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.

Effects of ACTH6-9-Pro-Gly-Pro Peptide on the Levels of Pro- and Anti-Inflammatory Cytokines in Wistar Rats under Conditions of Chronic Restraint Stress.

We evaluated the effect of ACTH6-9-Pro-Gly-Pro (ACTH6-9-PGP) peptide on the serum levels of pro- and anti-inflammatory cytokines in experimental animals under conditions of chronic restraint stress. Stress exposure over 2 weeks led to an increase in the levels of IL-1ß, IL-6, and IFNγ in rats. Daily intraperitoneal injection of ACTH6-9-PGP in a dose of 5 µg/kg before stress exposure significantly decreased the levels of IL-6 and IFNγ by 4.8 and 49.3% respectively. Administration of the peptide in a dose of 50 µg/kg decreased the levels of IL-1ß and IFNγ by 51.2 and 39.7%, respectively. However, no changes in the cytokine levels were observed after injection of the peptide in a dose of 500 µg/kg. Thus, ACTH6-9-PGP administered in doses of 5 and 50 µg/kg prevented the stress-induced changes in the levels of pro- and inflammatory cytokines.

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.