[A rare variant in the sortilin-related receptor 1 gene is associated with declined cognitive functions in the elderly]. / Redkii variant v gene sortilinpodobnogo retseptora 1: sviaz' s pokazateliami kognitivnykh funktsii u pozhilykh.

AIM: To estimate the association of rs11218343 in the sortilin-related receptor 1 (SORL1) gene with cognitive performance in the elderly and with Alzheimer's disease (AD) in the Russian population. MATERIAL AND METHODS: A sample included 586 elderly people (mean age 70.9±5.7 years) without AD diagnosis and 100 patients with late-onset AD (mean age 72.1±7.8 years) from the Tomsk population. SORL1 rs11218343 was genotyped using PCR and MALDI-TOF mass spectrometry. Cognitive performance in the sample of elderly without AD was assessed by Montreal Cognitive Assessment (MoCA) test. RESULTS: Allele frequencies of the SORL1 polymorphism were not significantly different between the elderly without AD and AD patients. However mean MoCA score in the carriers of the rare allele (19.00±6.61) was significantly lower than in homozygotes for the common variant (22.25±3.89) (F=4.97; p=0.026). CONCLUSION: The rare variant in SORL1 gene previously associated with AD in genome-wide association studies and meta-analyses was associated with lower total МоСА scores in the random sample of elderly people that suggests declined cognitive functions in the carriers of this variant in elderly.

[Genes for Fibrogenesis in the Determination of Susceptibility to Myocardial Infarction].

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19-2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05-2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06-4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07-2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03-2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02-2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

[The Study of Associations of Polymorphisms of Candidate Gene of Cardiovascular Diseases With Reduction of Glomerular Filtration Rate in Patients With ST Segment Elevation Myocardial Infarction].

AIM: to study associations of polymorphic genetic variants of inflammatory response, endothelial function, lipid metabolism, and blood coagulation with impaired renal function in patients with ST elevation myocardial infarction (STEMI). MATERIAL AND METHODS: We enrolled in the study 171 patients admitted to the Kemerovo Cardiology Dispensary within 24 hours after onset of STEMI. All patients underwent genotype identification of 25 polymorphic variants of 18 major candidate genes for cardiovascular disease. Genotyping was performed with DNA chip SINKAR-1 (Institute of Medical Genetics and LLC "Genomic Diagnosis"). Glomerular filtration rate (GFR) was estimated using serum creatinine level measured at admission. RESULTS: Comparison of allelic and genotype frequencies of the studied polymorphisms revealed that angiotensin-converting enzyme (ACE) gene rs4291 was associated with decreased GFR: odds ratio (OR) for carriers of rare TT genotype was 2.31 [1.01-5.25], =0.043. Analysis of genotype combinations of ACE rs4343 polymorphism and hepatic lipase gene (LIPC) rs1800588 showed that AA genotype of rs4343 polymorphism in combination with CC genotype of rs1800588 polymorphism was associated with lowest risk of renal dysfunction, whereas GG and AG genotypes of ACE rs4343 in combination with TT and CT genotypes of LIPC rs1800588.

[ Mitochondrial DNA polymorphism association with myocardial infarction and prognostic signs for atherosclerosis].

We have performed association analysis for mtDNA most common variants and haplogroups with myocardial infarction and some prognostic characteristics in patients. Comparison of patients (N=406) and controls (N=183) has shown higher frequency of HV0 haplogroup in patients (6.9% vs. 2.2%; p=0.033). Patients with early infarction (before age 55), comparing to patiens older than 55 and the first infarction, had higher frequency of 16189C variant (24.1 vs. 12.5%; p=0.008); also, haplogroup U2e was registered only in the subgroup with early infarction (4.4%; p=0.004). On the other side, haplogroup U5 was less frequent in the patients with early infarction (5.1% vs. 15.4%; p=0.002). The patients with recurring cardiovascular incidents during one year follow-up had higher frequency of haplogroup H1 (20% versus 4.5% in the patients without complications, p=0.002) and variant 16189C (30% versus 13.5%; p=0.018). Haplogroup U5 was more frequent in the group of patients with left ventricular ejection fraction less than 40%: 17.1% comparing to 8.2% in the group with ejection fraction>40%; p=0.034. The results suggest that mtDNA polymorphism contributes to coronary atherosclerosis. The associations could be explained by the polymorphism effect on oxidative phosphorylation and reactive oxygen production in mitochondria.

[Characteristic of the Genetic Variability of Four Polymorphic Variants (rs2069705, rs17880053, rs11126176, and rs804271) in Representative Samples of Indigenous and Alien Populations of Siberia].

The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the alien Russian population. All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.

Genomic Study of Cardiovascular Continuum Comorbidity.

Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.

[THE RELATIONSHIP BETWEEN POLYMORPHISMS OF G-1082A AND C-592A LOCI OF THE IL10 GENE AND MULTIFOCAL ATHEROSCLEROSIS IN PATIENTS WITH ACUTE CORONARY SYNDROME WITHOUT SEGMENT ST ELEVATION].

AIM: To study the relationship between polymorphous G-1082A (rs3024491) and C-592A (rs1800872) variants of the IL10 gene and multifocal atherosclerosis (MFA) in patients with acute coronary syndrome (ACS) without segment ST elevation. MATERIALS AND METHODS: Genotypes of polymorphous G-1082A (rs3024491) and C-592A (rs1800872) variants of the IL10 gene were determined in 178 patients. Interleukin-10 (IL-10) level was measured in 93 of them using solid-phase immunoenzymatic assay. All patients underwent visualization of coronary and peripheral arteries. RESULTS: C-592A (rs1800872) polymorphism ofthe IL10 gene tended to be associated with type 2 diabetes mellitus in the carriers of the CC (gg) genotype and with elevated concentration of high density lipoproteins and reduced intima-media thickness in the carriers of the AA (tt) genotype. The frequency of MFA in the carriers of different genotypes of rs1800872 polymorphism was practically identical while the CA(gt) genotype was associated with more severe manifestations of atherosclerosis and AA(tt) genotype with lower frequency of peripheral artery stenosis. Patients with AA(tt) genotype of rs1800872 polymorphism had higher IL-10 levels. No relationship between rs3024491 polymorphism of IL10 gene, blood IL-10 level, clinical risk factors, and MFA was documented. CONCLUSION: CC (gg) genotype of C-592A (rs1800872) polymorphism of the IL10 gene in patients with acute coronary syndrome (ACS) without segment ST elevation was associated with type 2 diabetes mellitus while the AA(tt) genotype of the same polymorphism with elevated concentration of high density lipoproteins, reduced intima-media thickness, low frequency of peripheral artery stenosis, and increased IL-10 production. CA (gt) genotype of rs1800872 polymorphism of the IL10 gene was associated with MFA.

[TOMM40 gene polymorphism association with lipid profile].

The distribution of the allele and genotype frequency for the TOMM40 gene polymorphic variants rs741780, rs157580, rs1160985, rs2075650, and rs8106922 was analyzed in a sampling of ethnic Russians from the city of Kemerovo. The study of the structure of linkage disequilibrium in terms of five studied polymorphic variants showed the presence ofa haplotype block 2 Kb in length, which includes three polymorphic variants, i.e., rs741780, rs1160985, and rs8106922. The differences in the frequencies of alleles and genotypes in terms of the polymorphic rs2075650 and rs157580 variants between ethnic Russians from the city of Kemerovo and other European populations were detected. It was discovered that polymorphic variants of TOMM40 rs741780, rs1160985, and rs8106922 are associated with serum triglyceride concentrations. In men, the polymorphic variant rs2075650 is associated with low-density lipoprotein cholesterol levels. In women, the polymorphic variant rs741780 is associated with diastolic blood pressure levels.

[Expression profile of calcineurin pathway genes in myocardium tissues in relation to ischemic heart remodeling in humans].

Calcineurin pathway plays the critical role in the cardiac remodeling of various origin, development of chambers dilatation and progression of heart failure. Components of calcineurin pathway are involved in myocardium hypertrophy regulation, angiogenesis and apoptosis. Results of quantitative expression profiling study of main calcineurin pathway genes PPP3CA, PPP3R1, PPP3CB, GATA4 and NFATC4 in myocardium of right atrium auricle of patients with a coronary heart disease, exposed to various types of surgical treatments depending on weight of a clinical finding (surgical reconstruction of the geometry of left ventricle (LV) (postinfarction aneurysm) or coronary artery bypass grafting in case of unaltered morphology of LV) are presented. In patients with sizable postinfarction LV dilatation (n = 21) expression level of calcineurin catalytic subunit genes PPP3CA and PPP3CB was 1.3 and 1.6 times lower (p = 0.018 and 0.023, accordingly) compared to patients with unaltered shape of the heart (n = 34). Expression level of PPP3R1 gene encoding calcineurin regulatory subunit B and GATA4 and NFATC4 genes for transcription factors did not differ in studied subgroups of patients. Thus, lower expression of PPP3CA and PPP3CB genes in atrium myocardium can be related to expressed postinfarction LV remodeling. Further studies of relation quantitative expression profiling of calcineurin pathway genes with the level of damage of myocardium is essential what may have important outcome for the prevention of adverse events of cardiosurgical treatments in patients with postinfarction remodeling.

[Prevalence of alleles of polymorphic variants Leu33Pro and Leu66Arg gene ITGB3 among inhabitants of Siberia].

The frequency of the polymorphic variant T196C (Leu33Pro, rs5918) of ITGB3 gene was studied in several groups of inhabitants of Siberia, including pregnant women with reproductive disorders (n = 186), patients with acute coronary syndrome (n = 330), and population control (n = 858). The frequency of the rare PLA2 allele among residents of Tomsk and Kemerovo was 14.7 and 15.0% respectively. There were no differences in the allele and genotype frequencies of polymorphic variant between patients with acute coronary syndrome and the control group (p = 0.925, p = 0.622). The highest frequency of abnormal PLA2 allele (22.1%) and the PLA2/PLA2 genotype (8.8%) was observed among women, who had miscarried, which was significantly different from the frequency of this allele and genotype in the control group (14.7%, p = 0.017; 2.1%, p = 0.0009). Sequencing showed that all samples with the nonspecific band had the polymorphic rs5918 variant and rs36080296 mutations (T216G, Leu66Arg). The frequency of the rs36080296 mutation among the residents of Siberia was 0.51%. Among the women with reproductive disorders, the frequency of rs36080296 was 2.7%, while in the group who suffered from miscarriages, it was 4.4%; this was different from the frequency in the control group (0.08%, p = 0.2 x 10(-6)). The accumulation of mutations was also observed among men with acute coronary syndrome (0.6%), but the differences from the control group (0%) had no statistical significance.

[The role of genetic factors in the prediction of myocardial infarction complications within one year follow up].

A sample of 165 patients with myocardial infarction (MI) with ST segment elevation has been studied to construct a prediction model for one-year period complications (recurrent nonfatal IM or cardiac death). Polymorphic genetic markers (n = 32) with confirmed role in pathogenesis of cardiovascular disease were analyzed. The best model to stratify patients by risk of post-IM complications included variants rs4291 (A-240T) in the ACE gene, rs6025 (G1691A, Leiden mutation) in the F5, and rs5918 (Leu59Pro) in the IGTB3. C statistics for the genetic model was 0.75 (0.64; 0.86), p = 0.001, which is comparable with characteristics of the GRACE scale for the same patients' population: 0.73 (0.61; 0.85). Thereby, analysis of a limited number of genetic markers was sufficient to create risk prediction model for post-MI complications with comparable effectiveness to the model, which is currently in use in clinical practice. To confirm the clinical validity, the predictive model obtained in the study should be evaluated in independent samples of MI patients. Association analysis of individual genetic markers with patients' outcomes has revealed that T allele carrier status (AT and TT genotypes) rs4291 of the ACE and CG genotype rs328 of the LPL gene are risk factors for cardiac death during one year after MI; Leiden mutation (rs6025) of the F5 gene is related to the higher risk of recurrent non-fatal MI or death during one year; CC genotype of the rs10811661, located in 9p21 locus has a protective effect against recurrent MI or death within one year after acute event.

[The glutathione peroxidase 1 (GPX1) single nucleotide polymorphism pro198Leu: association with life span and coronary artery disease].

In this study we genotyped polymorphism in GPX1 Pro198Leu (C > T) rs 1050450 in four groups: patients with coronary artery disease, long-livers - above 90 years, early died peoples (before 55 years) from cardiovascular diseases and Russian population as control group. We have found significant higher allele T frequency in men with coronary artery disease -34.84% (Chi2 = 5.228, p = 0.022; OR = 1.46) and in early died men from cardiovascular diseases--38.16% (Chi2 = 6.461, p = 0.011; OR = 1.69) compared with control men--26.8%. Moreover, significantly higher genotype TT frequency has been shown in patients with coronary artery disease and myocardial infarction before age 50--19.44% in comparison with control group--7.28% (Chi2 = 9.55, p = 0.002). The TT frequency in long-livers (4.39%) was the lowest and significantly different from coronary artery disease group--12.79% (Chi2 = 8.07, p = 0.0045) and from coronary artery disease subgroup with myocardial infarction before 50--19.44% (Chi2 = 14.49, p = 0.0001). Thus our results indicate that allele T (Leu) of GPX1 Pro198Leu (C > T) polymorphism is unfavorable for successful ageing. It predisposes to coronary heart disease, earlier myocardial infarction (before age 50) and earlier death (before age 55).

[ACE and AGTR1 genes polymorphisms in left ventricular hypertrophy pathogenesis in humans]. / Polimorfizm genov ACE i AGTR1 v patogeneze gipertorofii levogo zheludochka serdtsa u cheloveka.

The role of A2350G polymorphism in exon 17 of the ACE gene and A1166C - in 3'-UTR of the AGTR1 in the pathogenesis of left ventricular hypertrophy was studied in patients with essential hypertension (EH) and arterial hypertension combined with diabetes mellitus type 2 (AH + DM2). Patients with EH and AH + DM2 did not differ from the control sample of healthy individuals by allele or genotype frequencies. However, an association of both polymorphisms with LVH was detected in EH patients. The frequency of 1166C allele was higher in patients with LVH (33.6% vs 20.7% without LVH). A1166C polymorphism determined the magnitude of left ventricular mass index (LVMI) in EH patients as well (p = 0.007). 2350G allele frequency of the ACE gene was in 1.5, and GG genotype--in 3.5-fold higher in EH patients with LVH, as compared without LVH. LVMI was significantly higher in patients with GG genotype as compared with heterozygotes and AA homozygotes (p = 0.002). Thus the presence of 1166C allele of AGTR1 and 2350G allele of ACE can be considered as predisposing factors for LVH development in EH. In contrast, association of studied polymorphisms with presence or LVH degree was not detected in patients with arterial hypertension combined with DM2. This may indicate another structure of genetic component of predisposition to LVH in different causes.

[Polymorphic markers of GNB3 (C825T), AGTR1 (A1166C) and ACE (A2350G and I/D) genes in patients with arterial hypertension combined with diabetes mellitus type 2]. / Polimorfnye markery genov GNB3(C825T), AGTR1(A1166C), and ACE(A2350G and I/D) u bol'nykh arterial'noi gipertoniei, sochetaiushcheisia s sakharnym diabetom tipa 2.

AIM: To elicit correlations of polymorphic markers of GNB3 (C825T), AGTR1 (A1166C), ACE (A2350G and I/D) genes with arterial pressure, left ventricular hypertrophy (LVH) and blood concentrations of proinflammatory cytokines in hypertensive patients with diabetes mellitus type 2 (DM2). MATERIAL AND METHODS: Clinical parameters (24-h arterial pressure profile, echocardiographic findings, immunoenzymes level) were studied in 89 hypertensive patients with DM2. These patients had different genotypes by the studied allele variants of the genes determined by polymerase chain reaction. RESULTS: Polymorphism of A1166C gene of type 1 vascular receptor of angiotensin II (AGTR1) contributes to formation of arterial hypertension (AH) signs diversity in DM2 patients. GNB3, a gene C825T polymorphic marker, showed a correlation with diastolic arterial pressure but this variant of the gene locus is not associated with LVH. However, G-allele of ACE gene contributes much to appearance of this pathological sign. Mean values of IL-1beta and TNF-alpha as well as the presence of LVH depended on genotypes by ACE gene (polymorphism I/D). CONCLUSION: Polymorphic markers of ACE and GNB3 candidate genes influence clinical diversity of pathological signs in DM2 patients through modification of AH and LVH severity and the level of proinflammatory cytokines.