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HSPA8 is involved in many stroke-associated cellular processes, playing a pivotal role in the protein quality control system. Here we report the results of the pilot study aimed at determining whether HSPA8 SNPs are linked to the risk of ischemic stroke (IS). DNA samples from 2139 Russians (888 IS patients and 1251 healthy controls) were genotyped for tagSNPs (rs1461496, rs10892958, and rs1136141) in the HSPA8 gene using probe-based PCR. SNP rs10892958 of HSPA8 was associated with an increased risk (risk allele G) of IS in smokers (OR = 1.37; 95% CI = 1.07-1.77; p = 0.01) and patients with low fruit and vegetable consumption (OR = 1.36; 95% CI = 1.14-1.63; p = 0.002). SNP rs1136141 of HSPA8 was also associated with an increased risk of IS (risk allele A) exclusively in smokers (OR = 1.68; 95% CI = 1.23-2.28; p = 0.0007) and in patients with a low fruit and vegetable intake (OR = 1.29; 95% CI = 1.05-1.60; p = 0.04). Sex-stratified analysis revealed an association of rs10892958 HSPA8 with an increased risk of IS in males (risk allele G; OR = 1.30; 95% CI = 1.05-1.61; p = 0.01). Thus, SNPs rs10892958 and rs1136141 in the HSPA8 gene represent novel genetic markers of IS.

Background: Ischemic stroke (IS) is one of the most serious cardiovascular events associated with high risk of death or disability. The growing body of evidence highlights molecular chaperones as especially important players in the pathogenesis of the disease. Since six small proteins called "Hero" have been recently identified as a novel class of chaperones we aimed to evaluate whether SNP rs4644832 in SERF2 gene encoding the member of Hero-proteins, is associated with the risk of IS., Methods: A total of 1929 unrelated Russians (861 patients with IS and 1068 healthy individuals) from Central Russia were recruited into the study. Genotyping was done using a probe-based PCR approach. Statistical analysis was carried out in the whole group and stratified by age, gender and smoking status., Results: Analysis of the link between rs4644832 SERF2 and IS showed that G allele is the risk factor of IS only in females (OR=1.29, 95%CI 1.02-1.64, Padj=0.035). In addition, the analysis of associations of rs4644832 SERF2 and IS depending on the smoking status revealed that this genetic variant is associated with an increased risk of IS exclusively in non-smoking individuals (OR=1.26, 95%CI 1.01-1.56, P = 0.041)., Discussion: Sex- and smoking interactions between rs4644832 polymorphism and IS may be related to the impact of tobacco components metabolism and sex hormones on SERF2 expression., Conclusion: The present study reveals the novel genetic association between rs4644832 polymorphism and the risk of IS suggesting that SERF2, the part of the protein quality control system, contributes to the pathogenesis of the disease., Competing Interests: The authors declare no conflict of interests., (© 2023 The Authors.)

Background: Glutathione is a tripeptide detoxifying a variety of exogenous and endogenous free radicals and carcinogens, and a deficiency of glutathione is associated with an increased host susceptibility to oxidative stress, a pathological condition implicated in the development and progression of cancer. The catalytic subunit of glutamate-cysteine ligase (GCLC) is an enzyme responsible for the initial and rate-limiting step of glutathione biosynthesis., Methods and Results: The aim of this pilot study was to investigate whether genetic variation at the GCLC gene contributes to the risk of colorectal cancer (CRC). DNA samples from 681 unrelated Russian individuals (283 patients with CRC and 398 age- and sex-matched healthy controls) were genotyped for six common functional SNPs of the GCLC gene (SNPs) such as rs12524494, rs17883901, rs606548, rs636933, rs648595 and rs761142 of the GCLC gene using the MassARRAY-4 system. We found that genotype rs606548-C/T is significantly associated with increased risk of CRC regardless of sex and age (OR 2.24; 95% CI 1.24-4.03; P = 0.007, FDR = 0.04). Moreover, ten GCLC genotype combinations showed association with the risk of CRC (P < 0.05). Functional SNP annotation enabled establishing the CRC-associated polymorphisms are associated with a decreased GCLC expression that may be attributed to epigenetic effects of histone modifications operating in a colon-specific manner., Conclusions: The present study was the first to show that genetic variation at the catalytic subunit of glutamate-cysteine ligase may contribute to the risk of colorectal cancer risk. However, further genetic association studies with a larger sample size are required to substantiate the role of GCLC gene polymorphisms in the development of sporadic colorectal cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

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, p perm =0.03). Four haplotypes of MMPs have a protective effect on the development of stroke with hypertension (OR=0.48-0.50, p perm =0.02-0.03). Four models of gene-gene interactions of polymorphic MMPs loci (OR=2.19-2.55, p perm <0.001) and three four-factor models of gene-environment interactions of MMPs with alcohol abuse (OR=2.82-3.11, p perm <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.

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.

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.

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 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.

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.

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.

This study investigated whether common polymorphisms of cytochrome P450 2J2 (CYP2J2), a major enzyme that controls the biosynthesis of vasoactive epoxyeicosatrienoic acids, are collectively involved in the molecular basis of essential hypertension (EH). A total of 2314 unrelated Russian subjects from the Kursk (discovery sample: 913 EH patients and 645 controls) and Belgorod (replication sample: 345 EH patients and 411 controls) regions were recruited for this study. Eight single nucleotide polymorphisms (SNPs), including rs890293, rs11572182, rs10493270, rs1155002, rs2280275, rs7515289, rs11572325, and rs10889162, of CYP2J2 were genotyped using the MassARRAY 4 system and TaqMan-based assays. Significant associations were identified among the SNPs rs890293 (OR = 2.17, 95%CI 1.30-3.65), rs2280275 (OR = 1.59, 95%CI 1.10-2.37) and rs11572325 (OR = 1.89, 95%CI 1.22-2.95) and the risk of EH in females from the Kursk population. Sixteen CYP2J2 genotype combinations only showed significant associations with EH risk only in females. A common haplotype, T-T-G-C-C-C-T-A, increased the risk of EH in females. The bioinformatic analysis enabled identification of the SNPs that possess regulatory potential and/or are located within the binding sites for multiple transcription factors that play roles in the pathways involved in hypertension pathogenesis. Moreover, the polymorphisms rs890293, rs2280275, and rs11572325 were found to be significantly associated with hypertension risk in the Belgorod population. In conclusion, the rs2280275 and rs11572325 SNPs of CYP2J2 may be considered novel genetic markers of hypertension, at least in Russian women. However, sex-specific associations between CYP2J2 gene polymorphisms and hypertension require further investigation to clarify the specific genetic and/or environmental factors that are responsible for the increased disease susceptibility of women compared to that of men.

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.

Objective: The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH)., Methods: A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single-nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays., Results: We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01-1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52-0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation<0.0001). The mRNA expression and in-silico function prediction analyses have confirmed a regulatory potential for a majority of SNPs associated with EH susceptibility., Conclusion: Our pilot study was the first to show that gene-gene and gene-environment interactions in the AHR signaling pathway represent important determinants for the development of EH, and the pathway may become an attractive target for a pharmacological intervention in hypertensive patients in the future.

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.

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-1β, A RANTES (OR=5,56) and A RANTES with genotype CC IL-1β (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).

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.

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).

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).

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.

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., (© 2014 Blackwell Verlag GmbH.)

Objective: The study was designed to assess the effects of polymorphisms in genes associated with essential hypertension on the variation of erythrocyte membrane proteins (EMPs) in hypertensive patients., Methods: Major EMPs content was analyzed in blood from 1162 unrelated Russians (235 hypertensive patients, 176 healthy controls, and 751 random individuals from the Central Russia population). Essential hypertension patients were genotyped for 11 polymorphisms of essential hypertension susceptibility genes including ADD1 (rs4961), GNB3 (rs5443, rs16932941), NOS3 (rs1799983, rs2070744), ACE (rs5186), AGTR1 (rs5186), AGT (rs699, rs4762), MR (rs5534), and TGFB1 (rs1800471). EMP contents and their relationship with the genetic loci were analyzed using various statistical tests., Results: Sex-specific differences in EMP contents between the cases and controls were observed. Regardless of sex, hypertensives exhibited mainly decreased levels of alpha (SPTA1) and beta-spectrin (SPTB) and increased levels of glucose transporter (GLUT1) as compared with healthy subjects (P ≤ 0.001). EMP correlated differently in essential hypertension patients and controls. Almost 70% of the joint variation in the EMP levels is explained by five gender-specific principal components. The essential hypertension susceptibility genes showed considerable effects on the levels of spectrins and glucose transporter. A joint variation of the genes explained about half the total polygenic variance in the GLUT1, SPTA1, and SPTB levels in hypertensives., Conclusions: The study showed that essential hypertension susceptibility genes are the important factors of the inherited EMP variation, and their pleitropic effects may be mirrored in the altered expression of genes encoding cytoskeletal proteins and those related to intracellular glucose metabolism.

Introduction: Malfunctioning of the cardiovascular system during pregnancy may be responsible for adverse effects on the 'mother-fetus' system. The cardiovascular system of a pregnant woman develops adaptation to the increased load. Angiotensin-converting enzyme (ACE) is known to play an important role in the adaptation. The present study was designed to investigate whether the insertion-deletion (I/D) polymorphism of the ACE gene is associated with the level of arterial blood pressure in women before and during pregnancy., Materials and Methods: The level of blood pressure was measured in 591 Russian women (Central Russia) before and during (37-40 weeks term) pregnancy. The women were divided into three groups which were hypertensive, hypotensive, and normotensive according to blood pressure level. Genotyping of the ACE I/D polymorphism was performed using polymerase chain reaction (PCR) and amplified fragment length polymorphism assay., Results: Women with genotype DD showed the highest blood pressure level both during and at the end of pregnancy (p<0.05). The highest frequencies of allele D and genotype DD were found in pregnant women in the hypertensive group., Conclusions: The deletion variant of the ACE gene is associated with high blood pressure level at the end of pregnancy., (© The Author(s) 2013.)

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.

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.

N-acetyltransferase (NAT2) is a phase-II xenobiotic-metabolizing enzyme participating in the detoxification of toxic arylamines, aromatic amines and hydrazines. The present study was designed to investigate whether two common single-nucleotide polymorphisms (SNP) of the NAT2 gene (481C>T, rs1799929; 590G>A, rs1799930) are associated with susceptibility to idiopathic male infertility and to assess if the risk is modified by oxidant and antioxidant exposures. A total 430 DNA samples (203 infertile patients and 227 fertile men) were genotyped for the polymorphisms by PCR and restriction fragment length polymorphism. No association was found between the NAT2 polymorphisms and idiopathic male infertility. However, gene-environment interaction analysis revealed that a low-acetylation genotype, 590GA, was significantly associated with increased disease risk in men who had environmental risk factors such as cigarette smoking (OR 1.71, 95% CI 1.02-2.87, P = 0.042), alcohol abuse (OR 2.14, 95% CI 1.08-4.27, P = 0.029) and low fruit/vegetable intake (OR 1.68, 95% CI 1.01-2.79, P = 0.04). This pilot study found, as far as is known for the first time, that the polymorphism 590G>A of NAT2 is a novel genetic marker for susceptibility to idiopathic male infertility, but the risk is potentiated by exposure to various environmental oxidants., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

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.

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).

The study was designed to investigate the associations of polymorphisms Ile462Val and 3801T>C of the cytochrome P450 1A1 (CYP1A1) gene with idiopathic male infertility (IMI) and to assess the impact of smoking status on the relationship between the polymorphisms and the susceptibility to the disease. DNA samples from 203 patients with IMI and 227 fertile men were genotyped for the polymorphisms by a polymerase chain reaction and restriction fragment length polymorphism methods. We found for the first time that the increased risk of IMI in carriers of genotype 462Ile/Val of the CYP1A1 gene occurred only in smoker men (odds ratio [OR] = 1.91; 95% confidence interval [CI] 1.01-3.59), whereas nonsmoker men did not have the risk of infertility (OR = 1.58; 95% CI 0.66-3.76). The results of our study demonstrate that the analysis of gene-environment interactions is necessary to explain conflicting results of genetic studies of IMI and to improve our understanding of the mechanisms of the disease.

Study Design: A genetic association study of the transforming growth factor beta 1 (TGFB1) gene with adolescent idiopathic scoliosis (AIS) in Russian population., Objective: To determine whether common genetic polymorphisms C-509T (rs1800469) and Arg25Pro (rs1800471) of the TGFB1 gene are associated with susceptibility to AIS., Summary of Background Data: An importance of growth factors for the pathogenesis of AIS has been demonstrated by the findings of abnormal expression of these proteins in the spine and surrounding tissues in patients with AIS. However, no studies have been performed to investigate the relationship between genetic polymorphisms of the TGFB1 gene and susceptibility to AIS., Methods: A total of 600 unrelated adolescents from Central Russia (Moscow) were recruited in this study, including 300 patients with AIS and 300 age- and sex-matched healthy adolescents. The polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism., Results: The allele -509T and genotype -509TT of the TGFB1 gene were significantly associated with the increased risk of idiopathic scoliosis in both females and males (P < 0.01). Logistic regression analysis has revealed a recessive model of the genetic association between polymorphism C-509T of the TGFB1 gene and AIS. Moreover, we found sexual dimorphisms in the relationships of SNP C-509T of the TGFB1 gene with both the age of disease onset and curve severity: the polymorphism was found to determine both an early onset of scoliosis and the severity of curvature in females but not in males (P < 0.05)., Conclusion: This study, for the first time, highlights the importance of TGFB1 gene for the development and progress of AIS. We hypothesize several mechanisms by which the TGFB1 gene may contribute to spinal deformity in patients with AIS.

In the course of the performed study the significant influence of pesticides introduced into arable farmland, on the frequency of gynecological morbidity in adolescents in 21 districts of the Belgorod region was established. With increasing pesticide load on the soil the prevalence of gynecological pathology in adolescents in rural areas is raising.

We investigated association of polymorphisms of interleukin IA (IL-1A), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin-8 (1L-8) genes in elderly patients with predisposition to the development of chronic lym,nphocytic leukemia (CLL). Risk factor of chronic lymphocytic leukemia is a genetic variant -590T IL-4 (OR = 1,45) and protective factor -590S IL-4 (OR = 0,68). Genetic markers -590T IL-4 (OR = 2,46), -590TT IL-4 (OR = 6,65) and mix-590TT genotype of IL-4 allele 703S-IL-5 (OR = 6.70) were associated with stage 0-1 chronic lymphocytic leukemia whereas genetic markers -889T IL-1A (OR = 1,51), -703T IL-5 (OR = 1,52) and a combination of genotype -703ST IL-5 allele-251A IL-8 (OR = 2.85) were related to the development of stage II of the disease. Risk factor for the formation of II-IV stages of chronic lymphocytic leukemia is a genetic variant -703T IL-5 (OR = 1,95).

In the present study we have investigated the association of three single nucleotide polymorphisms in glutathione peroxidase (GPx) genes GPX1 rs1050450 (P198L), GPX3 rs2070593 (G930A) and GPX4 rs713041 (T718C) with the risk of cerebral stroke (CS) in patients with essential hypertension (EH). A total of 667 unrelated EH patients of Russian origin, including 306 hypertensives (the EH-CS group) who suffered from CS and 361 people (the EH-CS group) who did not have cerebrovascular accidents, were enrolled in the study. The variant allele 718C of the GPX4 gene was found to be significantly associated with an increased risk of CS in hypertensive patients (odds ratio (OR) 1.53, 95% confidence interval (CI) 1.23-1.90, P(adj) = 0.0003). The prevalence of the 718TC and 718CC genotypes of the GPX4 gene was higher in the EH-CS group than the EH-alone group (OR = 2.12, 95%CI 1.42-3.16, P(adj) = 0.0018). The association of the variant GPX4 genotypes with the increased risk of CS in hypertensives remained statistically significant after adjusting for confounding variables such as sex, body mass index (BMI), blood pressure and antihypertensive medication use (OR = 2.18, 95%CI 1.46-3.27, P = 0.0015). Multiple logistic regression analysis did not reveal any interaction between various combinations of GPX1, GPX3 and GPX4 genotypes regarding the risk of CS in patients with EH. The study demonstrated for the first time that the C718T polymorphism in the 3'-untranslated region of the GPX4 gene could be considered as a genetic marker of susceptibility to CS in patients with EH.

Yu. P. Altukhov suggested that heterozygosity is an indicator of the state of the gene pool. The idea and a linked concept of genetic ecological monitoring were applied to a new dataset on mtDNA variation in East European ethnic groups. Haplotype diversity (an analog of the average heterozygosity) was shown to gradually decrease northwards. Since a similar trend is known for population density, interlinked changes were assumed for a set of parameters, which were ordered to form a causative chain: latitude increases, land productivity decreases, population density decreases, effective population size decreases, isolation of subpopulations increases, genetic drift increases, and mtDNA haplotype diversity decreases. An increase in genetic drift increases the random inbreeding rate and, consequently, the genetic load. This was confirmed by a significant correlation observed between the incidence of autosomal recessive hereditary diseases and mtDNA haplotype diversity. Based on the findings, mtDNA was assumed to provide an informative genetic system for genetic ecological monitoring; e.g., analyzing the ecology-driven changes in the gene pool.

The study of the influence of geliophysical factors on neonatal morbidity in the Belgorod Region in 2000 to 2008 established a rise in the rate of congenital malformations, fetal hypoxia and asphyxia, prematurity, and overall neonatal morbidity during a period of high solar activity.

Data on the frequencies of all (50 412) surnames in a total population of 849 399 people have been treated by various methods of multivariate statistics (cluster analysis, multidimensional scaling, and factor analysis) to show that 22 district populations of the Central Chernozem region of Russia form a definite, ordered system of population groups. All raions (administrative districts) of Belgorod oblast (administrative region) have been grouped into four clusters corresponding to the actual geographic locations of the populations. Districts of the eastern cluster are characterized by very specific spectrum and frequencies of surnames; districts of the western cluster differ in a high proportion of Ukrainian surnames.

The model of the Belgorod oblast population has been used to demonstrate different effects of administrative reforms on microevolution in human populations. For the populations that formerly belonged to Kursk oblast, changes in the regional administrative structure (after which some of them remained in Kursk oblast and others were included into Belgorod oblast) have lead to an increase in the genetic distances between them. However, other populations (formerly belonging to Voronezh oblast) have become genetically closer to one another, although these populations now belong to different administrative regions (Belgorod and Voronezh oblasts).

The investigation revealed statistically significant positive and negative correlations between the impact of solar activity (SA) and the incidence of congenital malformations (CM). As SA decreased, the incidence of multiple CM, defects of the musculoskeletal system, and those as a whole increased, but among the nosological entities, there was a rise in the prevalence of diaphragmatic hernia and omphalocele. At the same time, increased SA determines the higher incidence of abnormalities of the central nervous system, sensory organs, face and neck, anencephalies, and cleft lips. The maximum influence of SA was established for CM of the skin (56.25%), face and neck (53.46%); and among the nosological entities of CM that was for the cleft lip (60.65%) and cerebrospinal hernia (46.51%).

Changes in the endogamy indices of district populations of the Central Chernozem region of Russia during the past 100 years were studied. The size of an elementary population in this region increased from that of a rural municipality in the mid-20th century to that of an administrative district in the late 20th century.

The characteristics of the gene pools of indigenous populations of Ukraine and Belarus have been studied using 28 alleles of 10 loci of biochemical gene markers (HP, GC, TF, PI, C'3, ACP1, GLO1, PGM1, ESD, and 6-PGD). The gene pools of the Russian and Ukrainian indigenous populations of Belgorod oblast (Russia) and the indigenous populations of Ukraine and Belarus have been compared. Cluster analysis, multidimensional scaling, and factor analysis of the obtained data have been used to determine the position of the Belgorod population gene pool in the Eastern Slavic gene pool system.

The frequencies of 33 alleles of 12 loci of immunological and biochemical gene markers (ABO, RH, HP, GC, TF, PI, C'3, ACP1, GLO1, PGM1, ESD, and 6-PGD) have been estimated in the indigenous Russian and Ukrainian populations of Belgorod oblast. Differences of the Belgorod population from other populations of Russia with respect to the genetic structure have been determined. It has been found that the frequency distributions of all alleles studied in the Belgorod population are similar to those typical of the genetic structure of Caucasoid populations.

S u m mary. The paper presents the results of studying the qualitative and quantitative representation of anthropogenic pollutants in the ambient air environment of Belgorod and evaluating their impact on the prevalence of neonatal congenital malformations. The level of atmospheric pollutant emissions is shown to vary by an average of 4 to 10 times in some areas. The vast majority (91.7%) of pollutants form clusters (n = 11), suggesting their combined influence. Each group of clusters includes 2 to 9 pollutants (median 4.64 pollutants). Atmospheric pollutants have been ascertained to adversely affect the prevalence of congenital malformations in children. A multiple regression equation has been derived to predict the frequency of congenital malformations, by taking into account the qualitative and quantitative spectrum of atmospheric pollutants.

Diseases of respiratory organs constitute a serious socio-medical problem in this country due to high morbidity, mortality, and disability rates. The development of medical nanotechnlogies opens up new prospects for the improvement of treatment and prevention of these pathologies. Of special interest is application of C60fullerenes with a broad spectrum of therapeutic activities and synthesis of their hydrated forms for enteral and parenteral administration producing no acute or chronic toxic effects.

The frequencies and spectra of surnames have been analyzed in groups of raions (districts) of the Belgorod oblast (region) with different degrees of population subdivision. The "family name portraits" of districts with low (0.00003 less sign f* < 0.00022, f*(r) = 0.00015) and moderate (0.00023 < f*(r) < 0.00042, f*(r) = 0.00029) inbreeding levels are similar both to each other and to the "family name portrait" of the Belgorod oblast as a whole. Districts with high subdivision levels (0.00043 < f*(r) < 0.00125, f*(r) = 0.00072) had very distinctive surname spectra and the highest surname frequencies. Intense immigration to the Belgorod oblast significantly affects its population genetic structure, decreasing the population subdivision.

The gene pool of the entire population of all the 21 raions (districts) of the Belgorod oblast (region) has been studied using anthroponymic data. Considerable geographic variations of the number of surnames and the degree of population subdivision (0.00003 < f(r)* < 0.00125) in the 21 districts have been demonstrated. Districts with low population subdivision levels are mainly located in the central and southwestern raions of the Belgorod oblast, contain an urbanized area (city), and border on Ukraine (they are characterized by a considerable Ukrainian immigration). Urbanization significantly affects the population structure of the Belgorod oblast. In urbanized districts, rural populations lack the relationships between the population size, number of surnames, and population subdivision level (f(r)).

The aim of the study was to investigate genetic characteristics of patients with chronic obstructive bronchitis (COB) using classic biochemical markers, their contribution to the development and course of the disease, and morphological peculiarities of erythrocytes in these patients. The subjects were 60 COB patients and 50 practically healthy people; their serum samples were studied. The following classic biochemical markers were investigated: haptoglobin; transferrin; C3 compliment component; group-specific component; ABO blood systems and Rh-factor. Erythrocytometry of blood smears was performed upon admission and before discharge. The study evaluated the contribution of heredity to the forming of COB and established specific genetic markers of predisposition to the development of COB and certain features of its clinical course; the condition of peripheral blood erythrocytes in COB patients was studied.

Based on the characteristics of body height and weight in 4905 newborns, the population-genetic structure of the rural raions (districts) of Kursk oblast (region) and in the city of Kursk was determined. An "adaptive norm area" with respect to body weight and height was distinguished for newborns in Kursk oblast. On the average, the anthropometric parameters of 20% of infants from the studied populations fell within this area. The height and growth of newborns exhibited a pronounced geographic variation and depended on the level of urbanization, as well as the sex and the health status of the newborns. In district populations, the body height and the variances of the body height and weight increased with an increase in endogamy. Therefore, the relative numbers of newborns with large values of both weight and height, as well as those with a medium body height and a small body weight, were increased. Conversely, the relative numbers of newborns with a low weight and height and with a disturbed weight-height correlation were decreased.

The distributions of AB0 and Rhesus phenotypes and the corresponding genes in the population of Kursk oblast were studied. Based on these data, genetic differentiation of rural populations with respect to the d gene frequency was revealed. The differentiation was determined by the differences in the genetic and demographic structure of these rural populations. The frequency of homozygotes for the recessive gene d and the incidence of malformations affecting the children's viability increased with an increase in the inbreeding level of a population. Genetic distances between the population of Kursk oblast and other populations were estimated.