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Type 2 diabetes mellitus

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Iuliia Azarova
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A common pathogenic link in type 2 diabetes mellitus (T2D) and coronary artery disease (CAD) is oxidative stress, which develops as a result of an imbalance in the production of reactive oxygen species (ROS) and their neutralization by the antioxidant defense system. Neutrophilic cytosolic factor 4 (NCF4) is directly involved in the synthesis of superoxide anion as part of NADPH oxidase. In this regard, the purpose of this study was to investigate the associations of eight single nucleotide polymorphisms of the NCF4 gene rs5995355 (A>G), rs5995357 (T>A), rs1883112 (G>A), rs4821544 (G>A), rs760519 (T>C), rs729749 (C>T), rs2075938 (G>A), rs2075939 (C>T) with a predisposition to T2D, as well as the risk of developing CAD in patients with T2D. The study included 1579 patients with T2D (448 of them were also diagnosed with CAD) and 1627 relatively healthy volunteers. Genotyping was performed using MALDI-TOF mass spectrometry on the MassArray Analyzer 4 platform. Statistical processing of the obtained data was carried out using the SNPStats online program. The allele and genotype frequencies of the studied SNPs in T2D patients did not differ from those in the control group (P>0.05). Associations of genotypes rs4821544-C/C (OR 1.71, 95CI 1.12-2.59, P=0.013) and rs5995357-A/A (OR 3.74, 95CI 1.14-12.31, P=0.026) with a predisposition to CAD in diabetic females were established. Despite the absence of associations of the studied SNPs NCF4 with CAD in males, associations of the haplotype structure of NCF4 (P=0.0064), as well as the haplotypes H2 (OR 1.79, 95CI 1.16-2.76, P=0.0085) and H3 (OR 1.77 , 95CI 1.06-2.97, P=0.03) with an increased risk of CAD were observed exclusively in diabetic males. In addition, a sex-independent relationship of the rs4821544-C/C genotype with an increased level of glycated hemoglobin (P=0.032) and oxidized glutathione (P=0.049) was revealed in patients with CAD and T2D. In the same category of patients haplotypes H4 rs5995355G-rs5995357A-rs1883112G-rs4821544C-rs760519T-rs729749C-rs2075938G-rs2075939C and H10 rs5995355A-rs5995357T-rs1883112G-rs4821544C-rs760519T-rs729749C-rs2075938A-rs2075939C of NCF4 gene were associated with an increase in the content of HbA1c 8.67 % (P=0.011) and 6.27% (P=0.038), respectively. The data obtained indicate a significant contribution of the NCF4 gene polymorphism to the pathogenesis of CAD in patients with T2D and create a scientific basis for the development of targeted therapy and prevention of this pathology.
Elena Klyosova
added a research item
In a study involving 2830 subjects including 1444 patients with type 2 diabetes (T2D) and 1386 healthy controls, an association of the rs1046495 polymorphism of the GFER gene encoding FAD-dependent sulfhydryl oxidase with decreased risk of the disease in non-obese patients was found (OR 0.76, 95CI 0,57-0,99, P=0,029). The protective effect of the gene polymorphism remained significant in individuals who consumed fresh vegetables and fruits (P=0.014), proteins (P=0.0017), and did consume carbohydrates and fat reached foods (P=0.0047). The mechanism of the relationship of the minor allele rs1046495-C with type 2 diabetes may be associated with its more pronounced effect on the expression of the GFER enzyme, which, as is known, through glutathionation, maintains the ROS level for the optimal functioning of complexes III and IV of the electron transport chain and promotes the formation of disulfide bonds in the CHCHD4 chaperone molecule, the impairment of the activity of which underlies mitochondrial dysfunction, that represents one of the key pathological changes in patients with T2D.
Iuliia Azarova
added a research item
Background: Phosphatidylethanolamine N-methyltransferase (PEMT) is the enzyme of lipid metabolism that catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine in a series of three methylation reactions. Low activity of the enzyme can increase the availability of phosphatidic acid for triacylglycerol synthesis and thus favor obesity, one of the most important risk factors for type 2 diabetes (T2D). The aim of the study: To study the relationship of the rs12449964 (C>T) in the regulatory region of the PEMT (phosphatidylethanolamine-N-methyltransferase) gene with blood plasma triglycerides, as well as the risk of obesity and T2D in population of Central Russia. Materials and methods: The study included 2060 unrelated individuals of Slavic origin, including 1024 patients with T2D and 1036 healthy volunteers. Genotyping of PEMT gene polymorphism (C>T, rs12449964) was performed by laser desorption / ionization time-of-flight mass spectrometry using the MassArray Analyzer 4 platform (Agena Bioscience). SNPStats online program was used for statistical analysis of the obtained data. Results: Linear regression analysis did not reveal an association of rs12449964 of the PEMT gene with a risk of developing T2D regardless of body mass index (P>0,05). However, the T/T genotype of the studied SNP is associated with an increased risk of obesity in patients with type 2 diabetes (OR 1.66; 95% CI 1.11-2.46; P = 0.011, adjusted for sex and age, recessive model). In addition, carriage of the T/T genotype was associated with a higher level of triacylglycerols in the blood plasma of patients with T2D, both in the presence of obesity and without it (P<0.05). According to GTEx Portal, the rs12449964T allele is associated with decreased PEMT expression in various tissues. Conclusion: The study revealed for the first time the association of rs12449964 of the PEMT gene with hypertriglyceridemia and an increased risk of obesity in patients with T2D, which may be due to the low transcriptional activity of the phosphatidylethanolamine- N-methyltransferase gene in carriers of the alternative allele of the studied SNP.
Iuliia Azarova
added a research item
The present study investigated whether type 2 diabetes (T2D) is associated with polymor-phisms 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.
Alexey V Polonikov
added a research item
The present study was designed to investigate whether the genetic predisposition to 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), and also to analyze in silico the molecular mechanisms of their involvement in disease pathogenesis. A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNP) of the GSS and GGT7 genes were genotyped using the MALDI-TOF mass spectrometry iPLEX platform. We found for the first time that SNPs rs11546155 (OR 0.42, 95%CI 0.22-0.80, P=0.022) and rs6119534 (OR 0.73, 95%CI 0.53-0.99, P=0.0003) of the GGT7 are significantly associated with T2D regardless of sex, age, and body mass index. The association of SNP rs11546155 with diabetes risk has been replicated in a large ethnically diverse cohort (P=0.018). The GSS and GGT7 polymorphisms in diabetics correlated with the levels of plasma glutathione, hydrogen peroxide, and fasting blood glucose in a gender-specific manner. Epistatic interactions between the gene polymorphisms determining disease susceptibility have been observed with strong protective effects of genotype combinations such as GGT7 rs6119534-C/T × GSS rs1801310-A/A and GGT7 rs6119534-C/T × GSS rs13041792-G/G against disease risk (FDR<1.8×10-5). The risk alleles of GSS and GGT7 correlated with tissue-specific expression of genes located at genomic region 20q11.22 that spans numerous genes involved in the unfolded protein response pathway and regulation of proteostasis. Transcriptome-wide association analysis has shown that pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked with the genetic susceptibility to type 2 diabetes. Taken together the study findings along with our previous results allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous deficiency of glutathione is a key condition responsible for impaired folding of proinsulin and triggering unfolded protein response which ultimately leads to β-cell apoptosis, disease development, and progression.
Iuliia Azarova
added a research item
The scientific article is devoted to the study of the relationship between the polymorphic loci in the CDKAL1 gene encoding the methylthiotransferase enzyme and the risk of developing type 2 diabetes mellitus (T2D) in 3206 unrelated individuals - 1579 patients with T2D and 1627 healthy volunteers. It was established for the first time in the Russian population that carriage of minor alleles of single nucleotide variants rs4712524 (G>A) and rs6931514 (G>A) in the CDKAL1 gene is associated with increased risk of T2D, regardless of age, sex and body mass index of the patients.
Alexey V Polonikov
added a research item
Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. The hypothesis that glutathione deficiency is the most plausible explanation for serious manifestation and death in COVID-19 patients was proposed on the basis of an exhaustive literature analysis and observations. The hypothesis unravels the mysteries of epidemiological data on the risk factors determining serious manifestations of COVID-19 infection and the high risk of death and opens real opportunities for effective treatment and prevention of the disease.
Elena Klyosova
added 3 research items
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.
Iuliia Azarova
added 2 research items
Дисбаланс в функционировании про- и антиоксидантной систем играет ключевую роль в патогенезе сахарного диабета 2-го типа (СД2) и отражается в характере манифестации заболевания, спектре и скорости прогрессирования развивающихся на его фоне осложнений, эффективности лечения. Цель исследования – изучить антиоксидантный статус больных СД2, а именно, содержание глутатиона и активных форм кислорода и азота (АФКА) в плазме крови, и установить связь этих фенотипических проявлений с генетическими полиморфизмами генов антиоксидантных ферментов глутатион-S-трансфераз M1 и T1. В исследование были включены 600 больных СД2 (средний возраст 61,7±10,1 лет) и 520 практически здоровых добровольцев (средний возраст 60,9±8,3 лет). Генотипирование делеционных (del) полиморфизмов генов GSTM1 и GSTT1 выполнено методом мультиплексной ПЦР. Содержание общего глутатиона и АФКА проводили с использованием наборов STA-312 и STA-347 (“Сell Biolabs”, США) на микропланшетном ридере “Varioscan Flash” (“Thermo Fisher Scientific”, США). Частоты генотипов GSTM1 у больных СД2 не отличались от соответствующих показателей лиц контрольной группы (р>0,05), тогда как частота делеционного генотипа del/del GSTT1 была значимо выше в группе больных (OR 1,60, 95CI 1,17–2,21, p=0,003) по сравнению со здоровыми. Обнаруженная ассоциация сохранила свою значимость после коррекции по полу, возрасту и индексу массы тела (р=0,004). Концентрация АФКА была выше в группе больных (3,21±1,18 мкмоль/л) по сравнению со здоровыми (2,50±1,33, р=0,02), что сочеталось с повышенным содержанием окисленного глутатиона: 7,72±5,93 мкмоль/л у пациентов с СД2 относительно 5,72±3,60 у лиц контрольной группы. Было обнаружено, что все носители генотипа del/del GSTT1 имели более высокие уровни АФКА (р=0,04) независимо от статуса болезни. Полученные результаты свидетельствуют о том, что антиоксидантные гены, в частности, GSTТ1, определяют эффективность обезвреживания АФКА и их количественное содержание в плазме крови. Косубстрат глутатион-S-трансфераз, глутатион, может рассматриваться как потенциально новый компонент антиоксидантной терапии, особенно для лиц с наследственной предрасположенностью к свободно-радикальной патологии, какой является СД2.
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 modifer (rs2301022, rs3827715, rs7517826, rs41303970 at GCLM) subunits are associated with susceptibility to type 2 diabetes. 2096 unrelated Russian subjects were enrolled for the study. Genotyping was done with the use of the MassArray System. Plasma levels of reactive oxygen species (ROS) and glutathione in the study subjects were analyzed by fuorometric and colorimetric assays, respectively.The present study found, for the frst time, an association of SNP rs41303970 in the GCLM gene with a decreased risk of T2D (P=0.034, Q=0.17). Minor alleles such as rs12524494-G GCLC gene (P=0.026, Q=0.17) and rs3827715-C GCLM gene (P=0.03, Q=0.17) were also associated with reduced risk for T2D. Protective efects of variant alleles such as rs12524494-G at GCLC (P=0.02, Q =0.26) and rs41303970-A GCLM (P=0.013, Q =0.25) against the risk of T2D were seen solely in nonsmokers. As compared with healthy controls, diabetic patients had markedly increased levels of ROS and decreased levels of total GSH in plasma. Interestingly, fasting blood glucose level positively correlated with oxidized glutathione concentration (rs=0.208, P=0.01). Three SNPs rs17883901, rs636933, rs648595 at GCLC and one rs2301022 at GCLM were associated with decreased levels of ROS, while SNPs rs7517826, rs41303970 at GCLM were associated with increased levels of total GSH in plasma. Single nucleotide polymorphisms in genes encoding glutamate cysteine ligase subunits confer protection against type 2 diabetes and their efects are mediated through increased levels of glutathione.
Iuliia Azarova
added a research item
Oxidative stress is an important component of the pathogenesis of type 2 diabetes mellitus (T2D). Glutathione peroxidase 2 is one of the antioxidant defense enzymes which uses glutathione as a co-substrate to reduce hydrogen peroxide and has the highest expression in the pancreas, an organ that is directly related to the development of diabetes. However, there is no data on the association of GPX2 with a predisposition to T2D. The aim of the study was to investigate the association of rs4602346 (A>G) in the intron of the GPX2 gene with a risk of T2D, as well as the effect of this SNP on blood plasma redox homeostasis. The study included 3197 unrelated individuals of Slavic origin, including 1570 patients with T2D and 1609 age- and sex-matching healthy volunteers. GPX2 gene polymorphism was genotyped using real-time PCR on a CFX96 Touch Bio-Rad thermal cycler. The G/G genotype was associated with an increased risk of the disease (OR 1,41, 95% CI 1,02-1,96, P=0,039, recessive model). The identified association retained its significance even after correction for gender, age, and body mass index (ORadj 1,50, 95% CI 1,04-2,16, Padj=0,03). Gender-stratified analysis revealed that the established association of rs4902346 was characteristic only for diabetic males (ORadj 2,09, 95% CIadj 1,22-3,59, Padj=0,0065), and was not observed in diabetic females (P>0,05). Assessment of redox status showed an increase in the content of hydrogen peroxide and a decrease in the level of total glutathione in the plasma of patients compared with the control (P <0.05). A correlation analysis found that patients' hydrogen peroxide levels are directly proportional to their fasting blood glucose concentrations. An analysis of the relationships between genetic and biochemical data showed that the G/G genotype rs4902346 is associated with a decrease in the content of reduced glutathione in the plasma of female patients with T2D (P=0,0086). Thus, we identified for the first time the association of rs4902346 with an increased risk of T2D and showed significant gender differences in the associations of the GPX2 gene with the studied phenotypes.
Iuliia Azarova
added a research item
The aim of the study was to investigate the associations of single-nucleotide polymorphisms (SNP) rs5917471, rs5963327 and rs6610650 of the gene encoding the beta chain of cytochrome b-245 of NADPH oxidase (CYBB gene) with the redox-homeostasis parameters of blood plasma and the risk of development of type 2 diabetes mellitus (T2D). The study included 2086 unrelated individuals of Slavic origin (1022 patients with T2D and 1064 healthy volunteers). Genotyping of SNPs was performed on a MassArray Analyzer 4 genomic mass spectrometer. Due to the localization of the CYBB gene on the X chromosome, the analysis of the effect of its single nucleotide variants on the predisposition to diabetes mellitus and the parameters of the redox status of blood plasma was carried out separately in men and women by the method of linear regression analysis, adjusted for age and body mass index. In men, the association of the allele T rs5963327 (OR 1.7, 95% CI 1.06–2.75, P = 0.028) and the allele A rs6610650 (OR 1.71, 95% CI 1.05–2.78, P = 0.029) with an increased risk of T2D development was established. Genotype T/T rs5963327 (OR 1.35, 95% CI 1.05–1.73, P = 0.017) and genotype A/A rs6610650 (OR 1.34, 95% CI 1.05–1.72, P = 0.020) were also associated with the risk of T2D development in women. The T-T-A haplotype, including minor alleles of the studied rs5917471–rs5963327–rs6610650 polymorphisms, was associated with an increased risk of developing diabetes mellitus in both men (OR 1.29, 95% CI 1.04–1.58, P = 0.022) and women (OR 1.27, 95% CI 1.02–1.58, P = 0.034). Patients with T2D had a significantly higher content of hydrogen peroxide in plasma compared to the control group (P < 0.05) regardless of sex, however, the relationship between rs5963327 and rs6610650 and the increased content of oxidized glutathione GSSG was found only in women. Thus, we detected for the first time the associations of rs5963327 and rs6610650 of the CYBB gene with the development of T2D and redox status of patients. The studied polymorphic variants of the gene encoding the beta chain of cytochrome b-245 of NADPH oxidase may contribute to a shift of balance in the redox homeostasis system towards the prooxidant status, characteristic of T2D.
Alexey V Polonikov
added a research item
Based on an exhaustive literature analysis and own observations, I proposed a hypothesis that glutathione deficiency is exactly the most plausible explanation for serious manifestation and death in COVID-19 infected patients. The major risk factors established for severe COVID-19 infection and relative glutathione deficiency found in COVID-19 infected patients with moderate-to-severe illness have converged me to two very important conclusions: (1) oxidative stress contributes to hyper-inflammation of the lung leading to adverse disease outcomes such as acute respiratory distress syndrome, multiorgan failure and death; (2) poor antioxidant defense due to endogenous glutathione deficiency as a result of decreased biosynthesis and/or increased depletion of GSH is the most probable cause of increased oxidative damage of the lung, regardless which of the factors aging, chronic disease comorbidity, smoking or some others were responsible for this deficit. The hypothesis provides novel insights into the etiology and mechanisms responsible for serious manifestations of COVID-19 infection and justifies promising opportunities for effective treatment and prevention of the illness through glutathione recovering with N-acetylcysteine and reduced glutathione.
Iuliia Azarova
added a research item
Background. Imbalance in the system of redox homeostasis is an important link in the pathogenesis of type 2 diabetes (T2D). Gamma-glutamyl cyclotransferase is an antioxidant defense enzyme directly involved in the metabolism of glutathione, an endogenous antioxidant. The aim of the study was to examine the association of single nucleotide polymorphisms (SNP) rs38420 (GA), rs4270 (TC), rs6462210 (CT) and rs28679 (GA) in GGCT gene with the risk of developing T2D. Materials and Methods. The study included 1022 T2D patients and 1064 healthy volunteers. Genotyping of GGCT gene loci was performed using iPLEX technology on a MassArray Analyzer 4 genome time-of-flight mass spectrometer (Agena Bioscience). Results. As a result, we identified for the first time the association of SNP rs4270 in the GGCT gene with the risk of T2D in the Russian population. We have also established genetic and environmental interactions associated with predisposition to the disease: protective effect of gamma-glutamyl cyclotransferase gene was observed only in non-smokers under condition of daily consumption of fresh vegetables and fruits, whereas in persons with insufficient consumption of plant foods, as well as in all smoking patients protective effect of GGCT was not observed. In patients with T2D, the level of hydrogen peroxide and glutathione monomer was sharply increased compared to the controls. SNP rs4270 was also found to be associated with elevated levels of reduced glutathione in the plasma of type 2 diabetics. Conclusion. Thus, for the first time it was established that polymorphic locus rs4270 in the GGCT gene is associated with a predisposition to T2D, but its relationship with the disease is modulated by smoking and fresh plant foods consumption.
Iuliia Azarova
added a research item
Background: Pancreatic beta-cell dysfunction, along with the insulin resistance of peripheral tissues, is a key element in the pathogenesis of type 2 diabetes (T2D). In this regard, of considerable interest is the study of the role of polymorphisms of the genes directly involved in the work of the beta cells of the islets of Langerhans in the formation of susceptibility to the disease. The aim of the study: To study the relationship of the polymorphic variant of the gene encoding insulin like growth factor 2 mRNA binding protein 2, IGF2BP2, (T>C, rs11927381) with the risk of developing T2D in the residents of the Kursk region. Materials and methods: The study included 559 patients with type 2 diabetes and 540 healthy volunteers. Genotyping of the IGF2BP2 gene polymorphism (T>C, rs11927381) was performed using iPLEX technology on a genomic time-of-flight mass spectrometer MassArray Analyzer 4 (Agena Bioscience). Statistical analysis was performed with the use of the online program SNPStats. Results: The frequency of the C/C genotype was significantly higher in the group of patients with T2D compared with the control group (OR 1.75; 95% CI 1.25-2.44; P=0.0026). The association retained its significance after adjustment for sex, age and body mass index (OR 1.87; 95% CI 1.26-2.78; P=0.0054). A gender-stratified analysis showed that the identified association was typical only for men (OR 2.27; 95% CI 1.17-4.40; P=0.041), while in women it was not observed (P>0.05). C/T and C/C genotypes were associated with a decrease in total cholesterol and low-density lipoproteins in patients with T2D (P<0.05). Conclusion: The established association indicates the involvement of the IGF2BP2 gene in the formation of susceptibility to T2D. The studied variant rs11927381 is also associated with lower levels of total cholesterol and low-density lipoproteins in type 2 diabetic patients that may account for the SNP effects on epigenetic markers, such as methylation and acetylation.
Iuliia Azarova
added 2 research items
Chronic hyperglycemia results in oxidative stress that has been implicated as the underlying cause of all DM complications. The glutathione-S-transferases (GSTs) are antioxidant enzymes that catalyze the conjugation of reactive oxygen and nitrogen species to glutathione. The present work aimed to study the effect of the genetic polymorphisms of the GSTM1, GSTT1 and GSTP1 genes on the risk of developing type 2 DM in Kursk population. The study groups included 321 patient (mean age 59,31±9,23) with type 2 DM who were admitted to the endocrinological department of Kursk Emergency Hospital from January to October 2016, and 330 age-and sex-matched healthy subjects (mean age 59,49±8,14). Genotyping of deletion (del) polymorphisms of GSTM1 and GSTT1 genes was performed by multiplex PCR with subsequent analysis of the amplification products using electrophoresis on a 2% agarose gel with ethidium bromide and visualization of results in UV light. Genotyping of GSTP1 Ile105Val polymorphism was performed by PDAF, PCR, real-time discrimination of alleles using TaqMan probes. There was no difference in genotype distribution among type 2 DM and control subjects in GSTM1 and GSTT1 genes (р0,05). Significant differences between the genotype frequencies for the GSTP1 105Ile/Val and GSTP1 105Val/Val polymorphisms were observed in diabetic patients (51,09%) as compared to controls (42,82%), (OR 1,39, 95%CI 1,02-1,90, р=0,03). The same association of genotypes GSTP1 105Ile/Val and GSTP1 105Val/Val was found in diabetic females (OR 1,59, 95%CI 1,07-2,38, р=0,02), whereas diabetic males showed greater frequency of the GSTT1 del/del genotype (OR 2,13, 95%CI 1,07-4,24, р=0,02). We observed a significant association of the double combinations GSTM1+  GSTP1 105Val/Val (OR 2,62; 95%СI 1,01-6,84, р=0,04) and GSTТ1del/del  GSTP1 105Val/Val (OR 4,82, 95%СI 1,21-19,10, р=0,02) with the risk of type 2 diabetes mellitus development. The established associations indicate the involvement of polymorphisms of glutathione-S-transferases in the formation of predisposition to T2DM and confirm the significant role of disturbances in antioxidant defense system in the pathogenesis of the disease.
Impairments of redox homeostasis play a key role in the development of type 2 diabetes mellitus (T2D). The main endogenous source of the superoxide radical is NADPH oxidase, one of the subunits of which is the light chain of cytochrome b-245, CYBA. The aim of the study was to study the associations of cytochrome b-245 alpha chain gene polymorphisms rs7195830 (G>A), rs8854 (C>T), rs9932581 (C>T) and rs4673 (G>A) with a risk of developing T2D. The study included 1022 patients with T2D (average age 61,1 ± 7,2 years) and 1064 sex-and age-matched healthy volunteers. Genotyping of CYBA gene polymorphisms was performed using iPLEX technology on a MassArray Analyzer 4 genome time-of-flight mass spectrometer (Agena Bioscience). The CYBA gene A/A genotype (rs4673, G>A) was associated with an increased risk of developing the disease (OR 1,49, 95%CI 1,111,99, P=0,0074, recessive model). The identified association remained significant even after the adjustment for gender, age, and body mass index (ORadj 1,51, 95%CI 1,09-2,09, padj=0,014). Gender-stratified analysis revealed that the established association rs4673 was characteristic only for females (ORadj 1,60, 95% CIadj 1,04-2,46, padj= 0,032). Patients with T2D had a significantly higher level of hydrogen peroxide in blood plasma compared with the control group (p<0,05), regardless of gender, however, the relationship between the A/A genotype rs4673 with the increase in the content of Н2О2 in plasma by 0,77 mmol/L (p = 0,044) was found only in males. The T/T genotype rs9932581 was associated with an increase in glycated hemoglobin level of 2,71% (p = 0,042) in the general group of patients with T2D, as well as with an increase in the same indicator by 4,44% (p = 0,03) among females. The association of the C/T genotype rs9932581 with an increase in the proportion of HbA1c by 0,61% (p = 0,018) and with an increase in blood glucose level by 1,06 mmol/L (p = 0,029) was noted exclusively in males. The association of fasting blood glucose level was also established with genotype A/A rs7195830, in which carriers the glucose concentration was 1.17 mmol/L higher than in homozygotes for the reference allele (P = 0,022).
Iuliia Azarova
added a research item
In the study, which included 579 patients with type 2 diabetes and 542 healthy individuals, for the first time in the Russian population, an association of polymorphism rs11827381 of the IGF2BP2 gene with an increased risk of developing the disease was established. However, the association of variant rs11827381 with an increased risk of developing type 2 diabetes was observed solely in smoking patients and was not detected in non-smokers. Bioinformatics analysis revealed that transcription factors, which binding sites appear in the presence of the C allele, differ from the spectrum of transcription factors specifically associated with the reference T allele and are involved in the regulation of the biosynthesis of ketone bodies, as well as the cellular response to glucocorticoid hormones. The results indicate the trigger role of smoking in the relationship of the polymorphic variant rs11827381 of the IGF2BP2 gene with the development of type 2 diabetes.