Elena Klyosova

Objective This pilot study investigated whether single nucleotide polymorphisms (SNP) in the NOX5 gene (NADPH oxidase 5) are associated with the type 2 diabetes (T2D) risk. Subjects and methods A total of 1579 patients with T2D and 1627 age- and sex-matched healthy subjects were recruited for this study. Genotyping of common SNPs, namely rs35672233, rs3743093, rs2036343, rs311886, and rs438866, was performed using the MassArray-4 system. Results SNP rs35672233 was associated with an increased risk of T2D (OR = 1.67, [...] ABSTRACT Objective This pilot study investigated whether single nucleotide polymorphisms (SNP) in the NOX5 gene (NADPH oxidase 5) are associated with the type 2 diabetes (T2D) risk. Subjects and methods A total of 1579 patients with T2D and 1627 age- and sex-matched healthy subjects were recruited for this study. Genotyping of common SNPs, namely rs35672233, rs3743093, rs2036343, rs311886, and rs438866, was performed using the MassArray-4 system. Results SNP rs35672233 was associated with an increased risk of T2D (OR = 1.67,

Aim. To study the effect of EDNRA rs6842241 and MRAS rs9818870 polymorphic variants on the lipid-lowering effect of rosuvastatin in patients with coronary artery disease (CAD), and to determine the role of these loci in the development of CAD among Central Russia residents.Material and methods. The pharmacogenetic study involved 116 patients with class II-III stable angina. Patients received rosuvastatin with dose titration to achieve target low-density lipoprotein cholesterol (LDL-C) levels. The genetic and epidemiological study included DNA samples of 1960 Central Russia residents (1261 patients with CAD and 699 healthy individuals). Genotyping of polymorphic variants was performed on a MassARRAY-4 genomic mass spectrometer. Associations of polymorphisms with lipid changes for 1, 6 and 12 months of follow-up were calculated using linear regression analysis adjusted for sex, age, body mass index and rosuvastatin dose; associations with CAD risk — using logistic regression analysis adjusted for sex and age. The statistical significance of associations was calculated using the permutation test.Results. Carriage of the AA and CA genotypes of EDNRA rs6842241 variant was associated with a weakening of the rosuvastatin lipid-lowering effect in relation to total cholesterol (β=0,075, p=0,001) and LDL-C (β=0,145, p=0,017) at the end of the first month and 12 months of therapy (β=0,049, p=0,013 and β=0,072, p=0,040, respectively). Carriage of the AA genotype of EDNRA rs6842241 variant was associated with an increased CAD risk (odds ratio 5,36; 95% confidence interval 1,62-17,71, p=0,004). MRAS rs9818870 variant was not associated with rosuvastatin pharmacogenetics or with the CAD risk. Both polymorphic variants were not associated with lipid levels outside of lipid-lowering therapy, as well as with the triglyceride changes. High-density lipoprotein cholesterol levels during the entire follow-up period changed insignificantly.Conclusion. The EDNRA rs6842241 variant is associated with both a weakening of the lipid-lowering effect of rosuvastatin in CAD and an increased risk of its development in the population.

Aim . To study the association of the rs386000 polymorphic variant in the LILRA3 gene with the risk of developing obliterating atherosclerosis of the lower extremity arteries (OALEA). Material and methods . 1277 individuals of Slavic origin were examined (629 patients with OALEA and 648 healthy volunteers). Genotyping of the LILRA3 gene rs386000 was performed with a MassARRAY-4 genomic mass spectrometer. Polymorphic variants of the LILRA3 gene, that encodes the leukocyte immunoglobulin-like receptor A3, may be attractive objects for studying the mechanisms of atherosclerosis. Results . The study showed that the rs386000 polymorphic variant in the LILRA3 gene was associated with the risk of developing OALEA. However, this association was characterized by sexual dimorphism: in men, carriage of the rs386000-C allele (p=0.03) and the rs386000-C/C genotype (p=0.01) was protective against the risk of developing OALEA, while in women, this polymorphism did not influence the susceptibility to the disease. Single nucleotide polymorphism (SNP) annotation showed that carriage of the rs386000‑C allele was associated with an increased expression of the LILRA2, LILRB5, LILRA6, LILRP1 and TSEN34 genes and a decreased expression of the LILRA3 and LILRA5 genes in the blood. Conclusion . The present study revealed for the first time an association of the rs386000‑C allele of the LILRA3 gene with a reduced risk of developing OALEA. Further studies, including experimental studies, will determine the specific mechanisms mediating the involvement of the LILRA3 gene rs386000 polymorphism in the molecular mechanisms for the development of obliterating atherosclerosis, as well as the nature of the sex-specific association of the polymorphism.

Aminopeptidase N (ANPEP), a membrane-associated ectoenzyme, has been identified as a susceptibility gene for type 2 diabetes (T2D) by genome-wide association and transcriptome studies; however, the mechanisms by which this gene contributes to disease pathogenesis remain unclear. The aim of this study was to determine the comprehensive contribution of ANPEP polymorphisms to T2D risk and annotate the underlying mechanisms. A total of 3206 unrelated individuals including 1579 T2D patients and 1627 controls were recruited for the study. Twenty-three common functional single nucleotide polymorphisms (SNP) of ANPEP were genotyped by the MassArray-4 system. Six polymorphisms, rs11073891, rs12898828, rs12148357, rs9920421, rs7111, and rs25653, were found to be associated with type 2 diabetes for the first time (P _perm ≤0.05). Common haplotype rs9920421G-rs4932143G-rs7111T was strongly associated with increased risk of T2D (P _perm =5.9×10 ^-12 ), whereas two rare haplotypes such as rs9920421G-rs4932143C-rs7111T (P _perm =6.5×10 ^-40 ) and rs12442778A-rs12898828A-rs6496608T-rs11073891C (P _perm =1.0×10 ^-7 ) possessed strong protection against disease. We identified 38 and 109 diplotypes associated with T2D risk in males and females, respectively (FDR≤0.05). ANPEP polymorphisms showed associations with plasma levels of fasting blood glucose, aspartate aminotransferase, total protein and glutathione (PANPEP , were discovered as novel susceptibility markers for type 2 diabetes mellitus. ne common and two rare haplotypes of ANPEP are strongly associated with increased and decreased risk of type 2 diabetes, respectively. Thirty eight and one hundred and nine ANPEP diplotypes influenced disease risk in males and females, respectively. Polymorphisms of ANPEP were associated with plasma levels of fasting blood glucose, aspartate aminotransferase, total protein, glutathione, reactive oxygen species and uric acid in diabetics. Increased plasma levels of ANPEP and liver enzymes (AST, ALT, and GGT) in T2D patients may reflect an adaptive response to glutathione deficiency through the formation of more amino acid precursors of glutathione.

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 p

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 rs2681472‑G and rs17249754‑A. 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.

Impaired redox homeostasis in the endoplasmic reticulum (ER) may contribute to proinsulin misfolding and thus to activate the unfolded protein response (UPR) and apoptotic pathways, culminating in pancreatic β-cell loss and type 2 diabetes (T2D). The present study was designed to identify differentially expressed genes (DEGs) encoding enzymes for glutathione metabolism and their impact on the expression levels of genes regulating protein folding and UPR in β-cells of T2D patients. The GEO transcriptome datasets of β-cells of diabetics and non-diabetics, GSE20966 and GSE81608, were analyzed for 142 genes of interest using limma and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism (ANPEP, PGD, IDH2, and CTH), protein-folding (HSP90AB1, HSP90AA1, HSPA1B, HSPA8, BAG3, NDC1, NUP160, RLN1, and RPS19BP1), and unfolded protein response (CREB3L4, ERP27, and BID). The GCLC gene, encoding the catalytic subunit of glutamate–cysteine ligase, the first rate-limiting enzyme of glutathione biosynthesis, was moderately down-regulated in diabetic β-cells from both datasets (p ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, GCLC, GCLM, and GSS affect the expression levels of genes encoding molecular chaperones and those involved in the UPR pathway. This study showed for the first time that diabetic β-cells exhibit alterations in the expression of genes regulating glutathione metabolism, protein-folding, and UPR and provided evidence for the molecular crosstalk between impaired redox homeostasis and abnormal protein folding, underlying ER stress in type 2 diabetes.

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and p-values were calculated through adaptive permutation tests by the PLINK software, v1.9. Over one-year rosuvastatin therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm < 0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm < 0.05). In conclusion, polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and P-values were calculated through adaptive permutation tests. Over one-year therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm<0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm<0.05). In conclusion, the polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.