Polymorphisms of ANPEP Gene Are Associated with Microvascular Complications of Type 2 Diabetes.

We studied the association of polymorphisms in the aminopeptidase N gene (ANPEP) with the development of diabetic retinopathy and nephropathy in patients with type 2 diabetes mellitus (T2DM). DNA samples from T2DM patients (n=1425) were genotyped for 23 single nucleotide polymorphisms (SNPs) using the MassARRAY system. Associations of SNP rs13380049 of the ANPEP gene with a lower risk of diabetic retinopathy (OR=0.

Serum Concentrations of Pro- and Anti-Inflammatory Cytokines in Wistar Rats Subjected to Immobilization Stress and Treated with Tuftsin-Pro-Gly-Pro Peptide.

It was found that 28-day immobilization stress in male Wistar rats leads to significant increase in the serum concentrations of proinflammatory cytokines IL-1β, IL-6, IFNγ, and monocyte chemoattractant protein-1 (MCP-1) and a decrease in the content of anti-inflammatory IL-10, as well as the ratio IL-1β/IL-10, IL-6/IL-10, and IFNγ/IL-10 compared to non-stressed animals. Administration of the heptapeptide tuftsin-Pro-Gly-Pro produced a corrective effect on cytokine concentrations under stress conditions: at a dose of 750 μg/kg, the peptide decreased the concentrations of IL-1β, IFNγ, and MCP-1 and cytokine ratios (IL-1β/IL-10 and IFNγ/IL-10), while at a dose of 250 μg/kg, it increased IL-10 levels and decreased IL-6/IL-10 and IFNγ/IL-10 ratios.

NADPH oxidase 5 is a novel susceptibility gene for type 2 diabetes mellitus.

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.

The link between the ANPEP gene and type 2 diabetes mellitus may be mediated by the disruption of glutathione metabolism and redox homeostasis.

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.

Lipid-associated GWAS loci as important markers of the risk, severity, and clinical course of peripheral artery disease.

Background: This study investigated the relationship between lipid-associated loci identified through genome-wide association studies (GWAS) and the risk of peripheral artery disease (PAD), its severity, as well as clinical and laboratory features.

Research Design And Methods: A study included 1263 unrelated Russian subjects, consisting of 620 patients diagnosed with PAD and 643 healthy controls. Thirteen single nucleotide polymorphisms (SNP) were genotyped using the MassArray-4 system.

The rs2341471-G/G genotype of activating transcription factor 6 (ATF6) is the risk factor of type 2 diabetes in subjects with obesity or overweight.

Background: Numerous studies have demonstrated that the onset of type 2 diabetes (T2D) is linked to the reduction in ß-cell mass caused by apoptosis, a process initiated by endoplasmic reticulum (ER) stress. The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the ATF6 gene (activating transcription factor 6), a key sensor of ER stress, and T2D susceptibility.

Methods: The study involved 3229 unrelated individuals, including 1569 patients with T2D and 1660 healthy controls from Central Russia.

The Promoter Polymorphism rs3918226 of the Endothelial Nitric Oxide Synthase Gene as a Novel Susceptibility Marker for Peripheral Artery Disease.

Background: This pilot study aimed to investigate the association between the single nucleotide polymorphism (SNP) rs3918226 in the promoter of the nitric oxide synthase (NOS3) gene and the risk of peripheral artery disease (PAD).

Methods: DNA samples from 1,263 unrelated subjects of Slavic origin, including 620 patients with PAD and 643 controls, were genotyped for the SNP rs3918226 using the MassArray-4 system.

Results: The rs3918226 polymorphism was found to be strongly associated with an increased risk of PAD regardless of coronary artery disease, hypertension, or cigarette smoking (odds ratio [OR] = 2.

The discovery of GGT1 as a novel gene for ischemic stroke conferring protection against disease risk in non-smokers and non-abusers of alcohol.

Objectives: Increased plasma gamma-glutamyl transferase (GGT1) has been identified as a robust and independent risk factor for ischemic stroke (IS), but the molecular mechanisms of the enzyme-disease association are unclear. The present study investigated whether polymorphisms in the GGT1 gene contribute to IS susceptibility.

Materials And Methods: DNA samples obtained from 1288 unrelated individuals (600 IS patients and 688 controls) were genotyped for common single nucleotide polymorphisms of GGT1 using the MassArray-4 platform.

Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus.

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 and GREIN software, respectively.

Lipid-Associated GWAS Loci Predict Antiatherogenic Effects of Rosuvastatin in Patients with Coronary Artery Disease.

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.

Single Nucleotide Polymorphisms of the Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes.

Single nucleotide polymorphisms (SNP) in the (Rac family small GTPase 1) gene have recently been linked to type 2 diabetes (T2D) and hyperglycemia due to their contribution to impaired redox homeostasis. The present study was designed to determine whether the common SNPs of the gene are associated with diabetic complications such as neuropathy (DN), retinopathy (DR), nephropathy, angiopathy of the lower extremities (DA), and diabetic foot syndrome. A total of 1470 DNA samples from T2D patients were genotyped for six common SNPs by the MassArray Analyzer-4 system.

Molecular Genetics of Abnormal Redox Homeostasis in Type 2 Diabetes Mellitus.

Numerous studies have shown that oxidative stress resulting from an imbalance between the production of free radicals and their neutralization by antioxidant enzymes is one of the major pathological disorders underlying the development and progression of type 2 diabetes (T2D). The present review summarizes the current state of the art advances in understanding the role of abnormal redox homeostasis in the molecular mechanisms of T2D and provides comprehensive information on the characteristics and biological functions of antioxidant and oxidative enzymes, as well as discusses genetic studies conducted so far in order to investigate the contribution of polymorphisms in genes encoding redox state-regulating enzymes to the disease pathogenesis.

The Joint Link of the rs1051730 and rs1902341 Polymorphisms and Cigarette Smoking to Peripheral Artery Disease and Atherosclerotic Lesions of Different Arterial Beds.

Genome-wide association studies (GWAS) have discovered numerous single nucleotide polymorphisms (SNP) contributing to peripheral artery disease (PAD), but their joint effects with risk factors like cigarette smoking (CS) on disease susceptibility have not been systematically investigated. The present study looked into whether CS mediates the effects of GWAS loci on the development of PAD and atherosclerotic lesions in different arterial beds. DNA samples from 1263 unrelated individuals of Slavic origin including 620 PAD patients and 643 healthy subjects were genotyped by the MassArray-4 system for rs1051730, rs10134584, rs1902341, rs10129758 which are known as PAD-associated GWAS loci.

A Polymorphism in the Gene Encoding Heat Shock Factor 1 () Increases the Risk of Type 2 Diabetes: A Pilot Study Supports a Role for Impaired Protein Folding in Disease Pathogenesis.

The aim of this pilot study was to investigate whether polymorphisms in the gene encoding heat shock factor 1 (), a transcriptional activator of molecular chaperones, play a role in the development of type 2 diabetes (T2D). A total of 3229 unrelated individuals of Slavic origin, including 1569 T2D patients and 1660 age- and sex-matched healthy controls, were enrolled for the study. Five common single nucleotide polymorphisms (SNPs) of the gene were genotyped using the MassArray-4 system.

[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.

ACTH(6-9)-Pro-Gly-Pro ameliorates anxiety-like and depressive-like behaviour and gut mucosal microbiota composition in rats under conditions of chronic restraint stress.

The effects of the peptide ACTH(6-9)-Pro-Gly-Pro at doses of 5; 50; 500 μg/kg on the Wistar rats' behaviour and gut mucosal microbiota composition under conditions of chronic immobilization stress (CRS) were studied. CRS increased anxiety-like and depressive-like behaviour, disturbances in locomotor activity and gut dysbiosis. Administration of ACTH(6-9)-Pro-Gly-Pro showed many phenotypic results.

The Impact of Genetic Polymorphisms in Glutamate-Cysteine Ligase, a Key Enzyme of Glutathione Biosynthesis, on Ischemic Stroke Risk and Brain Infarct Size.

The purpose of this pilot study was to explore whether polymorphisms in genes encoding the catalytic (GCLC) and modifier (GCLM) subunits of glutamate-cysteine ligase, a rate-limiting enzyme in glutathione synthesis, play a role in the development of ischemic stroke (IS) and the extent of brain damage. A total of 1288 unrelated Russians, including 600 IS patients and 688 age- and sex-matched healthy subjects, were enrolled for the study. Nine common single nucleotide polymorphisms (SNPs) of the GCLC and GCLM genes were genotyped using the MassArray-4 system.

Association between RAC1 gene variation, redox homeostasis and type 2 diabetes mellitus.

Background: Increased production of reactive oxygen species (ROS) and oxidative stress are known to play a key role in the pathogenesis of type 2 diabetes (T2D); however, the relationship between genes encoding a multi-subunit ROS-generated enzyme NADPH oxidase and disease susceptibility remains unexplored.

Aims: The present pilot study investigated whether single-nucleotide polymorphisms (SNP) at the RAC1 gene (Rac family small GTPase 1), a molecular switcher of NADPH oxidase, are associated with the risk of T2D, glucose metabolism and redox homeostasis.

Materials & Methods: DNA samples from 3206 unrelated Russian subjects (1579 T2D patients and 1627 controls) were genotyped for six common SNPs rs4724800, rs7784465, rs10951982, rs10238136, rs836478 and rs9374 of RAC1 using the MassArray-4 system.

Genetic variation at the catalytic subunit of glutamate cysteine ligase contributes to the susceptibility to sporadic colorectal cancer: a pilot study.

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).

Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease.

The study was designed to evaluate putative mechanisms by which lipid-associated loci identified by genome-wide association studies (GWAS) are involved in the molecular pathogenesis of coronary artery disease (CAD) using a comprehensive statistical and bioinformatics analysis. A total of 1700 unrelated individuals of Slavic origin from the Central Russia, including 991 CAD patients and 709 healthy controls were examined. Sixteen lipid-associated GWAS loci were selected from European studies and genotyped using the MassArray-4 system.

Pharmacogenetic loci for rosuvastatin are associated with intima-media thickness change and coronary artery disease risk.

Polymorphisms at , , , , and are attractive targets for assessment of their impact on lipid-lowering therapy with rosuvastatin. The present study investigated whether polymorphisms at these genes are associated with the risk of coronary artery disease (CAD) development, and reduction of atherogenic lipids and carotid intima-media thickness (CIMT) in CAD patients, taking rosuvastatin. 190 CAD patients and 1697 subjects were enrolled in pharmacogenetic and genetic association study, respectively.

The Link between Type 2 Diabetes Mellitus and the Polymorphisms of Glutathione-Metabolizing Genes Suggests a New Hypothesis Explaining Disease Initiation and Progression.

The present study investigated whether type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase () and gamma-glutamyl transferase 7 (). A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNPs) of the and genes were genotyped using the MassArray-4 system.

Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes.

Oxidative stress contributes to the pathogenesis of type 2 diabetes (T2D). This study investigated whether single nucleotide polymorphisms (SNPs) at genes encoding glutamate cysteine ligase catalytic (rs12524494, rs17883901, rs606548, rs636933, rs648595, rs761142 at GCLC) and modifier (rs2301022, rs3827715, rs7517826, rs41303970 at GCLM) subunits are associated with susceptibility to type 2 diabetes. 2096 unrelated Russian subjects were enrolled for the study.

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.

Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease.

The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome-wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome-wide associated loci for IS were done using Taq-Man-based assays and MALDI-TOF mass spectrometry iPLEX platform, respectively.