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. Allele − 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70‐0.96; P = 0.016). The model‐based multifactor dimensionality reduction method has revealed 21 two‐order, 124 three‐order, and 474 four‐order gene‐gene (G×G) interactions models meaningfully (Pperm < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery.

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The present study investigated whether type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7). A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNPs) of the GSS and GGT7 genes were genotyped using the MassArray-4 system. We found that the GSS and GGT7 gene polymorphisms alone and in combinations are associated with T2D risk regardless of sex, age, and body mass index, as well as correlated with plasma glutathione, hydrogen peroxide, and fasting blood glucose levels. Polymorphisms of GSS (rs13041792) and GGT7 (rs6119534 and rs11546155) genes were associated with the tissue-specific expression of genes involved in unfolded protein response and the regulation of proteostasis. Transcriptome-wide association analysis has shown that the pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked to the genetic risk of T2D. A comprehensive analysis of the data allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous glutathione deficiency might be a key condition responsible for the impaired folding of proinsulin which triggered an unfolded protein response, ultimately leading to beta-cell apoptosis and disease development.

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.

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. Results SNP rs7784465 was associated with an increased risk of T2D (p = .0003), and significant differences in the RAC1 haplotypes occurred between the cases and controls (p = .005). Seventeen combinations of RAC1 genotypes showed significant associations with T2D risk (FDR <0.05). Associations of RAC1 polymorphisms with T2D were modified by environmental factors such as sedentary lifestyle, psychological stresses, a dietary deficit of fresh fruits/vegetables and increased carbohydrate intake. RAC1 polymorphisms were associated with biochemical parameters in diabetics: rs7784465 (p = .015) and rs836478 (p = .028) with increased glycated haemoglobin, rs836478 (p = .005) with increased fasting blood glucose, oxidized glutathione (p = .012) and uric acid (p = .034). Haplotype rs4724800A–rs7784465C–rs10951982G–rs10238136A–rs836478C–rs9374G was strongly associated with increased levels of hydrogen peroxide (p < .0001). Conclusion Thus, polymorphisms in the RAC1 gene represent novel genetic markers of type 2 diabetes, and their link with glucose metabolism and disease pathogenesis is associated with the changes in redox homeostasis.