Association between Polymorphisms of Heat Shock Protein HSPA5 and Risk of Type 2 Diabetes Mellitus.

We studied the relationship between the HSPA5 gene polymorphisms and the risk of type 2 diabetes mellitus. Genotyping of three SNPs of the HSPA5 gene was performed in 1579 patients with type 2 diabetes mellitus and 1650 healthy individuals. It was found that the genotypes rs55736103-T/T, rs12009-G/G, and rs391957-T/C-T/T are associated with increased risk of type 2 diabetes in females. A rare haplotype, rs55736103C-rs12009A-rs391957T HSPA5, associated with a reduced risk of type 2 diabetes in females was found. Associations between polymorphisms of the HSPA5 gene encoding heat shock protein and the risk of type 2 diabetes mellitus were established for the first time.

Polymorphism in Genes Encoding Adaptor Proteins ST13 and STIP1 and the Risk of Ischemic Stroke: a Pilot Study.

Adaptor proteins stress induced phosphoprotein 1 (STIP1) and ST13 Hsp70 interacting protein (ST13) may play a crucial role in the pathophysiology of ischemic stroke through controlling protein folding, neuronal survival, and regulation of HSP70/HSP90. The present pilot study investigated whether tagSNPs in genes encoding ST13 (rs138335, rs138344, rs7290793, and rs138344) and STIP1 (rs4980524) are associated with ischemic stroke. DNA samples from 721 ischemic stroke patients and 471 healthy controls were genotyped using the MassArray-4. Our research revealed a relationship between rs138344 ST13 and the risk of ischemic stroke, which was seen only in females (risk allele G; OR=1.34, 95%CI=1.07-1.69; p=0.01). The haplotype rs138335G-rs138344C-rs7290793C ST13 was linked with lower risk of ischemic stroke in females: OR=0.42; 95%CI=0.26-0.68; p=0.0005. Thus, ST13 represents a novel genetic marker for ischemic stroke.

Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus.

We showed for the first time that polymorphisms rs2075938 and rs2075938 of the NCF4 gene are associated with the risk of chronic heart failure in patients with type 2 diabetes mellitus (n=1310). In particular, haplotypes ATGTCTAT (OR=1.74, 95%CI=1.23-2.47; p=0.0017) and ATATTCAC (OR=2.83, 95%CI=1.33-6.03; p=0.0072) of NCF4 increase the risk of chronic heart failure in type 2 diabetes mellitus patients. The results show that NADPH oxidase subunit NCF4 is involved in the molecular mechanisms of myocardial damage in type 2 diabetes mellitus.

The Protective Effect of Polymorphisms rs2681472 and rs17249754 of the ATP2B1 Gene Against Coronary Artery Disease and Hypertension is Abolished by Tobacco Smoking.

Aim    To study the relationship of single nucleotide polymorphisms rs2681472 and rs17249754 in the ATP2B1 gene with risk of ischemic heart disease (IHD) and arterial hypertension (AH) among residents of Central Russia and to evaluate the trigger role of smoking as a risk factor for development of IHD and AH in carriers of ATP2B1 gene polymorphic variants.Material and methods    The study included DNA samples from 1960 residents of Central Russia of Slavic origin. Among them, there were 1261 patients with cardiovascular diseases and 699 healthy persons. The vast majority of patients had both IHD and AH. Genotyping was performed using the iPLEX technique on a MassARRAY-4 genomic mass-spectrometer. The relationship of ATP2B1 alleles, genotypes, and haplotypes with the risk of diseases was calculated by logistic regression analysis with adjustments for sex and age.Results    Carriage of AG and GG (rs2681472) genotypes and GA (rs17249754) genotype was associated with a reduced risk of both IHD (p=0.0057 and p=0.022 for rs2681472 and rs17249754, respectively) and AH (p=0.016 and p=0.036, respectively). Rare rs2681472G-rs17249754G and rs2681472A-rs17249754A haplotypes were associated with a reduced risk of IHD (odds ratio, OR, 0.22; 95 % CI: 0.11-0.46, p=0.0001) and AH (OR, 0.22; 95 % CI: 0.10-0.47, p=0.0001). Analysis of the groups stratified by the smoking status showed that in smokers, the studied polymorphic variants did not have a protective action with respect of either IHD or AH. However, in non-smokers, the genotypes AG and GG rs2681472 (OR, 0.62; 95 % CI: 0.47-0.80, p=0.0004) and GA rs17249754 (OR, 0.61; 95 % CI: 0.47-0.81, p=0.0004) were associated with a reduced risk of IHD and AH (OR, 0.63; 95 % CI: 0.48-0.83, p=0.0004 for rs2681472; OR, 0.63; 95 % CI: 0.48-0.83, p=0.001 for rs17249754), as well as the carriage of the minor alleles rs2681472­G and rs17249754­A.Conclusion    It was shown for the first time that the polymorphic variants rs17249754 and rs2681472 of the ATP2B1 gene are associated with a reduced risk for IHD and AH only in non-smokers.

Polymorphism rs1046495 of the GFER Gene as a New Genetic Marker of Preposition to Type 2 Diabetes Mellitus.

The study involving 2830 subjects (1444 patients with type 2 diabetes mellitus and 1386 healthy controls) an association of the rs1046495 polymorphism of the GFER gene encoding FADdependent sulfhydryl oxidase with low risk of the disease in non-obese patients (OR=0.76, 95%CI 0.57-0.99, p=0.029). The protective effect of the polymorphic gene variant remained significant in individuals who consumed fresh vegetables and fruits (p=0.014), proteins (p=0.0017), and did not consume carbohydrate- and fat-reach food (p=0.0047). The association of the minor allele rs1046495-C with type 2 diabetes mellitus can be explained by its more pronounced effect on the expression of the GFER enzyme that through glutathionation maintains the ROS level for optimal functioning of complexes III and IV of the electron transport chain and promotes the formation of disulfide bonds in the CHCHD4 chaperone molecule. Impaired activity of this molecule underlies mitochondrial dysfunction, one of the key pathological changes in patients with type 2 diabetes mellitus.

[Polymorphic variants of glutathione reductase - new genetic markers of predisposition to type 2 diabetes mellitus].

AIM: To study the associations of three common single nucleotide variants of the gene encoding antioxidant system enzyme, glutathione reductase GSR with a predisposition to type 2 diabetes (T2D). MATERIALS AND METHODS: The observational mono-center transverse controlled study involved 1032 type 2 diabetics (640 women, 392 men; mean age 61.14.8 years) and 1056 healthy volunteers (676 women, 380 men; mean age 60.96.2 years). Eating habits were evaluated retrospectively according to questionnaire data. A 10 ml blood sample was drawn from all participants in the study for genetic and biochemical tests. Genotyping was done with the use of the iPLEX technology on MassArray System. RESULTS: We first identified the relationship of the polymorphisms rs2551715, rs2911678, rs3757918 of the GSR gene with a reduced risk of developing T2D in the Russian population. At the same time, the protective effects of the variants of the glutathione reductase gene manifested only in individuals with normal body weight provided they consumed fresh vegetables and fruits, whereas in those with insufficient consumption of plant foods, as well as in all overweight and obese patients, the protective effect of GSR was not observed. In patients with T2D, the plasma levels of hydrogen peroxide and the glutathione dimer were sharply increased compared with the controls. We also found that the rs2551715 polymorphism was associated with a lower concentration of hydrogen peroxide in the blood plasma of patients with T2D, while SNP rs2911678 was associated with a decrease in the concentration of the oxidized form of glutathione. Bioinformatical analysis confirmed the positive effect of alternative alleles on GSR expression and revealed the closest protein partners of the enzyme and their joint participation in the metabolism of acetyl-CoA, the catabolism of hydrogen peroxide and the control of cellular redox homeostasis. CONCLUSION: Polymorphic variants of the GSR gene rs2551715, rs2911678, rs3757918 are associated with a predisposition to T2D, but their relationship with the disease is modulated by the consumption of fresh vegetables and fruits and depends on body mass index.

[Polymorphic locus rs1061624 of the ТNFR2 gene is associated with the development of arterial hypertension in males].

Aim To study the involvement of cytokine polymorphous loci in development of arterial hypertension (AH) in men from the Central Black Earth region of Russia.Materials and methods 821 men were evaluated, including 564 patients with AH and 257 individuals of the control group. Analysis of 8 cytokine mononucleotide polymorphisms (MNP) was performed using the real-time polymerase chain reaction with TagMan probes. Statistical analysis was performed with the STATISTICA (v.10.0) and PLINK (v.1.06) software. The regulatory potential of MNP was analyzed with the HaploReg (v.4.1) service (http://archive.broadinstitute.org).Results The rs1061624 ТNFR2 polymorphous locus was associated with development of AH in men in recessive (odd ratio (OR), 0.33; 95 % confidence interval (CI): 0.18-0.61, рperm=0.0004) and additive (OR, 0.50, 95 % CI: 0.34-0.74, рperm=0.0006) genetic models and exerted a protective effect in development of AH. The rs1061624 MNP of the ТNFR2 gene has a regulatory significance; it is located in the DNA sites hypersensitive to the action of DNAase 1 and in binding sites for transcriptional factors and histones that mark enhancers and promoters in different organs and tissues.Conclusion The rs1061624 ТNFR2 gene polymorphism is involved in the development of AH in men of the Central Black Earth region of Russia.

rs11927381 Polymorphism and Type 2 Diabetes Mellitus: Contribution of Smoking to the Realization of Susceptibility to the Disease.

In the study that included 579 patients with type 2 diabetes mellitus and 542 healthy individuals from Slavonic population, an association was found between IGF2BP2 gene rs11927381 polymorphism and increased risk of developing the disease. However, this association was observed for smoking patients and was not detected for non-smokers. Bioinformatics analysis showed that the spectrum of transcription factors binding with high-risk C allele differ from the spectrum of transcription factors specifically binding with the reference T allele; these factors are involved in the regulation of the biosynthesis of ketone bodies and cellular response to glucocorticoid hormones. The results suggest that smoking plays a trigger role in the relationship of the polymorphic variant rs11927381 of the IGF2BP2 gene with the development of type 2 diabetes mellitus.

[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.

Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium.

BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.

[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.

Association of the HindIII Lipoprotein Lipase Gene Polymorphism with the Development of the Non-Biliary Acute Pancreatitis: a Pilot Study.

We studied the relationship between lipoprotein lipase (LPL) gene HindIII polymorphism and the development of acute pancreatitis in the Russian population. Whole blood samples were collected from 145 patients with acute non-biliary pancreatitis and 191 healthy individuals. Genotyping of LPL gene HindIII (rs320) polymorphism was performed by PCR with TaqMan assay. It was found that allele H+ (OR=0.63, 95%CI 0.41-0.96, p=0.03) and genotype H+/H+ (OR=1.79, 95%CI 1.06-3.04, p=0.03) were associated with the risk of acute non-biliary pancreatitis only in males. In this study, the relationship between HindIII polymorphism of LPL gene with the risk of acute non-biliary pancreatitis was revealed.

[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.

[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).

Association of Flavin Monooxygenase Gene E158K Polymorphism with Chronic Heart Disease Risk.

We studied the relationship between the risk of chronic heart disease and FMO3 gene polymorphism E158K analyzed by PCR and restriction fragment length polymorphism (RFLP) analysis. The homozygous 158KK genotype of FMO3 gene is associated with high risk of chronic heart disease in women, but not in men. FMO3 gene polymorphism E158K is a significant predictor of predisposition to chronic heart disease in women.

[The relationship between polymorphism 640A>G of the CYBA gene with the risk of ischemic stroke in the population of the Central Russia]. / Sviaz' polimorfizma 640a>g gena cyba s riskom razvitiia ishemicheskogo insul'ta u russkikh v Tsentral'noĭ Rossii.

AIM: Reactive oxygen species an important role in the pathogenesis of cerebrovascular disorders. NAD(P)H oxidases are one of the main sources of superoxide anions in cerebral arteries. NAD(P)H oxidase represents molecular complex and its p22phox subunit is coded by the CYBA gene located in the long arm of chromosome 16. We studied the association between the 640A>G polymorphism (rs1049255) of the CYBA gene with the risk of stroke in the Russian population. MATERIAL AND METHODS: Authors examined 887 people: 445 stroke patients, including 393 patients with ischemic stroke and 52 patients with hemorrhagic stroke, and 442 healthy people (controls). Genotyping was performed using real-time PCR and TaqMan allele discrimination assays. RESULTS: It was found that carriers of the heterozygous genotype 640AG of the CYBA gene were at a lower risk of stroke compared to the controls (OR=0.77, 95% CI=0.59-1.01, p=0.05). The stratified analysis showed that the genotype 640AG was associated with decreased risk of ischemic stroke (OR=0.75, 95% CI=0.57-0.99, p=0.04). CONCLUSION: The present study is the first to show that polymorphism 640A>G of the CYBA gene is associated with the risk of ischemic stroke.

[SMOKING AS A TRIGGER FACTOR IN THE DEVELOPMENT OF DIABETIC ANGIOPATHY OF LOWER EXTREMITIES IN MEN WITH METHYLENETETRAHYDROFOLATEREDUCTASE 677TT GENOTYPE].

Enhanced thrombogenesis in patients with diabetes mellitus (D) is related to genetically determined disorders of the blood coagulation system analogous to those associated with hereditary thrombophilia. The aim of this work was to elucidate the relationship between the functionally significant methylenetetrahydroxyfolatereductase (MTHFR) C677T (rs1801133) gene polymorphism and the development of diabetic angiopathy of lower extremities (DALE) in ethnic Russian men residing in Central Russia (mostly Kursk region). The study involved 434 subjects including 50 with DALE and 384 healthy volunteers. All of them were genotypedfor the MTHFR C677T gene polimorphim by real-time PCR with allele discrimination using TaqMan-probes. No significant differences in the frequency of alleles of MTHFR C677T gene polymorphism were documented between the general samples and sex-matched groups. Stratified sex-specific analysis showed that 677TT genotype is associated with increased risk of DALE in smoking men (OR 4.2; 95% CI 1.28-13.79, p=0.01). In non-smoking men the 677TTgenotype was unrelated to the development of this complication. It is concluded that the risk of DALE is determined by the close relationship between genetic (UTHFR gene) and exogenous (smoking) factors which suggests the multifactorial nature of this pathology.

[Genetic and biochemical mechanisms of involvement of antioxidant defense enzymes in the development of bronchial asthma].

In the present review we have analyzed and summarized recent literature data on genetic and biochemical mechanisms responsible for involvement of antioxidant defense enzymes in the etiology and pathogenesis of bronchial asthma. It has been shown that the mechanisms of asthma development are linked with genetically determined abnormalities in the functioning of antioxidant defense enzymes. These alterations are accompanied by a systemic imbalance between oxidative and anti-oxidative reactions with the shift of the redox state toward increased free radical production and oxidative stress, a key element in the pathogenesis of bronchial asthma.