GSTT1 Research Articles

Role of GSTT1 and GSTM1 gene polymorphism for development of preeclampsia in Bangladeshi women

Worldwide, pre‐eclampsia (PE) ranks as a major obstetric problem leading to substantial maternal and perinatal morbidity and mortality, especially in developing countries. Clinically it appears as a maternal syndrome, including hypertension and proteinuria after second half of pregnancy. PE affected by genetic trait, is associated with oxidative stress due to imbalance between the production of reactive oxygen species and the ability of antioxidant process. The glutathione S‐transferases (GST) are a group of enzymes which are involved in protecting cells from oxidative stress. In our study, we evaluated the risk of developing preeclampsia related to GSTT1 and GSTM1 genotypes. 104 patients having preeclampsia and 200 healthy controls having no history of preeclampsia were recruited for the study after getting written consent from them. DNA was extracted from the blood and Polymerase Chain Reaction (PCR) method was used to identify genotypes of GSTT1 and GSTM1 in study subjects. We used odds ratio to calculate the risk between cases and controls using SPSS 17. Genotype frequency of GSTM1 nul genotype showed significant difference between case and control group (p<0.001). Combined null genotype for GSTT1 and GSTM1 showed significant difference between two groups when compared to combined present genotype for GSTT1 and GSTM1 (p<0.001). There was significant association for GSTM1 null genotype with the development of preeclampsia (p<0.001) and the odds ratio was significantly higher in patients compared to control subjects (OR=4.75; 95% CI=2.17–10.39). For GSTT null genotype, there was increased risk for developing preeclampsia but the association was not significant (OR=1.22; 95% CI=0.58–2.57).In case of GSTT1 and GSTM1 combined genotype, patients having both null genotypes for GSTT1 and GSTM1 showed significance (p<0.001) and higher risk of developing preeclampsia when compared to control subjects (OR=7.64; 95% CI=2.38–24.60). We found a significant association between GSTM1 null genotype and the risk of developing preeclampsia in Bangladeshi population. No risk was found for GSTT1 null genotype and preeclampsia. For combined null genotype of GSTT1 and GSTM1, the risk was even higher relative to the risk of either GSTT1 null or GSTM1 null genotype alone.Support or Funding InformationDear colleague, I hereby, would like to express my motivation with this letter to attend the American Society for Biochemistry and Molecular Biology at San Diego, USA from 21–25 April 2018.The conference topics are relevant to my professional skills, and therefore I would welcome the opportunity to attend this conference having researchers from different countries of the world. I am working as an program coordinator at RHSTEP and at the same working as a predatory PhD student at Department of Biochemistry and Molecular Biology of Dhaka University.As a unique added value of this event, I will find a chance for networking with other scientists from different countries, which is an excellent opportunity for horizontal exchange of knowledge and experience. This networking will expand my opportunities for planning collaborative research projects in future.I have completed my MBBS from Moulana Bhasani Medical College and MPH from American International University, Bangladesh. In case of all three degrees, the medium of instruction was English.Unfortunately I do not have fund to attend this conference and I will apply for a travel grant.My attendance at this training will be very helpful for my carrier development and I would highly appreciate to be one of the selected participants.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

EPHX1 rs1051740 T>C (Tyr113His) is strongly associated with acute myeloid leukemia and KMT2A rearrangements in early age.

Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML's genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow.

Histone Methyltransferase Setd7 Regulates Nrf2 Signaling Pathway by Phenethyl Isothiocyanate and Ursolic Acid in Human Prostate Cancer Cells.

This study aims to investigate the role of the epigenetic regulator SET domain-containing lysine methyltransferase 7 (Setd7) in regulating the antioxidant Nrf2 pathway in prostate cancer (PCa) cells and examines the effects of two phytochemicals, phenethyl isothiocyanate (PEITC) and ursolic acid (UA). Lentivirus-mediated shRNA knockdown of Setd7 in LNCaP and PC-3 cells decreases the expression of downstream Nrf2 targets, such as NAD(P)H: quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase theta 2 (Gstt2). Downregulation of Setd7 decreases soft agar colony formation ability of PCa cells. Knockdown of Setd7 increases reactive oxygen species (ROS) generation. Furthermore, Setd7 knockdown attenuates Nqo1 and Gstt2 expression in response to H2 O2 challenge, whereas increased DNA damage is observed in Setd7 knockdown cells in comet assay. Interestingly, Setd7 expression could be induced by the dietary phytochemicals PEITC and UA. Chromatin immunoprecipitation (ChIP) assays show that Setd7 knockdown decreased H3K4me1 enrichment in the Nrf2 and Gstt2 promoter regions, while PEITC and UA treatments elevated the enrichment. Taken together, these results indicate that Setd7 knockdown decreases Nrf2 and Nrf2-target genes expression and that PEITC and UA induce Setd7 expression, which activates the Nrf2/antioxidant response element (ARE) signaling pathway and protects DNA from oxidative damage.

Glutathione S-transferase M1 and T1 null genotype frequency distribution among four tribal populations of western India

Glutathione S transferase (GST) family is a key contributor in the detoxification mechanism of our body.Deletion of the genes within this family has been reported in the failure of detoxification system, to some extent leading to various types of cancers and other life threatening diseases. The existing data and reports on the association of null genotype of both GSTM1 and GSTT1 genes for various diseases are inconsistent. But knowledge of the polymorphic distributions of genotypes in different populations is important for investigating the risk factors in different epidemiological studies. The present study thus aims to determine thefrequency of GSTM1 and GSTT1 null genotype frequency among four tribal groups, i.e. Mina, Garasia, Damor and Saharia of western India. A comparative analysis with different tribal as well as world population has also been undertaken to have a view of its worldwide frequency distribution. Our results reveal a frequency distribution varying from 22.6% to 66.9% with respect to GSTM1gene polymorphism and from 19.1% to 33.0% with respect to GSTT1 gene in the studied populations. To the best of our knowledge this is the first report on the GSTM1and GSTT1frequency distribution among the tribal population of western India and our study shows that the Mina tribal population has the highest frequency of GSTM1.

Detection of CYP1A1 and GSTP1 gene polymorphisms in bladder cancer patients in a Turkish population using a polymerase chain reaction-restriction fragment length polymorphism method.

Understanding genetic polymorphisms might facilitate the analysis of differences between individuals in their susceptibility to developing cancers as a result of environmental carcinogens. Skin, lung, colon and bladder cancers emerge from biological defects in GSTM1, GSTT1 and GSTP1 gene expressions. In this study, we aimed to investigate whether there was an association between CYP1A1 and GSTP1 gene polymorphisms and bladder cancer in a Turkish population. Blood samples were collected from 120 individuals (60 patients with bladder cancer and 60 healthy individuals), and their DNAs were isolated. A polymerase chain reaction-restriction fragment length polymorphism (PCR - RFLP) method was used to detect the frequencies of CYP1A1 NM_000499.3: c.*1189T > C and GSTP1 NM_000852.3: c.313A > G polymorphisms in bladder cancer patients. The frequency of the CYP1A1: c.*1189 TC genotype and C allele were significantly different between bladder cancer patients and healthy individuals (p=0.001 and p=0.005, respectively). However, there was no significant difference for the GSTP1: c.313 AG genotype or G allele between both study groups (p=0.699 and p=0.360, respectively). A polymorphic site of the CYP1A1 gene might be involved in the development of bladder cancer. However, the investigated GSTP1 polymorphic site did not represent an important risk factor for the development of bladder cancer in a Turkish population.

Interaction between dietary acrylamide intake and genetic variants for estrogen receptor-positive breast cancer risk

PurposeThe association between dietary acrylamide intake and estrogen receptor-positive (ER+) breast cancer risk in epidemiological studies is inconsistent. By analyzing gene-acrylamide interactions for ER+ breast cancer risk, we aimed to clarify the role of acrylamide intake in ER+ breast cancer etiology.MethodsThe prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55–69 years. At baseline, a random subcohort of 2589 women was sampled from the total cohort for a case–cohort analysis approach. Dietary acrylamide intake of subcohort members (n = 1449) and ER+ breast cancer cases (n = 844) was assessed with a food frequency questionnaire. We genotyped single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism, sex steroid systems, oxidative stress and DNA repair. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis, based on 20.3 years of follow-up.ResultsUnexpectedly, there was a statistically non-significant inverse association between acrylamide and ER+ breast cancer risk among all women but with no clear dose–response relationship, and no association among never smokers. Among the results for 57 SNPs and 2 gene deletions, rs1056827 in CYP1B1, rs2959008 and rs7173655 in CYP11A1, the GSTT1 gene deletion, and rs1052133 in hOGG1 showed a statistically significant interaction with acrylamide intake for ER+ breast cancer risk.ConclusionsThis study did not provide evidence for a positive association between acrylamide intake and ER+ breast cancer risk. If anything, acrylamide was associated with a decreased ER+ breast cancer risk. The interaction with SNPs in CYP1B1 and CYP11A1 suggests that acrylamide may influence ER+ breast cancer risk through sex hormone pathways.

Lung cancer survival and deletion of GSTM1 and GSTT1 genes. A case-series from Spain.

Lung cancer has a high incidence, and only 15% of all cases are alive 5 years after the diagnosis. Identifying the role of the genes implicated in the success of chemotherapy agents is crucial to predict survival. The objective of the study was to assess the effect of GSTM1 and GSTT1 gene deletion on lung cancer survival. A consecutive sampling of lung cancer cases was performed in 1999-2000 at the University Hospital of Santiago de Compostela, Spain, and GSTM1 and GSTT1 genes were genotyped. The effect of GSTM1 and GSTT1 deletion on survival was analyzed with the logrank test and with Cox regression. A total of 132 individuals were included, and more than half of them had stage IV lung cancer at diagnosis. Survival was similar irrespective of the presence or absence of the GSTM1 gene, whereas those with deleted GSTT1 had a significantly shorter survival. In multivariate Cox regression analysis, no significant effect was observed for the deletion of any of the genes, although there was a tendency towards a worse survival for those with deletion of GSTT1. The main limitation was that stage at diagnosis could not be considered in the analysis since most of the patients were diagnosed at stage IV. GSTT1 appears to influence lung cancer survival whereas GSTM1 seems to have no effect.

Screening for Genetic Polymorphisms of Glutathione- S-Transferase Genes and Risk Factors Among Breast Cancer Patients in Iraq

The study included 40 Iraqi women diagnosed as breast cancer patients who attended the Nuclear Medicine Hospital in Baghdad and 60 apparently healthy women as control .Genomic DNA extraction was performed using proteinase K / SDS method. Multiplex PCR techniques were followed to amplify the genes using specific primers. for detection of gstm1, gstt1 and albumin gene as a control. Genetic analysis showed that the percentage of deletions in breast cancer patients was 75% (gstm1 27.5%, null genotype 32.5 % and 15% for gstt1) versus 10 % were in the control samples (5 % gstt1, 3.33% gstm1 and 1.67% null genotype). Data were subjected to statistical analysis using Chi square ( X2 test ) to evaluate the association between etiological risk factors and having a risk for breast cancer . A significant association was considered at level ( P < 0.05 ) . Blood group O and A showed an interesting association with breast cancer risk. The percentage of deletion was 90.9% and 86.6% in O and A blood group, respectively. Age and family history had no significant risk association with breast cancer (P > 0.05) in this study

Detoxification genes polymorphisms in SIDS exposed to tobacco smoke

The best hypothesis to explain Sudden Infant Death Syndrome (SIDS) pathogenesis is offered by the “triple risk model”, which suggests that an interaction of different variables related to exogenous stressors and infant vulnerability may lead to the syndrome. Environmental factors are triggers that act during a particular sensible period, modulated by intrinsic genetic characteristics. Although literature data show that one of the major SIDS risk factors is smoking exposure, a specific involvement of molecular components has never been highlighted. Starting from these observations and considering the role of GSTT1 and GSTM1 genes functional polymorphisms in the detoxification process, we analyzed GSTM1 and GSTT1 null genotype frequencies in 47 SIDS exposed to tobacco smoke and 75 healthy individuals.A significant association (p < .0001) between the GSTM1 null genotype and SIDS exposed to smoke was found. On the contrary, no association between GSTT1 polymorphism and SIDS was determined. Results indicated the contribution of the GSTM1 −/− genotype resulting in null detoxification activity in SIDS cases, and led to a better comprehension of the triple risk model, highlighting smoking exposure as a real SIDS risk factor on a biochemical basis.

WITHDRAWN: GSTP1 A313G, GSTM1, and GSTT1 gene polymorphisms influence clinical outcome in advanced non-small cell lung cancer patients receiving first-line platinum-based chemotherapy: an updated metaanalysis with trial sequential analysis

// Qiang Xiao 1 , Quan Zhou 2 , Mu Mei 1 , Wenjun Pei 1 , Qiangye Zou 1 , Erdong Chen 1 , Susu Dong 1 , Yafen Tan 1 , Tianli Wang 1 and Wei Du 3 1 Department of Respiratory Medicine, The First People&rsquo;s Hospital of Changde City, Hunan Province, P.R. China 2 Department of Science and Education, The First People&rsquo;s Hospital of Changde City, Hunan Province, P.R. China 3 Department of Pathology, The First People&rsquo;s Hospital of Changde City, Hunan Province, P.R. China Correspondence to: Tianli Wang, email: wtl195@163.com Wei Du, email: dw417@sina.com Keywords : GSTP1; GSTM1; GSTT1; advanced non-small cell lung cancer; chemotherapy Received: April 07, 2017&nbsp;&nbsp;&nbsp;&nbsp; Accepted: December 27, 2017&nbsp;&nbsp;&nbsp;&nbsp; Epub: January 05, 2018&nbsp;&nbsp;&nbsp;&nbsp; Abstract The GSTP1 A313G , GSTM1 and GSTT1 gene polymorphisms reportedly correlate with prognosis in advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy, but the results are inconsistent. An updated meta-analysis and trial sequential analysis (TSA) were performed to further examine the correlation and determine whether currently available evidence is sufficient and conclusive. A total of 25 studies covering 4410 advanced NSCLC patients were included. For the GSTP1 A313G polymorphism, the G allele was associated with a better treatment response under four genetic models and better overall survival (OS) under the homozygote model (HR = 0.550, 95% CI = 0.337&ndash;0.898, P = 0.017). The GSTM1 null genotype was also correlated with a better response (OR = 1.654, 95%CI = 1.290&ndash;2.120, P = 0.000) but not better OS. However, the GSTT1 gene variant had no significant effect on clinical outcome. The TSA results indicated that the evidence of the effect was sufficient for GSTP1 A313G under three genetic models (dominant, heterozygote, and allele), for GSTM1 , and for GSTT1 , but the correlations were not confirmed for the homozygote and recessive models of GSTP1 A313G . Our study suggest the GSTP1 313G and GSTM1 null genotypes correlate with a better clinical outcome for advanced NSCLC patients receiving platinum-based chemotherapy.

Glutathione S-transferase mu-1, glutathione S-transferase theta-1 null genotypes, and oral cancer risk: A meta-analysis in the Chinese population.

Several studies have evaluated the correlation between glutathione S-transferase mu-1 (GSTM1), GST theta-1 (GSTT1) polymorphisms and oral cancer in Chinese people. However, the results are inconsistent. To assess the effects of GSTM1, GSTT1 null genotypes on the risk for development of oral cancer in the Chinese population, a meta-analysis was performed. Studies were identified using PubMed and Chinese databases through February 2016. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (CIs). This meta-analysis included six studies with 1306 oral cancer cases and 1484 controls. In the overall analysis, no significant association between GSTM1, GSTT1 polymorphisms and oral cancer was found in the Chinese population. In the subgroup analyses by geographic areas and source of controls, significant risk was found between GSTM1 null genotype and oral cancer in Mainland China (OR = 2.715, 95% CI = 2.17-3.38), but not in Taiwan China. Our meta-analysis suggested that GSTM1 null genotype might be associated with an increased risk of developing oral cancer in individuals from Mainland China.

ADH1B, ALDH2, GSTM1 and GSTT1 Gene Polymorphic Frequencies among Alcoholics and Controls in the Arcadian Population of Central India

BackgroundEpidemiological research has highlighted the global burden of primary liver cancer cases due to alcohol consumption, even in a low consumption country like India. Alcohol detoxification is governed by ADH1B, ALDH2, GSTM1 and GSTT1 genes that encode functional enzymes which are coordinated with each other to remove highly toxic metabolites i.e. acetaldehyde as well as reactive oxygen species generated through detoxification processes. Some communities in the population appears to be at greater risk for development of the liver cancer due to genetic predispositions.MethodsThe aim of this study was to screen the arcadian population of central India in order to investigate and compare the genotype distribution and allele frequencies of alcohol metabolizing genes (ADH1B, ALDH2, GSTM1 and GSTT1) in both alcoholic (N=121) and control (N=145) healthy subjects. The gene polymorphism analysis was conducted using PCR and RFLP methods.ResultsThe allele frequency of ALDH2 *1 was 0.79 and of ALDH2*2 was 0.21 (OR:1.12; CI (95%): 0.74-1.71). The null allele frequency for GSTM1 was 0.28 (OR:0.85; CI (95%): 0.50-1.46) and for GSTT1 was 0.20 (OR:1.93; CI (95%): 1.05-3.55). No gene polymorphism for ADH1B was not observed. The total prevalence of polymorphisms was 3.38% for ALDH2, GSTM1 and GSTT1.ConclusionThe results of this study suggested that individuals of the Central India population under study are at risk for liver disorders due to ALDH2, GSTM1 and GSTT1 gene polymorphisms. This results may have significance for prevention of alcohol dependence, alcoholic liver disorders and the likelihood of liver cancer.

Glutathione S-Transferase M1 and T1 Gene Deletions and Susceptibility to Acute Lymphoblastic Leukemia (ALL) in adults.

Objective:Biotransformation of xenobiotics are critical for their metabolism and removal from the body which is carried out by xenobiotic metabolizing enzymes. Individuals carrying variants of genes that encode these enzymes have an altered ability to metabolize xenobiotics which may lead to an increased risk of acute lymphoblastic leukemia. The current study aimed to investigate the impact of GSTM1 and GSTT1 gene deletions in causing predisposition to adult ALL.Methods:The current case-control study involved 62 adult ALL patients and 62 age and gender matched healthy controls. Whole blood samples processed with standard phenol chloroform protocol for DNA isolation were genotyped using multiplex PCR approach for simultaneous identification of GSTM1 and GSTT1 deletions. The genotype frequency obtained for patients was compared to controls using odds ratio and chi-square.Results:The null genotype frequency of GSTM1 and GSTT1 in a group of adult ALL patients from Pakistan were 47% and 11% respectively. Deletion of GSTM1 and GSTT1 did not show statistically significant association with adult ALL (p=0.86 and p=0.35 respectively). The combined GSTM1/GSTT1 deletion was observed in 2% patients and was not significantly associated with ALL in adults (p=0.85).Conclusions:The results reveal that homozygous null polymorphism of GSTM1 and GSTT1genes does not influence ALL susceptibility among adult patients. Cancer susceptibility associated with GST polymorphism varies with ethnic and geographic differences. Therefore, further investigation on different populations is needed to understand the role of these genetic variations in modifying adult ALL risk.

Null polymorphisms in GSTT1 and GSTM1 genes and their associations with smoking and cervical cancer

Human Papillomavirus (HPV) infection is the main risk factor for cervical cancer. However, other risk factors include smoking and genetic susceptibility. Glutathione-S-Transferases (GST) is enzymes involved in tobacco carcinogens metabolism and genes encoding these enzymes are highly polymorphic. The objective of this study was to compare the frequencies of GSTM1 and GSTT1 null polymorphisms in women with cervical cancer and in a control group, as well as the possible associations between such polymorphisms, cigarette smoking and the prognosis of cervical cancer. The series comprised 135 cervical cancer patients and 100 women without cancer. Genotypes were investigated by using polymerase chain reaction (PCR). The results were compared using the Chi-square test or Fisher's exact test, and survival analysis by Kaplan-Meier test and Log-rank. Among the cases, the frequency of GSTM1 gene null polymorphism was 22.2%, and for the GSTT1 gene it was 48.5%. Among the controls, the frequency of the GSTM1 gene null polymorphism was 45.0%, as for the GSTT1 it was 56.0%. Important association was demonstrated between smoking and cervical cancer (p=0.0062; OR=2.16). Differently from GSTM1, GSTT1 null polymorphism was not associated with cervical cancer risk in this study. GSTT1 null genotype was significantly associated to a worse prognosis. Overall survival rate for the cervical cancer group was 78.5% and, when stratified by genotypes, survival was higher in patients with positive genotypes, indicating a higher risk of death for those presenting dual nullity (p=0.031; RR=2.458).

Association of GSTT1 and GSTM1 gene polymorphisms with susceptibility to autoimmune diseases: A preliminary study

Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens. The aim of this study was to detrmine how polymorphisms of glutathione S-transferases T1 and M1 (GSTT1 and GSTM1) genes influences on the occurrence of two autoimmune diseases: multiple sclerosis (MS) and Hashimoto's thyroditis (HT). A multiplex polymerase chain reaction (PCR) was used to detect the deletions in GSTT1 and GSTM1 genes. Our results showed that patients with ADs had significantly higher (p 0.05). This study suggests the potential role of GSTM1 deletion on ADs susceptibility, but on the other hand this study should be repeated in other patients with the same or similar diagnosis of ADs.

Polymorphisms of NAT2, CYP2E1, GST, and HLA related to drug-induced liver injury in indonesian tuberculosis patients.

Gene polymorphisms have been associated with drug-induced liver injury (DILI). This study aimed to elucidate the association between polymorphisms of NAT2, CYP2E1, GSTT1, GSTM1, and HLA genes with isoniazid plasma concentration and DILI. This study was a prospective cohort study recruiting adult newly diagnosed tuberculosis (TB) patients who met the inclusion criteria from the Public Health Centers in Yogyakarta and Lampung. Defined single-nucleotide polymorphisms were rs1799929, rs1799930, rs1799931, rs1801280, and rs1041983 of NAT2; rs2031920, rs8192775, and rs2515641 of CYP2E1; rs1041981, rs1063355, and rs6906021 of HLA. GSTT1 and GSTM1 were defined as GSTT1, GSTM1, and GSTT1 deletion and GSTM1 deletion. The DNA was taken from the patient saliva. Data of anti-TB drug plasma concentration on the weeks 4-8 of treatment were retrieved from the patients' medical report. Statistical analysis was performed using Chi-square test, Student's t-test, and multinomial logistic regression. Over the 207 patients, up to 1.9% of them experienced DILI. The percentage of slow acetylators of NAT2 was 69.5%. Patients with extensive acetylator phenotype did not experience DILI (odds ratio [OR]: 0.46; 95% confidence interval [CI]: 0.23-0.94). The G carriership of HLA rs1063355 could protect the patients from the DILI (OR: 0.39; 95% CI: 0.14-0.9). Furthermore, the C carriership of HLA rs1041981 can protect the patients from DILI (OR: 0.38; 95% CI: 0.15-0.50). The genotype of HLA-DQB*0302 significantly affects the isoniazid concentration. The NAT2 genotype was significantly associated with DILI. Furthermore, the absence of G carriership of HLA-DQA*0102 could protect the patients from DILI without being associated with an effect on the isoniazid concentration.

Prognostic Significance of Comparison of Clinical Indicators with Manifestations of Genetic Polymorphism of Glutathione-S-Transferases in Non-Small Cell Lung Cancer

The article presented the results of comparison of polymorphic variants of the genes GSTM1, GSTT1, GSTP1 and clinical manifestations of non-small cell lung carcinoma. The association of the genotype GSTT1 (del) with the risk of developing squamous cell lung cancer has been revealed (OR = 2.54 CI: 1.13 - 5.72, p = 0.035). Analysis of patient survival rate (n = 173) in groups of various histological types of lung cancer showed that in the group of squamous cell lung cancer (n = 91) in patients with genotype GSTT1 (del), the survival rate median was significantly higher—84 months (95% CI 12.4 - 155.7) than in patients with the genotype GSTT1 (+)—36 months (95% CI 25.2 - 46.8, p = 0.045). In contrast, in the adenocarcinoma group (n = 82), the survival rate median in patients with the genotype GSTT1 (del) was 19 months. (95% CI 6.2 - 33.5), and in patients with genotype GSTT1 (+)—67 months (95% CI 50.1 - 84.0), which is the basis for continuing this comparison in an additional group of testees, as the sampling did not achieve the reliability of p = 0.12. Hypothetically, these differences may be due to differences in the gender composition of squamous cell lung cancer and adenocarcinoma and the involvement of GST enzymes in the metabolism of estrogens in adenocarcinoma in women and other hormonal background and reactivity of the male body with squamous cell carcinoma. Further research and subsequent analysis of the results will be aimed at confirming this hypothesis.

GENETIC SUSCEPTIBILITY AND HEALTH EFFECTS OF OCCUPATIONAL EXPOSURE TO NITROAROMATIC COMPOUNDS IN AMMUNITION INDUSTRY (B)

Introduction: In factory workers, exposure to nitroaromatic compounds has been linked to many adverse health effects. Aim of work: To study the role of polymorphisms of Glutathione S-transferase ( GST) gene as an effect modifier in relation to nitroaromatic induced health hazards. Materials and methods: The study was conducted on 40 workers as an exposed group comprising all workers engaged in ammunition production in a military factory in Helwan area, and a control group of 40 workers. All participants were subjected to an occupational and medical history questionnaire with full clinical examination, slit lamp examination, ECG scanning and laboratory investigations that included: liver and kidney functions, complete blood picture and serum 8-OHdG. Genetic study of GST gene polymorphism was done for the whole population. Multiplex PCR was performed for determination of GSTM1 and GSTT1 genes polymorphisms in the isolated DNAs, while PCR –Restriction Fragment Length Polymorphism (PCR- RFLP) was performed for GSTP1 gene polymorphisms. Results: Regarding frequency distribution of GST genes, in the exposed workers, intact gene of GST (M, T) and the wild GST (P) genes were more prevalent (57.5%, 65% and 62.5% respectively). However, in the control group, the intact gene of GST (M) and the wild GST (P) genes were more prevalent (95% and 77.5% respectively). In the exposed group regarding GST genes polymorphism, null GSTM gene group were predisposed to flushing, lower levels of Hematocrit value and Hb levels and blood urea. GSTP mutation group showed highly significant elevation of ALT and AST levels compared with intact gene group, while significant higher prevalence of ischemic heart diseases and level of Introduction Nitroaromatic compounds have been reported as toxic, mutagenic and carcinogenic. They are used in multiple applications as pharmaceuticals, antimicrobial agents, food additives, pesticides, explosives, dyes and raw materials in several industrial processes (Oliveira et al., 2010).TNT is one of the most recalcitrant and toxic of all the military explosives used (Padda et al., 2003). It is used in military shells, bombs, and grenades, in industrial uses, and in underwater blasting (Oliveira et al., 2010). TNT has accumulated in areas of manufacturing, storage, and decommissioning over recent decades. Various government agencies, such as the EPA have listed TNT as a priority pollutant and have recommended that it should be removed from contaminated sites to prevent environmental and health problems (Van Aken, 2009).Despite the strong causal associations between certain occupational exposures and related health hazards, still there are differences in disease incidence between workers that cannot be accounted for by differences in exposures or work practices. Genetic polymorphisms account for some of these differences, thus should be included as relevant variables in study design and analysis (NIOSH, 2004).Glutathione S-transferase (GST) enzymes comprise a family of phase II detoxifying metabolic enzymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates (Atkinson and Babbitt, 2009), thus preventing their interaction with crucial cellular proteins and nucleic acids (Hayes et al., 2005 and Josephy, 2010). It is an important detoxifying mechanism ensuring more soluble substrates and allowing them toALT in GSTT null gene carriers on the other hand a significant higher mean level of creatinine and lower mean level of AST, was noted among exposed workers with GSTT nun null gene carriers. Conclusion: Genetic polymorphism in members of the GST gene family may be considered as an effect modifier and as genetic susceptibility for some nitroaromatic compounds health hazards. Recommendations: Further studies are recommended on a larger scale to study the net effect of multiple contributing genes.

GSTM1 and GSTT1 Gene Polymorphisms, Gene-Gene Interaction, and Esophageal Carcinoma Risk: Evidence from an Updated Meta-Analysis.

Published data regarding the association between GSTM1 and/or GSTT1 gene polymorphisms and esophageal cancer (EC) susceptibility remain inconclusive. To clarify these associations, a meta-analysis was conducted. We conducted a comprehensive search in PubMed, Embase, and the China National Knowledge Infrastructure (CNKI) for all such manuscripts published as of May 1, 2017. The pooled odds ratio (ORs) with confidence intervals (95% CI) were estimated for each study to assess the strength of the association. A subgroup analysis, a sensitivity analysis, and a publication bias analysis were also performed. Data from 41 studies comprising 5291 EC cases and 8191 controls were available for analysis of the GSTM1 polymorphism, and data from 31 studies comprising 4330 EC cases and 6558 controls were available for analysis of the GSTT1 polymorphism. Analyses of the GSTM1 polymorphisms demonstrated that there was a significantly increased EC risk in GSTM1 null genotype carriers (OR = 1.319, 95% CI = 1.125-1.546, p for heterogeneity <0.001). In subgroup analyses by ethnicity, and categories of EC, a significantly increased EC risk was found in Asians (OR = 1.457, 95% CI = 1.212-1.751, p for heterogeneity <0.001) and patients whose histological type was unknown. Analyses of the GSTT1 polymorphisms indicated a positive correlation between the GSTT1 null genotype and the EC risk (OR = 1.233, 95% CI = 1.044-1.455, p for heterogeneity <0.001). In subgroup analyses stratified by ethnicity and categories of EC, similar statistical associations were observed in Asians, esophageal squamous cell carcinoma (ESCC) patients, and ESCC on Asian population. In the GSTM1-GSTT1 interaction analysis, we discovered remarkably enhanced EC risk for patients with the GSTM1 and GSTT1 dual null genotypes (OR = 1.962, 95% CI = 1.178-3.268, p for heterogeneity <0.001) compared with the reference GSTM1 and GSTT1 dual positive genotype. We conclude that the GSTM1 and GSTT1 null genotypes are associated with increased genetic susceptibility to EC in the overall human population, particularly among Asians. In addition, our findings suggest that persons with a null genotype for both the GSTM1 and GSTT1 genes are at higher risk of developing EC. Further well-designed studies are needed to confirm these associations.

GSTM1 and GSTT1 null polymorphism and antioxidant levels in oral submucous fibrosis, leukoplakia and oral cancer patients among a South Indian Population

ObjectiveWe investigated the null polymorphism in GSTM1 and GSTT1 genes and the antioxidant levels in oral submucous fibrosis (OSMF), leukoplakia and oral cancer patients along with healthy controls in a South Indian cohort. MethodsGenotyping was done using multiplex PCR and the antioxidant levels were estimated using biochemical methods Association between genotypes and different diseased states was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis and for antioxidant levels student’s t-test was used. ResultsThe relative risk for GSTM1 and GSTT1 gene polymorphisms was statistically insignificant for the 3 patient groups vs. controls. Comparing the frequency of the null genotypes between the groups of patients only GSTM1 polymorphism revealed a significant difference between OSMF & oral cancer subjects (p=0.02). Further, analysis of the antioxidant parameters shows ceruloplasmin levels to be significantly elevated between patient groups and controls and among OSMF vs. cancer patients (p<0.05). Similarly, malondialdehyde and glutathione levels were found to be significantly elevated among cancer and both cancer and leukoplakia subjects respectively in comparison with controls (p<0.05). Analysis between the patient groups revealed glutathione levels to be significantly elevated between OSMF vs. cancer patients and cancer vs. leukoplakia patients (p<0.05). ConclusionIn conclusion, this study finds GSTM1 null genotype and antioxidants (ceruloplasmin and glutathione levels) to be significantly higher in oral cancers than in precancerous lesions, and suggesting that they might be associated with the malignant transformation of the oral precancers.