[The role of gene-gene and gene-environmental interactions of polymorphic matrix metalloproteinases loci in the formation of the risk of stroke in men with hypertension]. / Rol' gen-gennykh i genno-sredovykh vzaimodeistvii polimorfnykh lokusov matriksnykh metalloproteinaz v formirovanii riska razvitiya ishemicheskogo insul'ta na fone arterial'noi gipertenzii u muzhchin.

OBJECTIVE: Analysis of the role of genetic polymorphisms of matrix metalloproteinases (MMPs), their gene-gene and gene-environment interactions in the formation of ischemic stroke in men with arterial hypertension (AI). MATERIAL AND METHODS: The study included 523 men with arterial hypertension: 201 patients with ischemic stroke and 322 patients without stroke. The association of MMPs loci with stroke with hypertension was determined by logistic regression analysis in dominant, recessive, additive genetic models in PLINK v.2.050. For five SNPs co-located on chromosome 11 (314.3 kb), haplotypic analysis was performed, the relationship of haplotypes with stroke development was determined by the EM algorithm. Gene-gene and gene-environment interactions of MMPs with smoking and alcohol consumption during stroke development were evaluated by GMDR (Generalized Multifactor Dimensionality Reduction) using GMDR v.0.9 software. RESULTS: Polymorphic locus rs3025058 is associated with stroke in men in dominant and additive genetic models (OR=0.63-0.74, pperm=0.03). Four haplotypes of MMPs have a protective effect on the development of stroke with hypertension (OR=0.48-0.50, pperm=0.02-0.03). Four models of gene-gene interactions of polymorphic MMPs loci (OR=2.19-2.55, pperm<0.001) and three four-factor models of gene-environment interactions of MMPs with alcohol abuse (OR=2.82-3.11, pperm<0.001) are associated with a high risk of ischemic stroke in men with hypertension. rs3025058, rs1320632, rs11225395 and rs1799750 demonstrate the greatest contribution to gene-gene and gene-environment interactions in the formation of AI. CONCLUSION: Thus, the results of the study indicate that the interactions of MMPs genes with each other and with modifiable environmental factors play a significant role in the development of stroke with hypertension in men.

[Study of the functional significance of polymorphic loci of the LOXL1 gene associated with glaucoma according to genome-wide studies (in silico analysis)]. / Izuchenie funktsional'nogo znacheniya polimorfnykh lokusov gena LOXL1, assotsiirovannykh s glaukomoi po dannym polnogenomnykh issledovanii (analiz in silico).

Glaucoma is one of the most common eye diseases leading to blindness, and whole-genome studies have shown that genetic factors are important in its formation.Purpose - to perform an in silico analysis of the functional significance of polymorphic loci of the LOXL1 gene associated with glaucoma, using data from wholegenome studies. MATERIAL AND METHODS: Using the catalog of genome-wide studies (GWAS) of the National Human Genome Research Institute (https://www.genome.gov/gwastudies/), three polymorphic loci of the LOXL1 gene (rs2165241, rs4886776, rs893818) associated with glaucoma (pseudoexfoliation glaucoma/syndrome) were chosen for the study. Using modern databases on functional genomics (SIFT, PolyPhen-2, HaploReg, GTExportal), the functional significance of these polymorphic loci was assessed (nonsynonymous substitutions, epigenetic effects, association with gene expression, associations with alternative splicing of gene transcripts). RESULTS: The work establishes the important functional significance of the rs2165241, rs4886776 and rs893818 polymorphic loci of the LOXL1 gene. They demonstrate significant epigenetic effects (affect the affinity to five transcription factors, are located in the region of promoters and enhancers, in the region of hypersensitivity to DNase-1), are associated with the expression and alternative splicing of three genes (LOXL1, LOXL1-AS1, RP11-24D15.1) in cell cultures, organs and tissues pathogenetically significant for development of glaucoma, are strongly linked to the rs1048661 polymorphism, which causes the replacement of the Arg141Leu amino acid in the LOXL1 polypeptide. CONCLUSION: Polymorphic loci of the LOXL1 gene (rs2165241, rs4886776, and rs893818) are of great functional importance (epigenetic, eQTL, and sQTL), which may be the biomedical basis of their associations with glaucoma.

[Analysis of the functional role of polymorphism in the CDKN2B-AS1 gene GWAS-significant for primary open-angle glaucoma (an in-silico study)]. / Analiz funktsional'nogo znacheniya GWAS-znachimogo dlya pervichnoi otkrytougol'noi glaukomy polimorfizma gena CDKN2B-AS1 (in silico issledovanie).

Primary open-angle glaucoma (POAG) is the most common form of glaucoma in which genetic factors play a significant role. According to genome-wide studies (GWAS), the CDKN2B-AS1 gene is associated with POAG. PURPOSE: To study in silico the functional significance of the CDKN2B-AS1 gene polymorphism GWAS-significant for primary open-angle glaucoma. MATERIAL AND METHODS: The in-silico analysis was based on data from the GWAS catalog, five polymorphic loci of the CDKN2B-AS1 gene (rs1063192, rs7865618, rs2157719, rs944800, rs4977756) associated with POAG were selected. The study evaluated the regulatory potential, the relationship with the expression and alternative splicing of genes of the CDKN2B-AS1 gene polymorphism using modern databases for functional genomics - HaploReg and GTExportal. RESULTS: An important functional significance of the polymorphic loci rs1063192, rs7865618, rs2157719, rs944800, rs4977756 of the CDKN2B-AS1 gene was revealed. These loci are located in the region of histones marking enhancers and in the region of hypersensitivity to DNAse-1, can be found in more than ten different organs and tissues, in the regions of regulatory DNA motifs to five transcription factors (AIRE, GATA, Tgif1, Pou2f2, and Zfp187), and are associated with expression of three genes (CDKN2B-AS1, CDKN2B, CDKN2A) and alternative splicing of transcripts of two genes (CDKN2B-AS1 and RP11-149I2.4) in cell cultures, organs and tissues with pathogenic significance for glaucoma development. CONCLUSION: Polymorphism of the CDKN2B-AS1 gene (rs1063192, rs7865618, rs2157719, rs944800, rs4977756) has significant regulatory potential and is associated with the expression and alternative splicing of genes, which possibly underlies its association with primary open-angle glaucoma.

[Genome-wide studies of primary open-angle glaucoma]. / Polnogenomnye issledovaniya pervichnoi otkrytougol'noi glaukomy.

The article reviews literature on developmental stages of genome-wide association studies (GWAS) of primary open-angle glaucoma (POAG). This problem is currently developing and one of the most complex in ophthalmology. The article considers main GWAS of POAG and established GWAS-significant polymorphisms associated with the disease. The topic of genome-wide studies of primary open-angle glaucoma will be of certain interest to ophthalmologists, materials on GWAS-significant loci can be used both in the selection of polymorphisms in replicative studies of POAG in various populations of Russia, and to expand ideas about the molecular genetic mechanisms of the development of the disease.

[The role of metalloproteinases in the development of primary open-angle glaucoma]. / Rol' matriksnykh metalloproteinaz v patogeneze pervichnoi otkrytougol'noi glaukomy.

The article reviews literature on the role of matrix metalloproteinases (MMP) in the development of eye pathologies, specifically primary open-angle glaucoma (POAG). Regulation of the extracellular matrix is carried out by proteolytic enzymes - metalloproteinases in particular - as well as specific inhibitors of their activity (tissue metalloproteinases inhibitors). The review also reveals its involvement in the pathogenesis of various types of glaucoma, decrease in stability of the intraocular liquid outflow, proves the role of MMR in the ganglionic apoptosis, remodeling of the optic disk and change of lamina cribrosa in primary open-angle glaucoma. There is research devoted to studying the interrelations of MMP genes with POAG development. Associations of single nucleotide polymorphic loci of MMP-1, MMP-2, MMP-9 genes with POAG are shown.

[Etiopathogenesis of primary open-angle glaucoma]. / Etiopatogenez pervichnoi otkrytougol'noi glaukomy.

The article reviews literature covering the etiopathogenesis and risk factors for the development of primary open-angle glaucoma (POAG). Currently, this problem is one of the most complex and controversial in ophthalmology. The review considers the main theories: vascular, mechanical (retentional, hydromechanical), dystrophic (theory of primary scleropathy), metabolic, concept of liquor hypertension, concept of the individual norm of intraocular pressure, as well as POAG risk factors.

[Study of associations of polymorphism of matrix metalloproteinases genes with the development of arterial hypertension in men].

The aim of research. To study the association of polymorphic loci of matrix metalloproteinases with the development of essential hypertension (EH) in men of the Central Chernozem Region of Russia. Materials and methods. A study of 564 men with EH and 257 control men was performed. Analysis of the polymorphic loci of metalloproteinases rs11568818 MMР7, rs1320632 MMР8, rs11225395 MMР8, rs1799750 MMР1, rs3025058 MMР3 was performed using real-time PCR. The study of associations of SNPs and their haplotypes with the development of arterial hypertension was carried out using logistic regression analysis in the PLINK software (v. 2.050). The regulatory potential of polymorphic loci was analyzed in the HaploReg software (v. 4.1) (http://archive.broadinstitute.org). The effect of SNP on gene expression was studied using the data of the Genotype-Tissue Expression project (http://www.gtexportal.org/). Results. Haplotype including rs11568818 MMP7, rs1320632 MMP8, rs11225395 MMP8 and rs1799750 MMP1 associated with a high risk of disease in men (OR=2,58, pperm=0,04). These polymorphisms located in region of promoter and enhancer histone marks and in the region of hypersensitivity to DNAse-1. They located in sites of proteins bound (TBP, CJUN, CFOS and GATA2) and they associated with the level of gene expression ММР7, ММР27 and RP11-817J15.3 (in peripheral blood, skeletal muscles, nervous tissue and other). Сonclusion. Haplotype G-A-C-1G for polymorphisms rs11568818 MMP7, rs1320632 MMP8, rs11225395 MMP8, rs1799750 MMP1 are associated with the development of essential hypertension in men in the Central Chernozem Region of Russia.

[The role of stress factors and genetic predisposition in the development of stroke in patients with essential hypertension]. / Rol' stressovogo faktora v realizatsii geneticheskoi predraspolozhennosti k razvitiiu insul'ta na fone gipertonicheskoi bolezni.

To study the interaction of polymorphic markers of matrix metalloproteinases (MMP) and chronic stress in the development of stroke associated with hypertension. MATERIAL AND METHODS: A total of 830 patients, including 303 patients with ischemic stroke associated with essential hypertension (EH) and 527 patients with EH without stroke, were examined. The study of metalloproteinases SNP was carried out using real-time PCR. The functional significance and influence of polymorphic loci on gene expression was studied using of HaploReg (v4.1) (http://archive.broadinstitute.org) and GTEx-portal (http://www.gtexportal.org). RESULTS AND CONCLUSION: An association of the genotype GG (rs11568818) of MMP7 with a high risk of stroke in patients exposed to regular stress (OR=1.71) was observed. It was found that allele 5A and genotype 5A/5A (rs3025058) of MMP3 had a protective effect on the development of stroke in patients without regular stress in the anamnesis (OR=0.73 and OR=0.60, respectively). Those SNPs are localized in the region of histone proteins H3K4me1 and H3K4me3, in the region of hypersensitivity to DNase-1, in the region of binding of regulatory proteins and transcription factors. The polymorphic locus rs11568818 is associated with the expression level of MMP7.

[Studying the association between genetic polymorphism of growth factors and the development of primary open-angle glaucoma]. / Izuchenie assotsiatsii geneticheskikh polimorfizmov faktorov rosta s razvitiem pervichnoi otkrytougol'noi glaukomy.

Primary open-angle glaucoma (POAG) is a multifactorial disease, etiopathogenesis of which largely depends on growth factors. Possessing a variety of medical and biological effects, these cytokines may influence the development and progression of POAG. AIM: to reveal the role of genetic polymorphisms of growth factors in predisposition to developing POAG that is refractory to local hypotensive therapy. MATERIAL AND METHODS: The object of the study were 162 patients with stage II-III POAG, in whom local hypotensive therapy was inefficient, 90 patients with stage II-III POAG well controlled on local hypotensive therapy, and 191 controls. The material for the study was venous blood taken from the cubital vein of a proband. Isolation of genomic DNA was performed by phenol-chloroform extraction. Analysis of genetic polymorphisms of growth factors was performed through allelic discrimination. For that, synthesis of DNA was carried out via polymerase chain reaction (PCR). RESULTS: It is found that the T IGFR-1 genetic variant (OR=1.34) and a combination of the C VEGF-A and T IGFR-1 genetic variants (OR=1.90) are risk factors of developing POAG that is refractory to local hypotensive therapy. A statistical model for predicting such a risk has been proposed that includes: VEGF-A с.-958C>T genetic marker (rs 833,061), age, concomitant non-inflammatory ocular diseases, microvascular changes in the conjunctiva, the degree of pigmentation of the angle of the anterior chamber, and pseudoexfoliative syndrome. Recognition accuracy of the model is 90.42%. CONCLUSION: The T IGFR-1 genetic variant and a combination of the C VEGF-A and T IGFR-1 genetic variants increase the risk of developing POAG that is refractory to local hypotensive therapy.

[Association of the -844G>A polymorphism in the catalase gene with the increased risk of essential hypertension in smokers]. / Assotsiatsiya polimorfizma -844G>A gena katalazy s povyshennym riskom razvitiya arterial'noi gipertonii u kuril'shchikov.

AIM: To investigate whether the functionally relevant -844G>A promotor polymorphism in the catalase (CAT) gene is associated with the development of essential hypertension (EH). SUBJECTS AND METHODS: The investigation enrolled 2,339 unrelated ethnic Russian people, including 1,269 EH patients and 770 apparently healthy individuals. Genotyping of CAT -844G>A (rs769214) polymorphism was performed using a TaqMan real-time polymerase chain reaction assay. RESULTS: The -844A allele (odds ratio (OR)=1.31; 95% confidence interval (CI), 1.04 to 1.64; р=0.02) and the -844AA genotype (OR=1.41; 95% CI, 1.02 to 1.94; р=0.03) were found to be related to a higher risk of EH in the smokers. No association was found between this polymorphism and EH risk in the non-smokers. CONCLUSION: Smoking is a predisposing factor for development of EH in CAT -844AA genotype carriers.

[ESTIMATING THE EFFECTIVENESS OF HYPOLIPIDEMIC THERAPY WITH ROSUVASTATIN IN PATIENTS WITH CORONARY HEART DISEASE DEPENDING ON THE GENOTYPE OF LIPOPROTEIN LIPASE].

Taking into account the genetic heterogeneity of hyperlipidemias, polymorphic genes involved in the regulation of lipid metabolism may explain differences in the efficacy of hypolipidemic therapy. In the present prospective and randomized study, we have investigated the efficacy of rosuvastatin (10 mg/day) in the therapy of atherogenic hyperlipidemias in a group of 62 patients with coronary heart disease (CHD), depending on the genotype of lipoprotein lipase (LPL). The pharmacological correction was carried out during one year under control of lipid metabolism parameters (total cholesterol, LDL-C, HDL-C, HDL-unrelated cholesterol, triglycerides, atherogenic index) at the baseline and on 4th, 8th, 24th and 48th week. The HindIII polymorphism (+495T > G, rs320) of the LPL gene was genotyped in all patients studied through a real-time PCR TaqMan assay. Rosuvastatin produced a significant hypolipidemic effect with respect to all investigated lipid metabolism parameters for 24 weeks of treatment. Changes in the parameters of lipid metabolism upon rosuvastatin treatment differed in patients with genotype +495GG as compared to the rest LPL genotypes. In comparison to the +495TT and TG genotypes, the genotype +495GG showed a greater reduction in total cholesterol on 8th week, and in LDL-C, HDL-unrelated cholesterol, and atherogenic index on the 48th week of rosuvastatin therapy (p <0.01). It can be suggested that the pronounced hypolipidemic effect of rosuvastatin in homozygotes +495GG of the LPL gene is associated with modulation of the LPL activity, as it has been previously reported for other statin drugs.

[Bioinformatic investigation of the involvement of candidate genes of cytokines in the formation of large myomatous nodes in women with uterine cancer in older age groups].

The aim was to study bioinformatics involvement of candidate genes of cytokines in the formation of large fibroids in women with uterine cancer in older age groups. Genotyping of 15 molecular genetic markers cytokines was performed in 120 patients with uterine myoma with large myoma nodes and 107 patients with myoma nodes of small size. The study found that genetic risk factors for fibroids with large uterine fibroids are two combinations of genetic variants: G SDF-1, CC IL-1ß, A RANTES (OR=5,56) and A RANTES with genotype CC IL-1ß (OR=4,60). 12 of 15 polymorphic loci studied in various combinations (8 revealed significant combinations) have protective value in the formation of large fibroids with uterine cancer (OR=0,09-0,31).

[Clinical features of patients of older age groups with uterine myoma].

The study analyzed 301 patients with uterine cancer at the age of 45 years and older and 304 patients with uterine myoma 45 years. It was found that patients with uterine myoma of the older age group (45 and older) have the following clinical features: overweight and thus increased BMI these women, a lower percentage of a family history of uterine cancer, a smaller percentage of infertility, a greater number of pregnancies, births, medical abortions, the high prevalence of diseases of the cardiovascular system and pathology of the cervix, large size fibroids and as a consequence more common compartment syndrome adjacent organs by myoma nodes (disuric disorders).

The role of cytokine gene polymorphism in the formation of arterial hypertension associated with metabolic syndrome.

We investigated the association of polymorphisms of genes tumor necrosis factors and their receptors (-308G/A TNFa, +250A/G Lta, +36 A/G TNFR1, +1663 A/G TNFR2) with the predisposition to the development of essential hypertension (EH) and the features of its clinical course in patients with metabolic syndrome. It has been demonstrated that the molecular genetic marker +36G TNFR1 (OR=1,25) is involved in the formation EH in individuals with metabolic syndrome. The risk of stage III EH in patients with metabolic syndrome is enhanced by genetic variants -308GA TNFa (OR=2,72), -308A TNFa (OR=2,72), +250G Lta (OR=1,80), and combinations thereof -308A TNFa with +1663G TNFR2 (OR=3,85), +250G Lta with +36G TNFR1 (OR=3,85), +250G Lta with +1663G TNFR2 (OR=3,85) while protective properties are inherent in -308GG TNFa (OR=0,32), +250AA Lta (OR=0,45), -308G TNFa (OR=0,37), +250A Lta (OR=0,56) and a combination of genetic markers -308GG TNFa with +250A Lta (OR=0,31), -308G TNFa with +250AA Lta (OR=0,39), -308G TNFa with +250A Lta (OR=0,31).

[GENE POOL SIMILARITIES AND DIFFERENCES BETWEEN UKRAINIANS AND RUSSIANS OF SLOBOZHANSHINA ON Y-CHROMOSOME DATA].

The results of the study of Y-chromosomal polymorphisms of Russian and Ukrainian population are presented for Slobozhanshina--contemporary border region, former "Wild Field" boundary, which was inhabited in XVII-XVIII centuries by both the Russians from the north and Ukrainians from the west. In general, Ukrainian and Russian populations of Slobozhanshchina genetically are very close, their set and frequency range of Y-chromosome haplogroups are typical for the Eastern Europe. But a detailed analysis of highly informative Y-chromosome markers showed that after 3,5 centuries of coexistence on the same historical territory, the both nations retain the ethnic specificity of their gene pools: Ukrainian populations are similar to the rest of Ukraine, and Russian populations are similar to the south of the European part of Russia. The genetic differences may be due to the spatial characteristics of marriage migration and the predominant ethnic environment.

Joint effect of glutathione S-transferase genotypes and cigarette smoking on idiopathic male infertility.

Inconsistent results of association studies investigated the role of glutathione S-transferase genes in idiopathic male infertility may be explained by ethnical differences in gene-gene and gene-environment interactions. In this study, we investigated a joint contribution of GSTM1, GSTT1 and GSTP1 gene polymorphisms and cigarette smoking to the risk of idiopathic infertility in Russian men. DNA samples from 203 infertile and 227 fertile men were genotyped by a multiplex polymerase chain reaction (GSTM1 and GSTT1 deletions) and PCR-restriction fragment length polymorphism (GSTP1 I105V) methods. The GSTP1 genotype 105IV was associated with increased risk of male infertility (OR = 1.50 95% CI 1.02-2.20 P = 0.04). Genotype combinations GSTP1 105II/GSTT1 del (G1), GSTM1 del/GSTT1 del (G2) and GSTM1 + /GSTT1 del (G3) were associated with decreased risk of male infertility (P ≤ 0.003), whereas a genotype combination GSTP1 105IV/GSTT1 + (G4) was associated with increased disease risk (P = 0.001). The genotype combinations G3 and G4 showed a significant association with infertility in smokers; however, nonsmokers carriers did show the disease risk. In conclusion, GSTM1, GSTT1 and GSTP1 genes are collectively involved in the development of idiopathic male infertility and their phenotypic effects on the disease risk are potentiated by cigarette smoking.

[Genetic studies of primary open-angle glaucoma].

The present review is devoted to genetic studies of primary open-angle glaucoma (POAG). Today, POAG is considered a multifactorial disease with threshold effect, which is associated with single or multiple genes mutation as well as external influences. According to molecular genetic studies, three causative genes (MYOC, optinevrin, WDR 36) and several dosens of candidate genes are involved in the development of POAG.

[Analysis of genetic diversity of Russian regional populations based on common STR markers used in DNA identification].

We conducted the first genetic analysis of a wide a range of rural Russian populations in European Russia with a panel of common DNA markers commonly used in criminalistics genetic identification. We examined a total of 647 samples from indigenous ethnic Russian populations in Arkhangelsk, Belgorod, Voronezh, Kursk, Rostov, Ryazan, and Orel regions. We employed a multiplex genotyping kit, COrDIS Plus, to genotype Short Tandem Repeat (STR) loci, which included the genetic marker panel officially recommended for DNA identification in the Russian Federation, the United States, and the European Union. In the course of our study, we created a database of allelic frequencies, examined the distribution of alleles and genotypes in seven rural Russian populations, and defined the genetic relationships between these populations. We found that, although multidimensional analysis indicated a difference between the Northern gene pool and the rest of the Russian European populations, a pairwise comparison using 19 STR markers among all populations did not reveal significant differences. This is in concordance with previous studies, which examined up to 12 STR markers of urban Russian populations. Therefore, the database of allelic frequencies created in this study can be applied for forensic examinations and DNA identification among the ethnic Russian population over European Russia. We also noted a decrease in the levels of heterozygosity in the northern Russian population compared to ethnic populations in southern and central Russia, which is consistent with trends identified previously using classical gene markers and analysis of mitochondrial DNA.

[The role of genetic polymorphisms of interleukins in chronic lymphocytic leukemia in patients of different ages].

Chronic lymphocytic leukemia (CLL) is a multifactorial disease, in which development the important role played the cytokine genes, in particular interleukins. This type of leukemia is more common in the elderly. The purpose of the study was to evaluate the association of genetic polymorphisms of interleukin with the development of chronic lymphocytic leukemia among residents of the Central Chernozem region of Russia. Genotyping of the -889C/T IL-1A, -590C/T IL-4 and VNTR IL-1 Ra was conducted in 206 patients with CLL and 307 individuals of the control group. The study found that the genetic risk factor for the development of CLL is allele -590T IL-4 (OR=-1,45). The development of thrombocytopenia in patients with CLL is associated with genetic variants -889T IL-1A (OR=1,95), -889TT IL-1A (OR=6,2) and IL-1Ra*1 (OR=-2,32).