The role of GSTM1 gene polymorphism in pathophysiology, evaluation, and management of constipation of anorectal outlet obstruction

Constipation of anorectal outlet obstruction may be caused by mechanical or functional causes. This complication is a debilitating disease that needs proper and timely treatment. Many studies have shown that there is a direct link between constipation and intestinal cancer. One of the most effective ways to prevent or diagnose intestinal cancer is through genetic studies. Evaluation of people's polymorphism shows how much they are at risk for cancer. Therefore, in this study, the GSTM1 gene polymorphism was evaluated in patients with constipation of anorectal outlet obstruction to assess better and manage this disease and investigate the possibility of anorectal cancer in these people. In this regard, 40 people with constipation of anorectal outlet obstruction were compared with 40 healthy people. In the case group (patients), in addition to demographic and clinical evaluations, the anorectal manometric test was used to diagnose the pathology of the disease. Results showed that out of 40 patients with constipation of anorectal outlet obstruction, 5 cases (12.5%) had megarectum, 7 cases (17.5%) had anismus, 10 cases (25%) had Hirschsprung's disease, 5 cases (12.5%) had descending perineum syndrome, 6 cases (15%) had rectal prolapse, 4 cases (10%) had enterocele, and 3 cases (7.5%) were with rectocele. Also, the results of GSTM1 gene deletion polymorphism showed that patients with constipation of anorectal outlet obstruction were almost two times more exposed to the null genotype than the control group (P <0.04). Therefore, in people with both constipation of anorectal outlet obstruction and null genotype (i.e., deletion in the GSTM1 gene), because they do not have glutathione-S transferase, they appear to be at higher risk for anorectal cancer than healthy people with the same genotype.

Gene polymorphism of the xenobiotic biotransformation system and the intrauterine fetal growth retardation in female workers of industrial enterprises

Intrauterine growth retardation is recognized as one of the leading causes of incidence and mortality in infancy and early childhood in all the countries of the world. The causes and mechanisms of development of this process are decisive when choosing the tactics of nursing such children. Of particular importance is the understanding of the functioning of the mother-placenta-fetus system, in particular the mechanisms of suppression of the detoxification function of the placenta in connection with the polymorphisms of the genes of the I and II phases of the xenobiotic biotransformation system. The aim of the study was to determine the relationship between the polymorphism of the genes of the I and II phases of the xenobiotic biotransformation system with the intrauterine fetal growth retardation in women living in the South of the Kemerovo region and working under harmful labor conditions. A survey of 39 women of reproductive age living in the territory of Novokuznetsk was carried out, 20 of them worked at various enterprises of the city. The study group included 14 women who gave birth to children with intrauterine growth retardation of varying severity. The comparison group (control) consisted of 25 women. They did not have spontaneous miscarriages and they carried a child without the intrauterine growth retardation. The work investigated the frequency of occurrence of polymorphisms of genes of the xenobiotic biotransformation system - CYP1A2*1F, GSTM1 (they determine the activity of detoxification enzymes), as well as their combinations - in a group of working women and housewives who gave birth to children with intrauterine growth retardation. The forms of genes associated with the intrauterine fetal growth retardation, as well as genes associated with the resistance to this pathology, were identified. Combinations of gene forms of different phases of the xenobiotic biotransformation and their relationship with intrauterine fetal growth retardation were shown. There were no statistically reliable differences between various cohorts of women. A positive association of a high risk of the intrauterine fetal growth retardation in women with A/A CYP1A2*1F genotype and deletion polymorphism of the GSTM1 "-" gene has been shown. The heterozygous form of the C/A CYP1A2*1F gene polymorphism is statistically reliably associated with the resistance to this pathology, as well as the normally functioning GSTM1 "+" gene. Genotype A/A CYP1A2*1F in the combination with the deletion polymorphism of GSTM1 "-" gene is statistically reliably associated with intrauterine fetal growth retardation, and C/A CYP1A2*1F genotype in the combination with normally functioning GSTM1 "+" gene is associated with a low risk of the intrauterine fetal growth retardation. Comparative analysis of the relationship of the studied forms of genes of the xenobiotic biotransformation system with the intrauterine fetal growth retardation in the groups of female workers and housewives did not show statistically reliable differences.

The degree of anthropogenic load, gene polymorphism of the xenobiotic biotransformation system and congenital malformations as links in the same chain

Introduction. According to epidemiological observations, the level of congenital malformations in children is associated with the degree of chemical pollution of the environment and certain forms of genes of the I and II phases of the xenobiotic biotransformation system. The study aimed to determine and compare the index of anthropogenic load with the probability of occurrence of congenital malformations of the fetus in combination with gene polymorphisms of I and II phases of the xenobiotic biotransformation system in women living in different administrative territories in the South of Kuzbass. Material and methods. The level of air pollution in the cities of the South of the Kemerovo region (Kuzbass) was established. Prenatal screening of 1,426 pregnant women at the term of 15-18 weeks in the cities of the South of Kuzbass was carried out. The Real Time-PCR method was used to determine the gene polymorphism of the xenobiotic biotransformation system (CYP1A2, GSTM1) in 53 women of Novokuznetsk who gave birth to newborns with congenital malformations. Results. In the cities of the South of Kuzbass, with a critical and high degree of pollution of atmospheric air and waterways, many women are at risk of congenital malformations in offsprings. The A/A CYP1A2*1F genotype in combination with the deletion polymorphism of the GSTM1 gene in the mother is reliably associated with the occurrence of congenital malformations in offsprings (χ2 - 4.72; р - 0.030; OR - 5.56; CI - 1.05-29.32), and the C/ACYP1A2*1F genotype in combination with the normal functioning GSTM1 “+” gene is associated with resistance to the development of congenital malformations (χ2 - 12.53; p - <0.001; OR - 0.11; CI - 0.03-0.4 ). Conclusion. Against the background of an increasingly unfavourable ecological situation in Kuzbass and raising the number of newborns with congenital malformations, it is essential to include in the algorithm for early prenatal diagnosis the determination of the forms of genes of different phases of the xenobiotic metabolism system to elaborate an algorithm for reducing the xenobiotic load on the body of pregnant women during critical periods of fetal organogenesis.

Association of Genetic Polymorphisms in Oxidative Stress and Inflammation Pathways with Glaucoma Risk and Phenotype

Oxidative stress and neuroinflammation are involved in the pathogenesis and progression of glaucoma. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in inflammation and oxidative stress genes on the risk of glaucoma, the patients’ clinical characteristics and the glaucoma phenotype. In total, 307 patients with primary open-angle glaucoma or ocular hypertension were enrolled. The control group included 339 healthy Slovenian blood donors. DNA was isolated from peripheral blood. Genotyping was performed for SOD2 rs4880, CAT rs1001179, GPX1 rs1050450, GSTP1 rs1695, GSTM1 gene deletion, GSTT1 gene deletion, IL1B rs1143623, IL1B rs16944, IL6 rs1800795 and TNF rs1800629. We found a nominally significant association of GSTM1 gene deletion with decreased risk of ocular hypertension and a protective role of IL1B rs16944 and IL6 rs1800629 in the risk of glaucoma. The CT and TT genotypes of GPX1 rs1050450 were significantly associated with advanced disease, lower intraocular pressure and a larger vertical cup–disc ratio. In conclusion, genetic variability in IL1B and IL6 may be associated with glaucoma risk, while GPX and TNF may be associated with the glaucoma phenotype. In the future, improved knowledge of these pathways has the potential for new strategies and personalised treatment of glaucoma.

ROLE OF GENETIC PREDISPOSITION, GENE POLYMORPHISM OF GLUTATHIONE-S-TRANSFERASE (GSTT1, GSTM1, GSTP1) AND SOME ADVERSE FACTORS IN DEVELOPMENT OF BRONCHIAL ASTHMA IN CHILDREN – RESIDENTS OF RADIOACTIVELY CONTAMINATED AREAS

Objective: to determine the influence of hereditary predisposition, polymorphism of GSTT1, GSTM1, GSTP1 genes and environmental factors on the development of bronchial asthma in children – residents of radioactively contaminated areas. Materials and methods. School-age children-residents of radioactively contaminated areas with bronchial asthma, and those without clinical signs of respiratory pathology were examined. Genetic, medical, biological and social risk factors were determined based on the study of anamnestic data and medical records. Ventilation lung capacity was assessed by the method of computer spirometry. Molecular genetic studies were carried out using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) for further analysis. Results. Molecular genetic studies of the distribution of genotypes and frequencies of polymorphic variants of the genes GSTT1, GSTM1, GSTP1 were performed in children living under long-term intake of 137Cs by food chains. It was found that in children with BA the tendency to frequency of the deletion variant of the GSTT1 and GSTM1 genes in comparison with children without bronchial and pulmonary pathology was increased. The study of distributing the GSTP1 A313G gene polymorphic variants revealed in children with BA a significant increase in the frequency of AG-genotype, compared with the data of reference group. Adverse factors that increase the risk of developing bronchoobstructive disorders and the probability of their implementation in the form of bronchial asthma in children residents of RCA have been identified. It is established that among them the leading role is played by hereditary predisposition to this disease. On the part of the child, such negative factors were unfavorable conditions of fetal development, the presence of signs of exudative-catarrhal diathesis, manifestations of allergies and frequent respiratory diseases from the first months of life. It was found that the risk of developing BA was significantly increased in children with the GSTT1 and GSTM1 gene deletion genotypes; an increased risk of developing BA in children with a combination of the GSTP1 A313G gene polymorphism with deletion polymorphism of the GSTT1 or GSTM1 gene was determined. Сonclusion. Оne of the leading mechanisms, due to which there is a realization of hereditary predisposition to bronchial asthma in children living under constant intake of radionuclides with a long half-life, is the polymorphism of certain glutathione-S-transferase genes, namely, GSTT1, GSTM1 and A313G gene deletion polymorphism and GSTP1 gene polymorphism. Key words: children, radioactively contaminated areas, risk factors, bronchial asthma, glutathione-S-transferase gene polymorphism.

Glutathione S-transferase M1 and T1 Genes Deletion Polymorphisms and Blood Pressure Control Among Treated Essential Hypertensive Patients in Burkina Faso.

ObjectiveGlutathione S-transferases have been associated with experimental resistance to some drugs. The present study investigated the factors associated with blood pressure control in patients with essential hypertension, especially the role of GSTT1 and GSTM1 genes polymorphisms. This cross-sectional study in Burkina Faso consisted of 200 patients with essential hypertension and under treatment. ResultsThis cross-sectional study population consisted of 57.5 % (115/200) of patients with their hypertension under control. No statistically significant difference (p > 0.05) was found between controlled and uncontrolled (SBP and/or DBP) groups for anthropometric and biochemical parameters as well as for GSTT1 or GSTM1 gene polymorphisms. However, current alcohol consumption (OR = 3.04; CI = 1.88 - 6.13; p < 0.001), physical inactivity (OR = 3.07; CI = 1.71 - 5.49; p < 0.001), severity of hypertension (Grade III [OR = 3.79; CI = 2.00 - 7.17; p < 0.001]) and heart damage (OR = 3, 14; CI = 1.59 - 6.02; p < 0.001) were statistically more frequent in uncontrolled essential hypertension group than controlled group.

Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients with Homozygous Glutathione Transferase M1 Gene Deletion

Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion. Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined. Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups. Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity.

POLYMORPHISMS IN GSTM1, GSTP1 AND GSTT1 GENES AND BREAST CANCER RISK IN WOMEN FROM KYRGYZSTAN

Aim: We studied the intergenic interactions and the contribution of polymorphic loci for GSTT1, GSTM1, GSTP1 genes in the formation of predisposition to breast cancer (ВС) in women of Kyrgyz nationality. Material and method: The study included 87 women of the Kyrgyz ethnic group with the morphologically verified diagnosis of BC and 96 women without cancer and chronic diseases. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using PCR-RFLP for rs1695 GSTP1 gene. Deletion polymophisms in GSTT1 and GSTM1 genes were determined using allele-specific real-time PCR. Analysis of the intergenic interactions conducted with MDR 3.0.2 software. Results: Among women of Kyrgyz nationality, deletion of the GSTM1 gene region is a genetic marker associated with an increased likelihood of developing breast cancer (OR = 2.18, 95% CI 1.38-3.44), p = 0.0007). The absence of deletion in this gene is associated with a protective effect. Analysis of polymorphic markers (GSTT1 gene) and p.Ile105Val (GSTP1 gene) did not reveal statistically significant differences in the frequency distribution of genotypes and alleles between breast cancer patients and women from the comparison group (p > 0.05). Analysis of intergenic interactions using MDR analysis showed that, with the simultaneous presence of the Arg/Gln genotypes (XRCC1 gene) and (GSTM1 gene), the probability of developing breast cancer was - OR = 2.63. Conclusions: Deletion of the GSTM1 gene and combinations of the Arg/Gln genotypes (XRCC1 gene) and (GSTM1 gene) may contribute to the genetic susceptibility of BC in Kyrgyz women.