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.

Genetic Variants rs1049255 CYBA and rs2333227 MPO are Associated with Susceptibility to Coronary Artery Disease in Russian Residents of Central Russia.

Aim      To study association of single-nucleotide polymorphisms rs1049255 CYBA and rs2333227 MPO with development of ischemic heart disease (IHD) in Russian residents of Central Russia.Material and methods  The study material was DNA samples from 436 patients with IHD (265 men, 171 women; mean age, 61 years) and 370 sex- and age-matched arbitrarily healthy volunteers (209 men, 161 women; mean age, 60 years). Genotyping was performed by allelic discrimination with TaqMan probes.Results Comparative analysis of genotype frequency (log-additive regression model) showed that SNP rs1049255 CYBA (odds ratio, OR, 0.79 at 95 % confidence interval, CI, from 0.65 to 0.96; p=0.02) and rs2333227 MPO (OR 0.72 at 95 % CI from 0.55 to 0.95; p=0.02) were associated with a decreased risk of IHD adjusted for sex and age. Analysis of sex-specific effects showed that the protective effect of rs1049255 CYBA was evident only in men (OR 0.72 at 95 % CI from 0.55 to 0.94; p=0.16).Conclusion      The study demonstrated a protective effect of rs1049255 CYBA and rs2333227 MPO with respect of IHD in Russians. The protective effect of rs1049255 CYBA was observed only in men.

[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.

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.

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.

[GENDER-SPECIFIC DIFFERENCES OF ENDOTHELIAL NITRIC OXIDE SYNTHASE E298D POLYMORPHISM AND THE RISK OF STROKE].

Genetic factors can account for the differences in the frequency of stroke between men and women. Despite the scarcity of special clinico-genetic studies of stroke frequency in the two genders, analysis of association between DNA polymorphism and risk of stroke may reveal the influence of genetic factors on the sex-related predisposition to cerebrovascular diseases. The present work was aimed to study the relationship between frequent polymorphisms -786T > C of endothelial nitric oxide synthase (NOS3) gene E298D and the risk of stroke in men and women. 904 DNA samples were obtained from unrelated Russian residents of Central Russia including 480 stroke patients and 424 healthy volunteers. Genotyping was performed by PCR in real time with allele discrimination using TaqMan probes. The homoygous genotype of NOS3 gene E298D was found to be associated with an increased risk of stroke in men (OR 2.60; 95% CI 1.28-5.29, p = 0.01). Neither men nor women showed association of polymorphism -786T > C with the predisposition to stroke. The E298D genotype in men was associated with the enhanced risk of both ischemic (OR 2.38; 95% CI 1.14-4.96, p = 0.02) and hemorrhagic (OR 5,58; 95% CI 1.95-16.05, p = 0.003) stroke. Thus, NOS3 gene E298D polymorphism is a reliable predictor of predisposition to various pathogenetic variants of stroke only in men.

[The combined effect of E298D polymorphism of the endothelial nitric oxide synthase gene and smoking on the risk of cerebral stroke].

Violations of the endothelium-dependent regulation of cerebral vessel tone are an important link in the pathogenesis of cerebrovascular disorders. The purpose of this study was to investigate the association of--86T>C and E298D polymorphisms of the endothelial nitric oxide synthase(NOS3) gene with the risk of ce-ebral stroke (CS) in Russian inhabitants of Central Russia, as well as to evaluate the trigger effect of smoking on the risk of CS in carriers of genotypes NOS3. Genotyping of-786T>C and E298D polymorphisms of the NOS3 gene was carried out through real time. CR and TaqMan allele discrimination assays. It was deter-ined that the genotype 298DD is associated with the risk of CS (OR =-1.71, 95% CII= 1.05-2.78, P= 0.03). Subsequent analysis showed that genotype 298 DD (OR = 3.75; 95% CII= 1.39-10.11; P= 0.01) is associatedw ith an increased risk of CS exclusively in smoking individuals. The combination ofg enotypes -786T/Cx298D/D was associated with the risk of CS. n smokers (OR = 7.71; 95% CI = 1.31-45.34; P = 0.02). In the present study, it was found that smoking is a significant modifying risk factor for cerebral stroke in the carriers of the 298DD and -786T/C. enotypes of endothelial nitric oxide synthase.

[Investigation of the association between the HindIII polymorphism of the LPL gene and the Taq1b polymorphism of the CETP gene with the risk of atherothrombotic stroke in the dwellers of Central Russia]. / Issledovanie vzaimosvyazi polimorfizmov HindIII gena LPL i Taq1b gena CETP s riskom razvitiya aterotromboticheskogo insul'ta u zhitelei Tsentral'noi Rossii.

AIM: To investigate the association between LPL HindIII (rs320) and CETP Taq1b (rs708272) polymorphisms with the risk of atherothrombotic stroke (ATS) in the population of Central Russia. MATERIAL AND METHODS: A total of 832 DNA samples obtained from 417 patients with ATS and from 415 healthy individuals of the corresponding gender and age were investigated. The polymorphisms were genotyped by a real-time PCR assay using TaqMan probes. RESULTS: The carriage of heterozygous LPL +495TG genotype was found to be associated with the lower risk of ATS (odds ratio (OR)=0.71; 95% CI: 0.53-0.94; p=0.02). A gender-stratified analysis showed that in the men the variant LPL +495TG genotype was associated with the increased risk of ATS (OR=2.06; 95% CI: 1.03-4.14; р=0.04) while the heterozygous +495GG genotype had a protective effect against the risk of stroke (OR=0.66; 95% CI: 0.45-0.97; р=0.04). Variance analysis established that this polymorphism was found to be associated with the increased prothrombin index in the men with ATS (p=0.01). CONCLUSION: This study was the first to reveal the association of the LPL HindIII (rs320) polymorphism with the increased prothrombin index and the risk of ATS in the Russian male population.