypes 4G/4G and 5G/4G of gene PAI1, together with increased level of PAI1 are diagnostically important markers of endothelium dysfunction, hypo fibrinolysis condition and hence are predictors of clotting. 

Aim. To assess the prognostic significance of preoperation C-r.p. concentration and polymorphic site of the gene CRP (rs3093077, rs1130864, rs1205) for the development of early cardiovascular complications after direct myocardial revascularization.

Material and methods. Totally 249 patients studied with CHD, underwent coronary bypass surgery (CBG). Concentration of C-r.p. was assessed with high-sensitive immune-turbidimetric method, genotyping was done by 96-hole format via TaqMan method, before CBG.

Results. The risk of perioperational CVC increased in presence of such factors as age more than 65 y. o. (р=0,037), preoperational C-r.p. concentration higher than 5 mg/mL (р=0,026), homozygous genotype GG in promoter region of CRP gene (rs3093077) (c2 =9,08, р=0,0011) within all other conditions different (presence or absence of atrial fibrillation (AF), diabetes mellitus (DM) 2 type, duration of hypertension anamnesis (AH). In patients older than 65 y. o. the CVC risk increased almost 3 times: OR=2,8 (95% CI=1,07-7,34), and in serum concentrations of C-r.p. more than 5 mg/mL — two and a half times: OR=2,5 (95% CI=1,11-5,77). The carriage of genotype GG rs3093077 СRP increases the risk of CVC in in-hospital period of CBG for more than 2 times.

Conclusion. For prediction of CVC in CBG it is necessary to evaluate not only clinical and anamnestic characteristics of a patient, but also the level of preoperation CRP, and genetic polymorphisms of their genes. 

Aim. The development of an optimal protocol for diagnostic search for mutations with the use of the new generation sequencing technique (NGS) and evaluation of the mutation spectrum in Russian selection of the patients with Marfan syndrome.

Material and methods. Totally 32 patients included with Marfan syndrome. For 24 the direct sequencing was done by Sanger, of 24-32 exons FBN1. For 10 persons the analysis performed of coding exons and close introns regiones of the gene FBN1 with the preparation of fragmented libraries and performing of NGS on the IonTorrent platform. For 12 persons the mutations search was done with the use of automatically developed panel of Ampliseq primers for multiplex amplification of coding regions of genes that are responsible for the connective tissue development.

Results. In investigation of 24-32 exones of FBN1 we found 3 replacements (p.C921R, p.C950S and p.I1048T). In complete analysis of FBN1 gene by fragmentation check of replacements we found 4 premature stop-codons (p.Y181*, p.R516*, p.Q1811*, p.R2776*) and 3 missense variants (C739W, p.C1095S, p. C2468R). In addition, there was deletion with the shift of translation frame and occurence of stop-codon in the 9th exon (c.661delT). In one female patient there was replacement variant c.4942+4A>G, with non-defined clinical significance. With the complete analysis of FBN1 using Ampliseq there were 2 premature codons found (р. Q520*, p.K2838*) and 2 deletions with the translation frame shift (c.40_49del, c.6751del). In 6 from 12 there were missense replacements found (p.N2144S, p.A986T, p.C2390S, p.С2276W, p.C1777R and p.C2363G).

Conclusion. In the case of absense of the “hot spot” exons, invention of NGS allows for optimization the search of mutations even in such long genes as the FBN1. Medical-genetic consultation and DNA-diagnostics are the integral methods for multidisciplinary care. 

Aim. To study the role of mononucleotide polymorphisms of the matrix metalloproteases genes MMP2 and MMP9 in the development of ascending aorta aneurism (AOA).

Material and methods. Totally 287 patients included with AOA and 227 persons of control group. All patients underwent echocardiography and assessment of mononucleotide gene polymorphisms of MMP2 (rs2285053) and MMP9 (rs11697325, rs2274755, rs17577) real-time, by PCR.

Results. The association of MMP9 (rs11697325) is confirmed for the formation of AOA. AA genotype was significantly more prevalent among AOA patients (c2 =7,2; p=0,01). AA genotype carriers had higher ascending aorta diameter comparing to other persons with different variants (p=0,02). The relation is shown of the polymorphism ММР2 (rs2285053) and AOA development. Persons with CC genotype were more prevalent in the group of the aorta pathology patients (c2 =7,0; р=0,03).

Conclusion. Genetic variants ММР9 and ММР2 can be additional risk factors of ascending aorta aneurism development. Therefore the assessment of different polymorphisms of matrix metalloproteases genes is useful for the risk stratification of the patients with ascending aorta dilation. 

Aim. To evaluate the influence of gene СYP2C9 activeness via losartan test on the warfarin dosage management in earlier and long-term post-operational periods.

Material and methods. Totally 33 patients included with artificial heart valves. All patients underwent assessment of genes carriage by polymorphic marker СYP2C9 by PCR after preparing of DNA from whole blood. The activeness of СYP2C9 was assessed with losartan concentration and its metabolite (E-3174) in urine after single intake of losartan 50 mg.

Results. The level of losartan and its active metabolite (E-3174) in urine was a prognostic marker determining therapeutic dose of warfarin in cardiac surgery patients in long-term post-operation period.

Conclusion. The СYP2C9 assessment by losartan concentration and E-3174 in“losartan test” might help to determine warfarin treatment dosage in delayed postoperational period that might improve the efficiency and safety of pharmacotherapy in valve prosthesis patients. 

Aim. To reveal the association of gene polymorphism CYP2С19*2 and recurrent early stent thrombosis in coronary vessels, and paradoxal response to clopidogrel intake in patients — the inhabitants of Siberian Region — after acute coronary syndrome.

Material and methods. Totally 105 patients studied, hospitalized for stenting of coronary arteries in acute coronary syndrome, never received clopidogrel previously. The polymorphism of studied СУР2С19: *2, *3, *17 alleles, as assessment of platelet aggregation with ADP before and after clopidogrel intake, as of endpoints on safety and efficacy during 30 days (thrombotic complications, bleeding).

Results. Within the selected patients there was no any significant association of any CYP2С19*2 and/or CYP2С19*3 alleles and paradoxic laboratory reaction. There was significant association of the CYP2C19*17 gene carriage and bleedings. When comparing the groups of patients having or not having complications related to clopidogrel (thrombotic or bleedings), there was significant difference in residual platelet aggregation.

Conclusion. The results of the study might be strongly significant for the decisions making on double antiplatelet therapy and on the tactics of drugs preference. 

Aim. To research on the influence of polymorphism G681A gene CYP2C19 on efficacy of clopidogrel for planned endovascular treatment in stable CHD with second type diabetes.

Material and methods. Totally 242 patients included, with chronic CHD, underwent planned angioplastics and stenting of coronary arteries. Of those 79 had 2nd type DM. All patients received double antiplatelet therapy, including acetylsalicylic acid and clopidogrel. For efficacy evaluation, we performed the test of induced platelet aggregation with ADP in 2,5 and 5,0 mcM concentrations after total dose of clopidogrel 300 mg. Genotyping was done with allele-specific polymerase chain reaction with commercial panel “SNP-express” (SPC “LITECH”, Moscow).

Results. In our selection, the carriers of allele A differed from homozygous GG with an increased grade of platelet aggregation in ADP stimulation, concentrations 2,5 mcM and 5,0 mcM. While selecting subgroups according to diabetes existence, the mention association was found in non-diabetic group, but not in comorbidity group (CHD and DM). In GG genotype, patients having 2 type DM showed the grade of induced platelet aggregation higher than in carriers of the same genotype without DM. At the same time, allele A carriers without DM did not differ from comorbidity selection in sense of ADP induced response of platelets.

Conclusion. So, A allele carriage of G681A polymorphism of gene CYP2C19 is a risk factor for lower clopidogrel efficacy. Diabetes of second type also negatively influences the sensitivity to clopidogrel, but only in GG homozygous. 

Aim. To assess the dynamics of parameters representing rhythmical activity of the heart related to the efficacy of pharmaco-invasive revascularization in STEMI patients.

Material and methods. Totally 56 STEMI patients included that had undergone effective thrombolysis by ECG criteria of reperfusion, after that in 3-24 hours the coronary arteriography and stenting was done. Before and after PCI the telemetric ECG registration was done via “Astrocard® — Telemetry” (Meditek Ltd.,Russia). The automatic analysis of spectral parameters was done for HRV, LVP, RT.

Results. In coronary artery re-thrombosis development there is a decrease of spectrum power (TotP) (p=0,001) and increase of vagosympathic balance (L/H) (p=0,005) that points on the increase of autonomic regulation and decentralization of heart activity management. Backward dynamics is registered after successful PCI that might be related with the balance restoration between sympathetic and parasympathetic systems in effective revascularization. The tendency revealed to the increase of QRSf in re-thrombosis group and it is shown that in delayed PCI there is a growth of RMS (p=0,04), that points on the higher risk of electrical instability development.

Conclusion. The markers of developing re-thrombosis of infarction-related artery in STEMI are increase of lower frequency parameters of HRV (VLfp and LfP), decrease of total spectrum power of HRV, increase of L/H index and increase of the duration of QRSf. In delayed PCI there are higher values of RMS that represents electrical instability of myocardium for this type of patients. Telemetric ECG monitoring in STEMI patients significantly increases opportunities of the dynamic evaluation of coronary flow and electrical instability of myocardium. 

Antiplatelet therapy is one of the most importance in therapy of patients with injured coronary, cerebral and peripheral arteries. The standard of acute coronary syndrome patients treatment is double antiplatelet therapy: acetylsalicylic acid with P2Y12receptor blocker. Some distinguished genetic specifics might lead to the development of resistance to antiplatelet therapy with further thrombotic complications. Current review focuses on the pharmacogenetic specifics of patients than lead clopidogrel resistance. 

Aortic stenosis (AS) is one of the most prevalent valvular heart disorders in patients older than 65 years. Regardless the studied molecular mechanisms of development and progression of the disease, surgical treatment is recently the only successful method of help. Due to lots of comorbidities of older patients, there are obstacles to recommend surgical valve replacement, even knowing an adverse prognosis of conservative treatment. Search for new approaches to earlier assessment of adverse risk factors, speed of progression of this disease, would help to evaluate the necessity of earlier treatment and could make to slow down the progression of the disease. One of directions for this — is a search for genetic markers. This review focuses on the main known molecular mechanisms and genetic markers related to them, that are associated with AS.