Null Polymorphism Research Articles

The Cumulative Effect of Gene-Gene Interactions Between GSTM1, CHRNA3, CHRNA5 and SOD3 Gene Polymorphisms Combined with Smoking on COPD Risk.

BackgroundChronic obstructive pulmonary disease (COPD) is a multifactorial disorder which is affected by external and internal risk factors. People with no external risk factors may be significantly affected and develop pulmonary disease. The study aimed to define gene–gene and gene–environmental effects on COPD.MethodsA case control study involved 181 COPD patients and 292 healthy individuals, with peripheral blood sampling and adequate questionnaires. Genotyping was done with various types of PCR design for GSTM1 (null del), GSTT1 (null del), EPHX1 (rs2234922 and rs1051740), GSTP1 (rs1695 and rs1138272), CHRNA3 (rs1051730 and rs12914385), CHRNA5 (rs16969968 and rs17486278), and SOD3 (rs1799895 and rs699473) gene polymorphisms. Gene–gene and gene–environmental interactions were investigated using multidimensional regression analysis.ResultsFrequency of risk alleles of rs1051730 (p = 0.001), rs16969968 (p <0.001), and rs1799895 (p <0.001) polymorphisms were significant in univariate analysis. For gene–gene interaction, GSTM1 null, rs1051730, rs16969968, and rs1799895 polymorphisms independently contributed to risk of COPD and any combinations of the risk genotypes have a higher risk of disease. A cumulative effect of the four risk polymorphisms increased the risk of COPD for the smoking index (cOR = 13.6, p <0.001), cigarettes per day (cOR = 32.08, p <0.01), nicotine dependence (cOR = 12.0, p <0.01), and smoking status (cOR = 17.02, p <0.01) for gene–environmental interaction.ConclusionSeveral pivotal genes showed distinct effects for COPD, and some synergistic effects affected the disease progression. The development of COPD was synergistically increased with gene–gene and gene–environmental risk factors.

Heavy metal-associated oxidative stress and glutathione s-transferase polymorphisms among E-waste workers in Pakistan

Increased E-waste generation during recent times has become a global concern, especially for developing countries that are at receiving end from the developed countries. Their improper handling and lacking management practices in developing countries including Pakistan are contributing enormous addition of toxicants into the environment and affecting the health of exposed workers associated with E-waste recycling activities. A systematic cross-sectional study was designed comprising workers associated with E-waste recycling activities in Peshawar city, Pakistan. The study aimed to investigate metal concentrations in dust, particulate matter and urine of exposed workers and correlate with oxidative stress and glutathione S-transferases genotypes (GSTM1 and GSTT1) that play a role in detoxification of metals in humans. A total of 120 blood samples comprising dismantlers (n = 52), repairers (n = 21), smelters (n = 17) and controls (n = 30) were collected. Results showed that metal concentrations were significantly higher in the dust (P = 0.020), particulate matter (P = 0.021) and urine samples (P = 0.00) as compared to controls. We observed significant increase in MDA (P = 0.00) and decrease in SOD (P = 0.00) and CAT (P = 0.00) levels among exposed subjects as compared to controls. Additionally, GSTT1 null genotype was more significantly associated with the dismantlers (P = 0.02). The study shows that E-waste workers are exposed to high level of toxic metals through dust and particulate matter, resulting in significant oxidative stress and related health implications, while GSTT1 null polymorphism is associated with increased susceptibility to these metals and induced health outcomes.

Status of Catalase, Glutathione Peroxidase, Glutathione S-Transferase, and Myeloperoxidase Gene Polymorphisms in Beta-Thalassemia Major Patients to Assess Oxidative Injury and Its Association with Enzyme Activities.

Beta-thalassemic patients require regular blood transfusion to sustain their life which leads to iron overload and causes oxidative stress. The aim of this study was to investigate the status of variants in genes including GSTM1 , GSTT1 (null/present), CT-262 (C > T) and CT-89 (A > T), glutathione peroxidase (GPx), and myeloperoxidase (MPO). The genotype studies were conducted with 200 thalassemia major (TM) patients and 200 healthy controls. Genotyping of GST gene was performed by multiplex polymerase chain reaction (PCR), whereas for CT, GPx and MPO genesvariants PCR- restriction fragment length polymorphism technique used. However, the enzyme activities were measured only in the patients group to assess the association with the genotypes. All enzyme estimations were performed by ELISA. We observed higher frequency of GSTT1 null, CT-89 (A > T), GPx1 198 (C > T) and MPO-463 (G > A) polymorphisms in TM patient than healthy controls. However, CT-262 (C > T) polymorphism was not found to be statistically significantly different between patients and controls. Our results suggest that frequency of null allele of glutathione-S-transferase is significantly high among TM patients. The other alleles CT-89 (A > T), GPx1 198 (C > T), and MPO-463 (G > A) are linked to decreased CT, GPX, and MPO enzyme activities.

Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk.

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

The role of polymorphisms in glutathione-related genes in asbestos-related diseases.

BackgroundThe study investigated the influence of GCLC, GCLM, GSTM1, GSTT1 and GSTP1 polymorphisms, as well as the influence of interactions between polymorphism and interactions between polymorphisms and asbestos exposure, on the risk of developing pleural plaques, asbestosis and malignant mesothelioma (MM).Subjects and methodsThe cross sectional study included 940 asbestos-exposed subjects, among them 390 subjects with pleural plaques, 147 subjects with asbestosis, 225 subjects with MM and 178 subjects with no asbestos-related disease. GCLC rs17883901, GCLM rs41303970, GSTM1 null, GSTT1 null, GSTP1 rs1695 and GSTP1 rs1138272 genotypes were determined using PCR based methods. In statistical analysis, logistic regression was used.ResultsGSTT1 null genotype was associated with the decreased risk for pleural plaques (OR = 0.63; 95% CI = 0.40–0.98; p = 0.026) and asbestosis (OR = 0.51; 95% CI = 0.28–0.93; p = 0.028), but not for MM. A positive association was found between GSTP1 rs1695 AG + GG vs. AA genotypes for MM when compared to pleural plaques (OR = 1.39; 95% CI = 1.00–1.94; p = 0.049). The interactions between different polymorphisms showed no significant influence on the risk of investigated asbestos-related diseases. The interaction between GSTT1 null polymorphism and asbestos exposure decreased the MM risk (OR = 0.17; 95% CI = 0.03–0.85; p = 0.031).ConclusionsOur findings suggest that GSTT1 null genotype may be associated with a decreased risk for pleural plaques and asbestosis, may modify the association between asbestos exposure and MM and may consequently act protectively on MM risk. This study also revealed a protective effect of the interaction between GSTP1 rs1695 polymorphism and asbestos exposure on MM risk.

Association of GSTM1 and GSTT1 Null Deletions and GSTP1 rs1695 Polymorphism with the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis

Context: Hepatocellular carcinoma (HCC), as the most common type of primary liver cancer (accounting for 70% - 90% of all liver cancers), is the seventh most common malignancy worldwide. Glutathione S-transferases (GSTs) are a specific group of enzymes that are responsible for the detoxification of carcinogens. According to the available literature, genetic variations in this group of enzymes may be associated with the risk of HCC. In this study, we aimed to assess the association of GSTM1 and GSTT1 null deletions and GSTP1 rs1695 polymorphism with the risk of HCC. Methods: We systematically searched electronic databases, including PubMed, Scopus, and Web of Science, using appropriate keywords to gather relevant data until March 2019. Studies that met the inclusion criteria were included in the meta-analysis, using either fixed- or random-effects models based on the presence of heterogeneity. Results: This meta-analysis pooled 19 studies for GSTM1 null deletions, 14 studies for GSTT1 null deletions, and five studies for GSTP1 rs1695 polymorphism. In terms of heterogeneity, the pooled odds ratio (OR) was calculated in a random-effects model for both Asian and non-Asian populations. HCC was found to be associated with GSTM1 null deletions (OR = 1.26, 95% CI: 1.00 - 1.58, P = 0.05) and GSTT1 null deletions (OR = 1.39, 95% CI: 1.10 - 1.74, P = 0.005); however, no significant association was found between HCC and GSTP1 rs1695 polymorphism (OR = 1.14, 95% CI: 0.86 - 1.50, P = 0.36). Conclusions: We found that GSTM1 and GSTT1 null deletions increased the risk of HCC; however, the GSTP1 rs1695 polymorphism did not have a similar effect.

GSTM1 null polymorphism and palmar dermatoglypics in oral leukoplakia.

An individual's risk towards development of cancer depends not only on environmental factors or extrinsic exposure to carcinogens but also on individual's genetic susceptibility. To determine two genetically established parameters such as prevalence of GSTM1 null polymorphism and analysis of Palmar dermatoglypics (PD) in patients with Oral Leukoplakia (OL) and Controls. Group I (cases) 30 patients with established histopathological diagnosis of OL and Group II (controls) 30 patients without any habits of tobacco, alcohol usage and without OL were selected. After informed consent, the palm prints were recorded using a Canon PIXMA MP250 scanner and 2 ml of blood was collected and transported under cold cycle and taken for evaluation of GSTM1 null polymorphism using Multiplex PCR. There exists a highly significant difference in GSTM1 null polymorphism (p-0.002), Finger ridge patterns (arches- p-0.027, loops p-0.001, whorls p-0.001), hypothenar pattern (p-0.015), ATD angle (p-0.001), AB count (p-0.007) between cases and controls. Similarly, when analysing the GSTM1 null polymorphism with PD among cases, there exists a significant association between loops (p-0.001), AB count (p-0.058) and hypothenar pattern (p-0.076), respectively 43% of OL cases had alteration in both which implies that those patients are at a higher risk of developing cancer. Not all patients who smoke or chew tobacco develop cancer. This could probably be due to the individual's genetic susceptibility. Environment gene interactions, in the form of GSTM1 polymorphism, and carcinogenesis, share links that can help in the prediction of risk for oral cancer development, and use of such markers can aid in prediction of oral cancer susceptibility in exposed individuals. Palm prints once formed do not change throughout life and are not influenced by environment. It can also serve as genetic markers to predict the risk of occurrence of oral cancer.

LATE BREAKING NEWS E-POSTER PRESENTATION: LBP 10 ACTN3 genotype influences skeletal muscle mass regulation and the response to dexamethasone

Homozygosity for the common ACTN3 null polymorphism (ACTN3 577X) results in α-actinin-3 deficiency in ∼20% of humans worldwide and is associated with reduced sprint and power performance in both elite athletes and the general population. α-Actinin-3 deficiency is also associated with reduced muscle mass and strength, increased sarcopenic risk in the elderly, and modifies disease severity and progression in a number of neuromuscular disorders such as Duchenne muscular dystrophy (DMD). Using an Actn3 knockout mouse model, we now show that α-actinin-3 plays a key role in the regulation of protein synthesis and breakdown in skeletal muscle, and its influence on muscle mass begins during early postnatal muscle development.

Glutathione S-transferase gene polymorphisms (GSTT1 and GSTM1) and risk of schizophrenia: A case-control study in Chinese Han population.

Schizophrenia (SCZ) is a chronic disability disorder related to oxidative stress. Glutathione S-transferase (GST) is a group enzyme that protects cells and tissues from oxidative stress damage. Among GSTs, GSTT1 and GSTM1 have well defined genetic polymorphisms. The purpose of our research was to explore the correlation between GSTT1 and GSTM1 polymorphism and SCZ risk in Chinese Han population.A total of 650 subjects (386 SCZ patients and 264 healthy individuals) were included in this case–control designed study. The GSTT1 and GSTM1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR). We explored the relationship between these 2 polymorphisms and the risk of SCZ.We found that the GSTT1 null genotype had a protective effect on the development of SCZ [odds ratio (OR) = 0.601, 95% confidence interval (95% CI) = 0.412–0.986, P = .031]. We also found that the combination of null genotypes of the GSTT1 and GSTM1 genes was made at a lower risk of SCZ (OR = 0.452, 95% CI = 0.238–0.845, P = .028). However, we found no correction between Positive and Negative Syndrome Scale score (PANSS) and GSTM1, GSST1 genotypes in SCZ patients.Our finding revealed that GSTT1 null polymorphisms may be related to the reduced risk of SCZ in Chinese Han population, and this risk was further reduced with the combination of GSTT1 null polymorphisms and GSTM1 null polymorphisms.

GST null polymorphisms may affect the risk of coronary artery disease: evidence from a meta-analysis

BackgroundWhether glutathione S-transferase (GST) null polymorphisms, namely GSTM1 null, GSTP1 null and GSTT1 null polymorphisms, influence the risk of coronary artery disease (CAD) or not remains unclear. Thus, the authors performed a meta-analysis to more robustly estimate associations between GST null polymorphisms and the risk of CAD by integrating the results of previous publications.MethodsMedline, Embase, Wanfang, VIP and CNKI were searched comprehensively for eligible studies, and 45 genetic association studies were finally selected to be included in this meta-analysis.ResultsWe found that GSTM1 null polymorphism was significantly associated with the risk of CAD in overall population (OR = 1.37, p = 0.003) and mixed population (OR = 1.61, p = 0.004), GSTP1 null polymorphism was significantly associated with the risk of CAD in overall population (OR = 1.23, p = 0.03), whereas GSTT1 null polymorphism was significantly associated with the risk of CAD in overall population (OR = 1.23, p = 0.02), Caucasians (OR = 1.23, p = 0.02) and East Asians (OR = 1.38, p < 0.0001).ConclusionsThis meta-analysis demonstrated that GSTM1 null, GSTP1 null and GSTT1 null polymorphisms were all significantly associated with an increased risk of CAD.

Genotype of Null Polymorphisms in Genes GSTM1, GSTT1, CYP1A1, and CYP1A1*2A (rs4646903 T>C)/CYP1A1*2C (rs1048943 A>G) in Patients with Larynx Cancer in Southeast Spain.

Simple SummaryEpidemiological studies have shown that individual susceptibility to cancer is mediated by genetic and environmental factors. The aim of the present study is to evaluate the individuals’ metabolic genetic susceptibility to toxic habits (smoking and alcohol consumption) by detecting polymorphisms CYP1A1 rs1048943 T>C and CYPA1A2 rs4646903 A>G, and null polymorphisms in GSTM1 and GSTT1 genotypes, comparing a group of healthy control subjects with a population of larynx cancer patients from southeastern Spain. As results patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.Background: some types of cancer have been associated with the presence of single nucleotide polymorphisms (SNPs) of some genes that encode enzymes: glutathione-S transferase (GST), whose alteration leads to loss of function and a lower capacity to eliminate toxic GSTM1 and GSTT1 null genotypes; SNPs causing loss of function of CYP1A1 or CYP1A1–2 cytochrome P450 enzymes related with a lower capacity to deactivate hydrocarbons related to smoking, which involves a higher risk of developing some smoking-dependent cancers including larynx cancer. Objective: to compare the presence of null SNPs in genes GSTM1, GSTT1, and CYP1A1 rs 4646903 T>C, and CYP1A1–2 RS1048943 A>G in patients with hypopharyngeal and larynx cancer with a healthy control group. Materials and method: The study included a total of 80 patients with hypopharyngeal and laryngeal cancer and 23 healthy subjects. Genomic DNA was obtained from saliva samples, determining genotype GSTM1 (present +, or null −), GSTT1 (present + or null −). Polymorphisms (SNP) in CYP1A1 T>C (present + CC, or absent − TC/TT), and CYP1A1–2 A>G (present + GG, or absent − AG/AA). Results: the mean age of patients with larynx cancer was 62 years and of control subjects 63 years. Of the total sample, over 95% were men, and over 90% were smokers. The presence of null genotypes for GTM1 was 50% in patients with larynx cancer (p = 0.042), while GSTT1 was 88.75% (p = 0.002). CYP1A1 rs4646903 T>C polymorphisms were detected in 100% of cases of larynx cancer and 17.39% of healthy subjects (p > 0.001). Conclusions: patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.

GSTM1 and GSTT1 Null Genotype Polymorphisms and Susceptibility to Arsenic Poisoning: a Meta-analysis.

The value of the glutathione S-transferase (GST) null genotype in patients with arsenic poisoning has been recognized, but the conclusions of previous studies remain inconsistent. The objective of this study was to evaluate the relationship between GST mu 1 (GSTM1) and GST theta 1 (GSTT1) null genotype polymorphisms and susceptibility to arsenic poisoning. PubMed, Medline, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, and WeiPu databases were systematically searched for publications up to March 31, 2020. The quality of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to estimate the relationship between GSTM1 and GSTT1 null genotype polymorphisms and arsenic poisoning. The meta-analysis was conducted using STATA 14.0 software. Nine articles with 3324 subjects were included in the meta-analysis. A significantly negative correlation was observed between the GSTM1 null genotype and susceptibility to arsenic poisoning (OR = 0.731; 95% CI: 0.536-0.999; P = 0.049; I2 = 70.5%). There was no significant correlation between the GSTT1 null genotype (OR = 1.009; 95% CI: 0.856-1.189; P = 0.915, I2 = 36.8%) and GSTM1-GSTT1 double null genotype (OR = 1.105; 95% CI: 0.670-1.822; P = 0.695; I2 = 64.7%) and the risk of arsenic poisoning. Egger's and Begg's tests indicated no publishing bias. Compared with controls, individuals with the GSTM1 null genotype were less susceptible to arsenic poisoning. The GSTT1 single null genotype and GSTM1-GSTT1 dual-null genotype were not associated with the risk of arsenic poisoning. The GSTM1 single null genotype may have potential as a genotoxic biomarker to identify individuals who are not prone to arsenic poisoning, and as a reference for guiding the prevention of arsenic poisoning.

Glutathione S-transferase activity and genetic polymorphisms associated with exposure to organochloride pesticides in Todos Santos, BCS, Mexico: a preliminary study.

The objective of this study was to identify and evaluate the impact of exposure to mixtures of organochloride pesticides (OCPs) in agricultural workers by detecting their effects on the activity of the enzyme glutathione S-transferase (GST) and the presence of polymorphisms of the GSTT1 and GSTM1 genes. The presence of OCPs was identified and quantified by gas chromatography, while spectrophotometry was used to measure enzymatic GST activity. The frequencies of the GSTM1 genotypes were analyzed by multiplex PCR. A total of 18 metabolites of OCPs were identified in the workers' blood, most of which are either prohibited (DDT and its metabolites p, p'DDD and p, p'DDE, dieldrin, endrin, aldrin) and/or restricted (δ hexachlorocyclohexane, cis chlordane, methoxychlor, and endosulfan). The results obtained indicate lower levels of GST activity at higher OCPs concentrations detected in blood from exposed workers, together with an increase in OCP levels in individuals who presented the GSTT1*0 and GSTM1*0 genotypes. These conditions place the detoxification process in agricultural workers with null polymorphisms in the GST genes and high concentrations of OCPs in the blood (especially DDT and its metabolites, DDD and DDE) at risk, and increase their susceptibility to develop serious diseases.

Polymorphism in GSTM1 and GSTT1 genes influence DNA damage in personnel occupationally exposed to volatile anaesthetics (VA), from Peshawar, Pakistan

ObjectivesThe objective of this study was to assess the influence of antioxidant gene GSTM1 and GSTT1 on DNA damage in personnel occupationally exposed to volatile anaesthetics (VA).MethodsThe study groups were...

Genetic Polymorphisms of Glutathione S-Transferase and Risk of Acute Myeloid Leukemia: Case-Control Study and Meta-Analysis

Background: Acute myeloid leukemia (AML) is a complex disease that is linked to genetic and environmental factors. The gluthatione S-transferase (GST) is a family of enzymes that play a crucial role in the detoxification of carcinogens. These compounds could cause DNA damage, which might lead to the development of cancer. Interindividual inherited differences caused by the presence of single nucleotide polymorphisms (SNPs) in detoxification enzyme, could play a major role in cancer predisposition. The present study aimed to investigate the association between GST gene polymorphisms and AML risk. Methods: The GSTP1 genotype was determined by the PCR-RFLP and multiplex PCR for GSTT1 and GSTM1. Meta-analysis was conducted to evaluate the association between GST gene and the risk of AML. Results: We found that GSTT1 null genotype was significantly associated with the risk of AML. However, GSTM1 and GSTP1 polymorphisms did not influence the AML risk. Subjects carrying the GSTM1 Present, GSTT1 null and GSTP1 Ile / Val et Val /Val genotypes had a higher risk of developing AML. The results of meta-analysis showed a positive association between GSTM1 null, GSTT1 null and Ile105Val GSTP1 polymorphisms and AML risk in East Asians, Caucasians, and mixed populations, respectively. Conclusion: GST gene polymorphisms may be risk factors for acute myeloid leukemia.

Abstract P1-19-20: Safety of palbociclib in African American women with hormone receptor positive HER2 negative advanced breast cancer and benign ethnic neutropenia: PALINA study

Abstract Background: There are significant racial disparities in breast cancer outcomes between African American women (AAW) and Caucasian women (CW) in the US. It has been reported that AAW have more chemotherapy dose reductions than CW which results in worse clinical outcomes (Schneider BP et al. JCO Precis Oncol 2017). Given the high incidence of benign ethnic neutropenia (BEN) in AAW, we sought to evaluate the hematological safety of palbociclib in this group of patients. A polymorphism (SNP rs2814778 at chromosome 1q23.2) in the Duffy Antigen Receptor Chemokine (DARC) gene is implicated in the pathophysiology of BEN. AAW have been historically underrepresented in clinical trials including studies that led to the FDA approval of palbociclib. This diversity gap can compromise the generalizability of clinical trial results and further exacerbate minority health disparities. Methods: PALINA is a phase II study that evaluated the hematological safety of palbociclib with endocrine therapy (ET) in 35 AAW with HR positive HER2 negative advanced breast cancer (ABC) and ANC ≥1,000 cells/mm3. Eligible patients were self-identified as African, African-American or Black, PS 0-2 and had not received a prior CDK4/6 inhibitor (CDK4/6i). Treatment included palbociclib 125mg daily for 21 days followed by 7 days off and either an aromatase inhibitor (AI) or fulvestrant per investigator discretion. Maximum time allowed on study was 12 months. Responding patients could continue palbociclib off trial. Presence of the Duffy null polymorphism as a predictive marker for neutrophil count was assessed at baseline. Metabolite and exosomal signature (proteins and RNA) of drug resistance were also evaluated at different time points and will be reported separately. Primary endpoint was the proportion of patients who completed planned oncologic therapy without the development of a hematological event defined as episodes of febrile neutropenia (FN) or treatment discontinuation due to neutropenia. A two-stage design was used to test if the completion rate of planned oncologic therapy without a hematological event was at least 80% versus if it was below 60%, with 80% power at a significance level of 5%. Results: 35 women were enrolled from 5 different institutions. Mean age was 64 years (30-90). 9% (3/35) of patients had PS of 2. Visceral involvement was present in 51% (18/35) of patients; 60% (21/35) received an AI and 40% (14/35) received fulvestrant. Baseline median ANC was 3,100 (1,300-11,100) cells/mm3. None of the patients had FN or required discontinuation of therapy due to neutropenia. Grade 3 and 4 neutropenia were experienced by 46% (16/35) and 3% (1/35) of patients respectively. Dose delays occurred in 17 patients, and 13 patients required dose reduction (5 to 100mg and 8 to 75 mg). Clinical benefit rate (CR+PR+SD persisting for ≥6 months) was 70%. Of the 29 patients who have completed study participation, the median time on treatment was 280 days (14, 385) and 15 continued on commercial palbociclib. Last visit on study estimated for 10/2019. The Duffy polymorphism was evaluated in 94% (33/35) of patients. The Duffy null phenotype was present in 58% (19/33) of the patients. Lower baseline ANC (2,400 vs 4,300 cells/mm3, p0.006), grade 3 neutropenia (63.2 vs 21.4%, p0.003) and dose reductions (52.6 vs 7.1%, p0.009) were more common in patients with the Duffy null polymorphism. Conclusion: This is the first trial specifically designed to evaluate the hematologic toxicity of a CDK4/6i in AAW. Although patients with the Duffy null phenotype had more dose reductions and treatment delays due to neutropenia, this did not result in episodes of FN or treatment discontinuation due to neutropenia. This analysis suggests that palbociclib with ET is safe in AAW including those with the Duffy null phenotype. Citation Format: Filipa Lynce, Rebecca Zhuo, Matthew Blackburn, Christopher Gallagher, Olwen Hahn, Maysa Abu-Khalaf, Mahsa Mohebtash, Tianmin Wu, Paula Pohlmann, Asma Dilawari, Shruti Tiwari, Ami Chitalia, Robert Warren, Ming Tan, Ayesha Shajahan-Haq, Claudine Isaacs. Safety of palbociclib in African American women with hormone receptor positive HER2 negative advanced breast cancer and benign ethnic neutropenia: PALINA study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-20.

Association Between Glutathione-S-Transferase Gene Polymorphisms and Responses to Tyrosine Kinase Inhibitor Treatment in Patients with Chronic Myeloid Leukemia: A Meta-analysis.

Although many earlier studies revealed an effect of glutathione-S-transferase (GST) gene polymorphisms on tyrosine kinase inhibitor (TKI) treatment responses in chronic myeloid leukemia (CML) patients, the significance of this relationship remains controversial. This study aimed to review and meta-analyze treatment responses to TKIs in patients with CML and GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1. We searched four medical databases, PubMed, Web of Science, the Cochrane Library, and Embase, by using keywords related to GST gene polymorphisms and clinical responses in CML patients receiving TKI treatment. The meta-analysis was performed using RevMan version 5.3 and Comprehensive Meta-Analysis software version 3.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between GSTT1, GSTM1, and GSTP1 polymorphisms and TKI treatment responses in patients with CML. The null polymorphisms of GSTT1 and GSTM1 did not affect TKI treatment responses, while the GSTP1 Ile105Val polymorphism had a significant impact on responses to TKI. Patients who were GSTP1 variant allele carriers (AG + GG) had poor responses to TKI treatment compared to patients who were wild-type homozygote carriers (AA) (OR 1.85, 95% CI 1.31-2.62; p < 0.001). This meta-analysis of patients with CML showed that G allele carriers with GSTP1 Ile105Val polymorphism had significantly worse responses to TKI treatment than wild-type homozygote carriers.

Environmental exposure pathway analysis of trace elements and autism risk in Pakistani children population

The pursuit of industrialization and urbanization in developing countries disrupt the fragile environment, resulting in biogeochemical extra-emission of the trace elements into human inhabitance causing serious health concerns. We aimed to determine the associations between Autism spectrum disorder (ASD) risk and exposure to trace elements (As, Zn, Ni, Pb, Hg, Cu, Cd, and Co), associations between the internal doses and environmental sources of these elements were also assessed. Genetic susceptibility to toxins was assessed through GSTT1 and GSTM1 null polymorphism analysis. Our results showed that lower BMI in children was significantly associated with ASD (p < 0.05, AOR = 0.86; 95% CI: 0.76, 0.98). As was significantly higher in both hair (p < 0.01, AOR = 18.29; 95% CI: 1.98, 169) and urine (p < 0.01, AOR = 1.04; 95% CI: 1.01, 1.06) samples from children with ASD; urinary Hg (p < 0.05, AOR = 2.90; 95% CI: 1.39, 6.07) and Pb (p < 0.05, AOR = 1.95; 95% CI: 1.01, 3.77) were also positively associated with ASD. Regarding the genetic susceptibility, Cu was significantly associated with GSTM1 positive genotype (p < 0.05, AOR = 1.05; 95% CI: 1.00, 1.10). Children inhabiting the urban areas exposed to significantly higher levels of studied trace elements. The Estimated Daily Intake (EDI) values highlighted that the different land use settings resulted in children's source specific exposure to studied trace elements. The exposure pathway analysis showed that the distal factors of land-use settings associated with children increased exposure risk for most of the investigated elements, noticeably As, Pb and Hg associated with ASD prevalence.

A Case Control Study of Gene Environment Interaction in Pre-Eclampsia with Special Reference to Organochlorine Pesticides

Objectives: To study and compare the frequency of GSTM1 & T1 gene polymorphism in cases (Pre-eclampsia) and controls (normal pregnancy), to estimate and compare serum levels of Glutathione-S-Transferase enzyme in cases and controls, to quantify and compare Organochlorine pesticides levels in maternal blood of cases and controls and to evaluate the correlation; if any; amongst GSTM1 & T1 gene polymorphism, GST activity and Organochlorine pesticides levels in cases. Methodology: Maternal blood samples of 66 Pre-eclampsia cases and equal number of matched control were collected. Samples were analyzed for OCPs levels, GST activity and GST M1 and T1 gene polymorphism. Results: β-HCH, Heptachlor, Dieldrin, Endosulphan-I levels were found in higher amounts in cases as compared to controls. GSTT1-/GSTM1- (double null polymorphism) was significantly high in cases as compared to controls. GSTT1-(null) genotype was exclusively associated with severe pre-eclampsia. When GST activity was correlated with genotypic variation of GSTT1/M1 gene, null genotypes significantly downregulated GST activity, lowest being with double null genotype. Conclusions: There is a possible role of gene-environment interaction in the pathogenesis of pre-eclampsia. An interaction of increased levels of pesticides with GST polymorphisms (null type) causes low levels of GST enzyme levels (an anti-oxidant) resulting in increased oxidative stress causing pre-eclampsia.

Beyond detoxification: Pleiotropic functions of multiple glutathione S-transferase isoforms protect mice against a toxic electrophile.

Environmental and endogenous electrophiles cause tissue damage through their high reactivity with endogenous nucleophiles such as DNA, proteins, and lipids. Protection against damage is mediated by glutathione (GSH) conjugation, which can occur spontaneously or be facilitated by the glutathione S-transferase (GST) enzymes. To determine the role of GST enzymes in protection against electrophiles as well as the role of specific GST families in mediating this protection, we exposed mutant mouse lines lacking the GSTP, GSTM, and/or GSTT enzyme families to the model electrophile acrylamide, a ubiquitous dietary contaminant known to cause adverse effects in humans. An analysis of urinary metabolites after acute acrylamide exposure identified the GSTM family as the primary mediator of GSH conjugation to acrylamide. However, surprisingly, mice lacking only this enzyme family did not show increased toxicity after an acute acrylamide exposure. Therefore, GSH conjugation is not the sole mechanism by which GSTs protect against the toxicity of this substrate. Given the prevalence of null GST polymorphisms in the human population (approximately 50% for GSTM1 and 20–50% for GSTT1), a substantial portion of the population may also have impaired acrylamide metabolism. However, our study also defines a role for GSTP and/or GSTT in protection against acrylamide mediated toxicity. Thus, while the canonical detoxification function of GSTs may be impaired in GSTM null individuals, disease risk secondary to acrylamide exposure may be mitigated through non-canonical pathways involving members of the GSTP and/or GSTT families.