Olga Bushueva

The C718T polymorphism in the 3′-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension

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, Padj=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, Padj=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.

The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility

Gene encoding flavin-containing monooxygenase 3 (FMO3), a microsomal antioxidant defense enzyme, has been suggested to contribute to essential hypertension (EH). The present study was designed to investigate whether common functional polymorphism E158K (rs2266782) of the FMO3 gene is associated with EH susceptibility in a Russian population. A total of 2 995 unrelated subjects from Kursk (1 362 EH patients and 843 healthy controls) and Belgorod (357 EH patients and 422 population controls) regions of Central Russia were recruited for this study. DNA samples from all study participants were genotyped for the FMO3 gene polymorphism through PCR followed by RFLP analysis. We found that the polymorphism E158K is associated with increased risk of essential hypertension in both discovery population from Kursk region (OR 1.36 95% CI 1.09–1.69, P = 0.01) and replication population from Belgorod region (OR 1.54 95% CI 1.07–1.89, P = 0.02) after adjustment for gender and age using logistic regression analysis. Further analysis showed that the increased hypertension risk in carriers of genotype 158KK gene occurred in cigarette smokers, whereas nonsmoker carriers of this genotype did not show the disease risk. This is the first study reporting the association of the FMO3 gene polymorphism and the risk of essential hypertension.

A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility

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.

The cardio-ankle vascular index and ankle-brachial index in young russians.

AIM A noninvasive approach to assess atherosclerosis in young people is of great concern. The cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) reflect the arterial conditions, although the CAVI has not fully been studied in Russian populations. This study aimed to determine the CAVI and ABI in young Russians, to compare these findings with those in their Japanese peers and to investigate the lifestyle correlates and genetic associations with the CAVI and ABI in the Russians. METHODS In addition to several atherosclerotic parameters and self-reported lifestyle factors, the CAVI and ABI levels were measured in 114 Russians (mean 21 years). Four gene polymorphisms, including cholesteryl ester transfer protein (CETP) Taq1B polymorphism, were typed in some of the subjects. RESULTS The Russians exhibited significantly higher CAVI levels compared to their Japanese counterparts (5.87 vs. 5.36; p＜0.05), while the ABI levels were similar between the two populations. In the Russians, the ABI was significantly correlated with the mean blood pressure (r=-0.26) and heart rate (r=-0.43), while the CAVI did not show such correlations. No significant associations existed between lifestyle-related factors and the CAVI or ABI levels. A lower ABI level was found in carriers with the T-allele of CETP Taq1B in the Russians. CONCLUSIONS The reference CAVI value can be specified for individual ethnic populations. Our findings suggest that Russians may develop atherosclerosis-related conditions at a younger age compared to Japanese subjects, although this must be verified in additional studies. The possible association between CETP polymorphisms and the ABI deserves further investigation.

Altered erythrocyte membrane protein composition mirrors pleiotropic effects of hypertension susceptibility genes and disease pathogenesis.

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.

Alcohol Consumption and Cigarette Smoking are Important Modifiers of the Association Between Acute Pancreatitis and the PRSS1-PRSS2 Locus in Men.

Objectives The present study was designed to investigate whether the susceptibility to acute pancreatitis (AP) attributable to polymorphism rs10273639 at the PRSS1-PRSS2 locus is dependent on alcohol consumption and cigarette smoking. Methods A total of 603 unrelated Russian individuals including 304 patients with physician-diagnosed AP and 299 sex- and age-matched healthy controls have been recruited for the study. A polymorphism rs10273639 (–408C>T) of PRSS1-PRSS2 was genotyped by TaqMan-based assay. Results A variant allele –408T (P = 0.003) and genotypes –408CT plus TT (P = 0.002) were associated with decreased AP risk only in men. The odds ratios for AP in the CC homozygotes versus the variant genotypes were 1.95 [95% confidence interval (CI), 0.65–5.85; P = 0.23], 1.72 (95% CI, 0.93–3.20; P = 0.08), and 2.37 (95% CI, 1.09–5.13; P = 0.03) for men who consumed up to 28, 29 to 59, and more than 60 alcohol drinks a week, respectively. Cigarette smokers with the –408CC genotype had an increased risk of AP (odds ratio, 2.07; 95% CI, 1.25–3.42; P = 0.004), whereas nonsmoker carriers did not have a disease risk (odds ratio, 1.48; 95% CI, 0.58–3.82; P = 0.42). Conclusions We confirmed a robust association of polymorphism rs10273639 at PRSS1-PRSS2 with AP in the Russian population. The present study is the first to show that relationship between the locus and disease is significantly modified by alcohol consumption and cigarette smoking.

Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population

Epoxyeicosatrienoic acids (EETs) are important vasoactive products of arachidonic acid metabolism with a wide range of biological actions in the cardiovascular system. The present study investigated whether single nucleotide polymorphisms (SNP) of genes coding cytochrome P450 2C subfamily, enzymes involved in biosynthesis of EETs, are associated with the risk of coronary heart disease (CHD). A total of 1255 unrelated Russian subjects comprising 561 patients with angiographically diagnosed CHD and 694 age- and sex-matched healthy subjects were included in the study. DNA samples from all study participants were genotyped for six common SNPs rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. SNP rs4918758 of CYP2C9 was associated with decreased risk of CHD (codominant model) at a borderline significance with odds ratio adjusted for sex and age 0.61 (95% CI: 0.41-0.92, P=0.038, Q=0.20). SNP rs9332242 of CYP2C9 showed a trend towards association with increased CHD risk in cigarette smokers (P=0.049, Q=0.29). Log-likelihood ratio test (LRT) pointed out epistatic interactions between rs9332242 and rs61886769 of CYP2C9 (codominant model, Pinteraction=0.02), however, this P-value did not survive after correction for multiple tests. Bioinformatic analysis revealed a regulatory potential for a majority of the investigated SNPs. Our preliminary results demonstrate that polymorphisms of genes encoding CYP2C subfamily represent potential genetic markers of CHD susceptibility. Further studies are required to substantiate the contribution of these genes to the disease risk.

Antioxidant-related gene polymorphisms associated with the cardio-ankle vascular index in young Russians

The cardio-ankle vascular index is a measure of arterial stiffness, whereas oxidative stress underlies arterial pathology. This study aimed to investigate the association between the cardio-ankle vascular index and antioxidant-related gene polymorphisms in young Russians. A total of 89 patients (mean age, 21.6 years) were examined by the cardio-ankle vascular index and for 15 gene polymorphisms related to antioxidant enzymes including FMO3 (flavin-containing monooxygenase 3), GPX1 (glutathione peroxidase 1), and GPX4 (glutathione peroxidase 4). A higher cardio-ankle vascular index level was detected in carriers with the KK-genotype of FMO3 polymorphism rs2266782 than in those without (mean levels: 6.2 versus 5.6, respectively, p<0.05). Similarly, a higher cardio-ankle vascular index level was seen in carriers with the CC-genotype of GPX4 polymorphism rs713041 than in those without (6.0 versus 5.5, respectively, p<0.05). We did not observe significant associations between the cardio-ankle vascular index levels and the other gene polymorphisms. Although carriers with the LL-genotype of GPX1 polymorphism rs1050450 showed a higher diastolic blood pressure level than those without, the polymorphism did not affect the cardio-ankle vascular index level. This study showed a significant association between rs2266782 and rs713041 polymorphisms and arterial stiffness, as measured by the cardio-ankle vascular index, in young Russians. The pathways utilised by antioxidant enzymes may be responsible for early arterial stiffening in the Russian population.

Glutathione S-transferase genes and the risk of type 2 diabetes mellitus: the role of sexual dimorphism, gene–gene and gene–smoking interactions in disease susceptibility

Compromised defense against reactive oxygen species (ROS) is considered important in the pathogenesis of type 2 diabetes mellitus (T2DM); therefore, genes encoding antioxidant defense enzymes may contribute to disease susceptibility. This study investigated whether polymorphisms in genes encoding glutathione S‐transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) jointly contribute to the risk of T2DM.

Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia

The aim of this study was to examine the role of hereditary thrombophilia in the development of fetal growth retardation (FGR) in the population of Central Russia.