Effect of Ozone on Allergic Airway Inflammation

Background: Exposure to O3 has been associated with increased risk of exacerbations of asthma, but the underlying mechanisms are not well studied. We hypothesized that O3 exposure would enhance airway inflammatory responses to allergen and the GSTM1 null genotype would modulate this enhancement. Procedures: In a cross-over design, 10 asthmatic subjects (50% with GSTM1 null genotype) who had specific sensitization to Dermatophagoides pteronyssinus (DP) were exposed to 160 ppb O3 or filtered air (FA) control for 4 h with intermittent exercise on two separate days at least three weeks apart. 20 h post-exposure, endobronchial challenge with DP allergen, and sham normal saline (NS) instillation, were performed in two separate lung lobes. Six h later, a second bronchoscopy was performed to collect bronchoalveolar lavage (BAL) fluid from the DP- and NS-challenged lobes for analyses of cellular and biochemical markers of inflammation. Multiple variable regression was used to compare cell and cytokine responses across the four exposure groups (FA-NS, O3-NS, FA-DP, O3-DP). Effect modification by GSTM1 genotype was assessed in stratified regressions. Main Findings: BAL eosinophil and lymphocyte counts were increased in segments challenged with DP compared to segments that received sham challenges (p<0.01). DP challenge compared to sham challenge also caused a significant increase in BAL concentrations of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 (p<0.03 for all comparisons). O3 exposure did not significantly affect BAL cells or cytokine levels although BAL neutrophil count with DP challenge was non-significantly higher after O3 compared to after FA exposure (p<0.11). Compared to GSTM1-present subjects, GSTM1-null subjects had significantly reduced inflammatory responses including lower eosinophil (p<0.041) and IL-4 (p<0.014) responses to DP challenge after O3 exposure. Conclusions: O3 appears to have mixed effects on allergen-induced airway inflammation. While O3 did not cause a clear differential effect on airway cellular or cytokine responses to allergen challenge, those responses did appear to be modulated by the antioxidant enzyme, GSTM1, as evident by the attenuation of airway inflammatory responses to allergen after O3 exposure in the absence of the gene.

Prenatal Exposure to Parabens Affects Birth Outcomes through Maternal Glutathione S-Transferase (GST) Polymorphisms: From the Mothers and Kids Environmental Health (MAKE) Study

Introduction: Human exposure to parabens is very common in daily life, and prenatal exposure to these chemicals is associated with poor birth outcomes. Therefore, the aim of this study was to investigate the effect of glutathione S-transferase (GST) polymorphisms on the association between prenatal exposure to parabens and birth outcomes. Methods: We conducted a multivariate analysis involving 177 subjects to determine the association between paraben concentrations and birth outcomes in mothers with GST mu 1 (GSTM1) and GST theta 1 (GSTT1) polymorphisms from 2017 to 2019. Furthermore, we determined the interactive effect between paraben levels and GSTM1/GSTT1 polymorphisms using regression analysis, in addition to a generalized linear model after stratifying GSTM1/GSTT1 genotype into three categories. Results: Methyl and propyl paraben concentrations were significantly and positively associated with birth weight (methyl, β = 116.525, 95% confidence interval (CI) = 22.460–210.590; propyl, β = 82.352, 95% CI = 9.147–155.557) in individuals with the GSTM1-null genotype. Moreover, the propyl paraben concentration was significantly associated with an increase in gestational age (β = 0.312, 95% CI = 0.085–0.539) in individuals with the GSTM1-null genotype. Conclusions: This study reported the association between prenatal paraben exposure and birth outcomes in individuals with GST polymorphisms. We found positive relationships of maternal exposure to methyl parabens with birth weight in both mothers with GSTM1 and GSTT1-null genotypes.

An updated meta-analysis showed smoking modify the association of GSTM1 null genotype on the risk of coronary heart disease

Background Oxidative stress is considered to be involved in the pathogenesis of coronary heart disease (CHD). Glutathione-S-transferase (GST) enzymes play important roles in antioxidant defenses and may influence CHD risk. The present meta-analysis was performed to investigate the link between glutathione S-transferase M1 (GSTM1) null genotype and CHD and to get a precise evaluation of interaction between GSTM1 null genotype and smoking by the case-only design. Methods PubMed and EMBASE databases were searched through 15 December 2020 to retrieve articles. Odds ratios (ORs) were pooled using either fixed-effects or random-effects models. Results Thirty-seven studies showed that GSTM1 null genotype was associated with risk of CHD in total population, Caucasians and Asians (for total population, OR = 1.38, 95% confidence interval (CI): 1.15, 1.65; for Caucasians, OR = 1.34, 95% CI: 1.04, 1.72; for Asians, OR = 1.40, 95% CI: 1.11, 1.77). After adjustment for heterogeneity, these relationships were still significant. After adjustment for heterogeneity, case-only analysis of 11 studies showed a positive multiplicative interaction between GSTM1 null genotype and smoking (ever smoking vs. never smoking) (OR = 1.27, 95% CI: 1.08, 1.50; I2 = 0%, P=0.553). Conclusions The overall results indicated that GSTM1 null genotype was associated with a higher risk of CHD, and the association may be affected by smoking status. This is the first meta-analysis to prove a positive effect of the interaction between GSTM1 null genotype and smoking status on the risk of CHD. Well-designed studies are needed to investigate the possible gene–gene or gene–environment interactions.

Individual and combined effects of GSTM1 and GSTT1 polymorphisms on colorectal cancer risk: an updated meta-analysis

Background. The presence or absence of glutathione S-transferase M1 gene (GSTM1) and glutathione S-transferase T1 gene (GSTT1) polymorphisms, and their combined effects have been suggested as a risk factor for colorectal cancer (CRC). However, the results are inconsistent. Objectives. An updated meta-analysis was performed to solve the controversy. Methods. Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines were used. Results. Overall, the GSTM1 null genotype was associated with an increased CRC risk in Caucasians (odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.05–1.23), Asians (OR = 1.19, 95% CI: 1.08–1.32), high-quality studies (OR = 1.12, 95% CI: 1.06–1.18). Moreover, the GSTM1 null genotype was also associated with an increased colon cancer risk (OR = 1.32, 95% CI: 1.16–1.51). The GSTT1 null genotype was also associated with an increased CRC risk in Asians (OR = 1.08, 95% CI: 1.02–1.15) and Caucasians (OR = 1.24, 95% CI: 1.09–1.41). Moreover, The GSTT1 null genotype was associated with an increased rectal cancer risk (OR = 1.13, 95% CI: 1.01–1.27, I2 = 8.3%) in subgroup analysis by tumor location. Last, the GSTM1 null/GSTT1 null genotype was associated with an increased CRC risk in Asians. Conclusion. This meta-analysis indicates that the GSTM1 and GSTT1 null genotypes are associated with increased CRC risk in Asians and Caucasians, and the GSTM1 null/GSTT1 null genotype was associated with increased CRC risk in Asians.

P1577DOES VITAMIN E -COATED MEMBRANES INFLUENCE ON MARKERS OF OXIDATIVE STRESS IN HEMODIALZSIS PATIENTS WITH HOMOZYGOUS GST M1 GENE DELETION?

Background and Aims Increased free radicals production and down-regulated antioxidant enzymes activities contribute to protein, lipid and DNA oxidative damage particularly in HD patients lacking for GSTM1 enzyme activity. At the same time, those patients exhibit higher mortality rate than those with active GSTM1 genotype. It has been shown that vitamin E-coated membranes (VitEM) may decrease oxidative stress and inflammatory status in overall HD patients. Therefore, for the first time we analyzed VitEM dialyzers in patients who are homozygote for GSTM1 gene deletion and in whom anti-oxidative and anti-inflammatory benefit could be the greatest. Method GSTM1 genotypes were determined by 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 VitEM, while other forty were dialyzed with high-flux polysufone membranes of the same surface. Markers of protein and lipid oxidative damage, inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined at the start and at the end of the study. Results Seventy-five patients’ finished the study. There were no significant differences in baseline characteristics between the two groups (age, sex, body weight, dialysis vintage, vascular access, presence of diabetes, dialyzers surface, Kt/V and CRP). Also, there were no significant differences at baseline markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, thiol groups increased significantly in both groups, but without statistical significance between groups (Table 1). SOD did not change significantly during three month period. IL-6 increased in control group, at the same time decreased in VitEM group, but without statistical significance. Conclusion Vitamin E-coated membranes did not influence markers of oxidative stress in HD patients with GSTM1-null genotype. Further studies in the field are required.

Polymorphisms and endometriosis: a systematic review and meta-analyses

BACKGROUND Endometriosis is an estrogen-dependent gynecological disorder that affects at least 10% of women of reproductive age. It may lead to infertility and non-specific symptoms such as chronic pelvic pain. Endometriosis screening and diagnosis are difficult and time-consuming. Late diagnosis (with a delay ranging from 3.3 to 10.7 years) is a major problem and may contribute to disease progression and a worse response to treatment once initiated. Efficient screening tests might reduce this diagnostic delay. As endometriosis is presumed to be a complex disease with several genetic and non-genetic pathogenic factors, many researchers have sought to identify polymorphisms that predispose to this condition. OBJECTIVE AND RATIONALE We performed a systematic review and meta-analysis of the most regularly reported polymorphisms in order to identify those that might predispose to endometriosis and might thus be of value in screening. SEARCH METHODS The MEDLINE database was searched for English-language publications on DNA polymorphisms in endometriosis, with no date restriction. The PubTator text mining tool was used to extract gene names from the selected publications’ abstracts. We only selected polymorphisms reported by at least three studies, having applied strict inclusion and exclusion criteria to their control populations. No stratification based on ethnicity was performed. All steps were carried out according to PRISMA guidelines. OUTCOMES The initial selection of 395 publications cited 242 different genes. Sixty-two genes (corresponding to 265 different polymorphisms) were cited at least in three publications. After the application of our other selection criteria (an original case-control study of endometriosis, a reported association between endometriosis and at least one polymorphism, data on women of reproductive age and a diagnosis of endometriosis in the cases established by surgery and/or MRI and confirmed by histology), 28 polymorphisms were eligible for meta-analysis. Only five of the 28 polymorphisms were found to be significantly associated with endometriosis: interferon gamma (IFNG) (CA) repeat, glutathione S-transferase mu 1 (GSTM1) null genotype, glutathione S-transferase pi 1 (GSTP1) rs1695 and wingless-type MMTV integration site family member 4 (WNT4) rs16826658 and rs2235529. Six others showed a significant trend towards an association: progesterone receptor (PGR) PROGINS, interCellular adhesion molecule 1 (ICAM1) rs1799969, aryl-hydrocarbon receptor repressor (AHRR) rs2292596, cytochrome family 17 subfamily A polypeptide 1 (CYP17A1) rs743572, CYP2C19 rs4244285 and peroxisome proliferator-activated receptor gamma (PPARG) rs1801282), and 12 showed a significant trend towards the lack of an association: tumor necrosis factor (TNF) rs1799964, interleukin 6 (IL6) rs1800796, transforming growth factor beta 1 (TGFB1) rs1800469, estrogen receptor 1 (ESR1) rs2234693, PGR rs10895068, FSH receptor (FSHR) rs6166, ICAM1 rs5498, CYP1A1 rs4646903, CYP19A1 rs10046, tumor protein 53 (TP53) rs1042522, X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) rs25487 and serpin peptidase inhibitor clade E member 1 (SERPINE1) rs1799889; however, for the 18 polymorphisms identified in the latter two groups, further studies of the potential association with the endometriosis risk are needed. The remaining five of the 28 polymorphisms were not associated with endometriosis: glutathione S-transferase theta 1 (GSTT1) null genotype, vascular endothelial growth factor alpha (VEGFA) rs699947, rs833061, rs2010963 and rs3025039. WIDER IMPLICATIONS By carefully taking account of how the control populations were defined, we identified polymorphisms that might be candidates for use in endometriosis screening and polymorphisms not associated with endometriosis. This might constitute the first step towards identifying polymorphism combinations that predispose to endometriosis (IFNG (CA) repeat, GSTM1 null genotype, GSTP1 rs1695, WNT4 rs16826658 and WNT4 rs2235529) in a large cohort of patients with well-defined inclusion criteria. In turn, these results might improve the diagnosis of endometriosis in primary care. Lastly, our present findings may enable a better understanding of endometriosis and improve the management of patients with this disease.

A novel association between GSTM1 null variant and anthracycline-induced cardiac dysfunction (ACD) in childhood cancer survivors (CCS): A COG ALTE03N1 report.

10030 Background: ACD is a leading cause of mortality in CCS. Previous studies have identified genomic variants that moderate the ACD risk. An agnostic evaluation of differential gene expression between those with and without ACD has not been explored, and could provide insights into the mechanism of cardiotoxicity. Methods: Gene expression profiles in leukocyte RNA from anthracycline-exposed non-Hispanic white (NHW) CCS (20 with ACD [cases]; 20 without ACD [controls]) used Illumina HumanHT-12 v4.0 Expression Beadchips. Gene expression profiles in h uman iPSC-derived cardiomyocytes (hiPSC-CMs – Day 30) from 6 childhood cancer patients (3 each with and without CD) treated with 1μM doxorubicin or vehicle for 24 h, used RNA-seq. Genotyping in leukocyte DNA from anthracycline-exposed NHW CCS (65 cases; 76 controls) to determine if the differentially-expressed genes mapped to genetic variants that modified ACD risk, used conditional logistic regression analysis adjusted for sex, age at cancer diagnosis, chest radiation and anthracycline dose. Patient characteristics are in Table. Results: Gene-expression in survivors:Glutathione S transferase mu 1 ( GSTM1) was differentially-expressed; RT q-PCR showed significant downregulation of GSTM1 in cases (0.67±0.57 vs. 1.33±1.33, p=0.049). hiPSC-CMs gene expression: GSTM1 was downregulated in patients with ACD (logFC = -1.4). Genotyping: Using PCR for GSTM1 null, we observed a significant association between CD risk and GSTM1 null genotype (OR=3.0; 95%CI, 1.4-6.2, p=0.003). Conclusions: We report an association between GSTM1 null genotype and ACD, previously unreported likely because GWAS studies did not examined gene deletions. GSTM1 is involved in detoxification of anthracyclines. This finding could facilitate identification of childhood cancer survivors at increased risk of ACD. [Table: see text]

The GSTM1 and GSTT1 Null Genotypes Increase the Risk for Type 2 Diabetes Mellitus and the Subsequent Development of Diabetic Complications: A Meta-analysis

Background:Studies pertaining to association of GSTM1 and GSTT1 null genotypes with risk of T2DM and its complications were often inconclusive, thus spurring the present study.Methods:Meta-analysis of 25 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in determining the risk for T2DM and 17 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in development of T2DM related complications were conducted.Results:Our study revealed an association between GSTM1 and GSTT1 null polymorphism with T2DM (GSTM1; OR=1.37;95% CI =1.10-1.70 and GSTT1; OR=1.29;95% CI =1.04-1.61) with an amplified risk of 2.02 fold for combined GSTM1-GSTT1 null genotypes. Furthermore, the GSTT1 null (OR=1.56;95%CI=1.38-1.77) and combined GSTM1-GSTT1 null genotypes (OR=1.91;95%CI=1.25- 2.94) increased the risk for development of T2DM related complications, but not the GSTM1 null genotype. Stratified analyses based on ethnicity revealed GSTM1 and GSTT1 null genotypes increase the risk for T2DM in both Caucasians and Asians, with Asians showing much higher risk of T2DM complications than Caucasians for the same. </P><P> Discussion: GSTM1, GSTT1 and combined GSTM1-GSTT1 null polymorphism may be associated with increased risk for T2DM; while GSTT1 and combined GSTM1-GSTT1 null polymorphism may increase the risk of subsequent development of T2DM complications with Asian population carrying an amplified risk for the polymorphism.Conclusion:Thus GSTM1 and GSTT1 null genotypes increases the risk for Type 2 diabetes mellitus alone, in combination or with regards to ethnicity.

Glutathione S-Transferase Genotype polymorphism and Primary Open-Angle Glaucoma in an Italian population

PurposeOxidative damage to the trabecular meshwork (TM) represents one of the pathogenic mechanisms leading to primary open angle glaucoma (POAG). Glutathione S-transferase mu 1 (GSTM1) may neutralizes reactive oxygen species protecting the TM. The present paper investigates the prevalence of GSTM1 null genotype in an Italian population, and its association with POAG treated either medically or surgically.MethodsIn a case-control study, the GSTM1 genotype was identified in POAGs and controls. The POAGs patients were divided in two groups: medical POAGs and surgical POAGS. Medical POAGs consisted of patients with a well-controlled intraocular pressure (IOP) by IOP-lowering medications and a stable visual field (VF). Patients with an uncontrolled IOP and a progressing VF that were submitted to incisional surgery formed the surgical POAGs’ group.ResultsWe enrolled 104 medical POAGs, 158 surgical POAGs and 263 Controls. No significative differences between the groups existed regarding age and gender (p=0.275 and p=0.950, respectively). All the enrolled subjects were Caucasian of Italian descents. The GSTM1 null genotype was identified in 57 (45.2%) medical POAGs, 91 (57.6%) surgical POAGs and, 119 (45.3%) controls (p=0.033). The association between medical POAG and GSTM1 null status was non-significant (OR= 1.44, 95% IC = 0.86 to 2.39) whereas the association was significant for surgical POAGs (OR= 2.01, 95% IC= 1.26 to 3.21)ConclusionsOur results showed an association between the GSTM1 null genotype and glaucoma that require surgery in an Italian population. GSTM1 null genotype detection may help to identify high-risk glaucoma patients that require a closer follow-up and a more aggressive treatments.

Glutathione S-transferase M1-T1 null genotypes and susceptibility to Hodgkin’s lymphoma

Hodgkin?s Lymphoma (HL) is a heterogeneous malignant disease of lymph node. The glutathione S-transferases (GSTs) have an important role in the detoxification of a wide variety of toxins and carcinogens. Studies have been indicated that genetic variation in the GST gene family may lead to susceptibility in HL. Hereby, we investigated the association of GSTT1 and GSTM1 null genotypes with HL in the Iranian population. This case-control study consisted of 76 patients suffering from HL and 120 healthy individuals as a control group. Genomic DNA was extracted and genotyping of GSTT1 and GSTM1 genes for the identification of their null genotypes was carried out using multiplex PCR method. Our findings indicated that GSTM1 null genotype is associated with risk of developing HL in our population (P=0.025; OR=2.00; 95%CI=1.110- 3.602); however, no association was found for GSTT1 null genotype. Our study also showed that the GSTM1 null genotype increased the risk of disease in the individuals younger than 45 years, and it had a positive association with low ESR. GSTM1 null genotype may have the key role in increasing the risk of HL in the Iranian population.