GSTT1 Deletion Research Articles

Deletion polymorphism of GSTT1 gene and lipid peroxidation hyperactivation in menopausal insomnia

A comparative analysis of the parameters of lipid peroxidation - antioxidant defense system in menopausal women with- and without insomnia, depending on the GSTT1 polymorphism. The study included 181 menopausal Caucasian women (ethnic group - Russians), who according to the results of the clinical-anamnestic examinations were divided into insomnia group (n=120, age 53.68±4.61 years, body mass index 26.47±3.73 kg/m2) and control group (n=61, age 52.64±4.91 years, body mass index 27.69±3.11 kg/m2). The insomnia group was formed according to the clinical guidelines for the diagnosis and treatment of chronic insomnia in adults, and scores of the Insomnia Severity Index. The study of the GSTT1 gene polymorphism was carried out using polymerase chain reaction. The lipid peroxidation - antioxidant system parameters were determined by spectrofluorophotometric methods. In the insomnia group, carriers of the normal GSTT1 genotype had higher diene conjugates with lower glutathione peroxidase activity as compared to controls. When comparing groups of women with the deletion in GSTT1, an increase in the content of substrates and lipid peroxidation products was observed at all stages of lipid peroxidation, oxidized glutathione, glutathione S-transferase activity with a decrease in the content of reduced glutathione and retinol in the insomnia group as compared to controls. In the insomnia group, carriers of the deletion genotype had a higher content of ketodienes/conjugated trienes and active products of thiobarbituric acid, a lower content of retinol and α-tocopherol as compared to the patients with normal GSTT1 genotype. Conclusions. Insomnia in the menopausal women is accompanied with the intensification of lipid peroxidation only in the carriers of the GSTT1 deletion genotype.

Glutathione S-transferases gene polymorphism influence on the age of diabetes type 2 onset

IntroductionType 2 diabetes (T2D) is a multifactorial disease affecting mostly adults older than 40 years. The aim of the study was to examine GST gene polymorphism influence on the risk...

ALL-198: Pharmacogenetic Study on Central Nervous System Relapse Among Patients with Pediatric Acute Lymphoblastic Leukemia in Hungary

<h3>Context</h3> Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In order to further improve results, gaining a better understanding of its complications is needed. Central nervous system (CNS) is an important site of relapse in ALL. In this study, the incidence of CNS relapse (REL) was investigated. <h3>Objective</h3> CNS-REL might associate with interindividual genomic differences. Single nucleotide polymorphisms (SNPs) are able to affect the function of metabolizing enzymes and transporters located in blood-brain-barrier (BBB). This may change the concentration of chemotherapeutic agents in CNS. <h3>Design</h3> Clinical data were collected retrospectively. DNA was isolated from peripheral blood collected in remission (QIAmp® Blood DNA Maxi Kit, Qiagen), genotyping was performed using TaqMan® OpenArray™ Genotyping System (Thermo Fisher Scientific). Association between 57 SNPs and the incidence of CNS-REL was studied. Logistic regression adjusted for potential confounders and Cox-regression to study survival were performed using SPSS v25 and RStatistics. <h3>Patients</h3> Study population consisted of 676 pediatric patients (0-18 years) diagnosed with ALL between 1990-2017. Cases (n=16) were isolated CNS-RELs or combined CNS and bone marrow RELs. <h3>Main outcome measures</h3> Candidate gene association study was performed to analyze SNPs' associations with the incidence of CNS- REL. <h3>Results</h3> GSTT1*0 genotype associated with the presence of CNS-REL (OR=3.95; P=0.002) in our cohort. <h3>Conclusions</h3> GSTT1 deletion correlated with the incidence of CNS-REL. This result may contribute to personalized medicine in ALL. <h3>Acknowledgements</h3> The study was supported by the UNKP-19-3-IV New National Excellence Program of the Ministry for Innovation and Technology; the National Research, Development and Innovation Office (NKFIH) Grants No. PD109200 (ÁF Semsei) and K115861 (DJ Erdélyi) and by the Hungarian Paediatric Oncology Group (07/MGYH-MGYGYT/2018).

CYP1A1 and GSTs common gene variations and presbycusis risk: a genetic association analysis and a bioinformatics approach.

Antioxidant enzymes such as glutathione S-transferases (GSTs) and cytochromes P450 (CYPs) are involved in the metabolism and detoxification of cytotoxic compounds, as well as the elimination of reactive oxygen species (ROS). Therefore, alterations in the structure of these enzymes could result in prolonged production of ROS with subsequent risk of development of disorders such as presbycusis. This study aimed to investigate the association between CYP1A1 (rs4646903, rs1048943) and GSTs (GSTM1-deletion, GSTT1-deletion, GSTP1-rs1695) with presbycusis risk in an Iranian population which was followed by an in silico approach. In a case-control study, 280 subjects including 140 cases with presbycusis and 140 healthy controls were enrolled. Genotypes of single-nucleotide polymorphisms (SNPs) were detected by PCR-RFLP method and the genotype of the above mentioned deletions was determined by touchdown PCR. Some bioinformatics tools were employed to evaluate the impact of SNPs on the gene function. SNP analysis revealed that there are significant associations between rs1048943 (AG vs. AA: OR = 2.46, 95%CI = 1.30-4.65, p = 0.006; GG + AG vs. AA: OR = 2.53, 95%CI = 1.36-4.69, p = 0.003; G vs. A: OR = 2.36, 95%CI = 1.33-4.17, p = 0.003) and rs4646903 (C vs. T: OR = 1.45, 95%CI = 1.02-2.06, p = 0.040) variations and increased risk of presbycusis. However, there was no significant association between rs1695 and presbycusis risk. Also, significant associations were observed between GSTM1 (OR = 4.28, 95%CI = 1.18-15.52, p = 0.027) and GSTT1 (OR = 1.64, 95%CI = 1.02-2.65, p = 0.041) deletions and elevated risk of presbycusis. Moreover, the combination analysis revealed a significant association between GSTM1+/GSTT1- genotype and presbycusis susceptibility (OR = 1.63, 95%CI = 1.00-2.67, p = 0.049). In silico analysis revealed that the rs1048943 SNP could influence significantly on the RNA structure of CYP1A1 (distance: 0.1454; p value: 0.1799). Based on our findings, the rs4646903, rs1048943 SNPs as well as GSTM1 and GSTT1 deletions could be considered as genetic risk factors for the development and progression of presbycusis.

Relevance of genetic polymorphisms in tobacco-related detoxifying enzymes in non-small cell lung carcinoma susceptibility

BackgroundTobacco smoking plays a role in the onset and development of non-small cell lung cancer (NSCLC). Biotransformation and detoxification of tobacco smoke carcinogens are brought about by xenobiotic-metabolizing enzymes (XME). Germline mutations in CYP1B1 (Ala119Ser) and GSTT1 (+/−) have been known to affect the functionality of these enzymes, thereby modifying their effect; amino acid substitution and complete gene deletion abolish enzyme activity. CYP1B1 (Ala119Ser) and GSTT1 (+/–) genotypic interactions and gene-smoking inteaction associated risk of NSCLC information is not documented in the literature. ObjectiveThe role of gene-gene and gene-smoking interaction with the clinicopathological parameters to estimate the risk of NSCLC among the North Indian population. MethodsCYP1B1 and GSTT1 genotypes were determined by the PCR-RFLP in 158 cases of NSCLC and 155 controls; demographical parameters and clinicopathological characteristics were recorded. ResultsGSTT1 (−/−) genotype demonstrated a four-fold risk of NSCLC and was significantly associated with squamous cell lung carcinoma (OR: 3.35). Synergistic interaction of CYP1B1 (Variant) and GSTT1 (−/−) enhanced the risk of NSCLC by 6.5 fold. CYP1B1 mutant genotypes in tobacco smokers showed a 3.5 fold risk, which was significantly (p = 0.02) higher than the non-smokers (OR: 1.67, p = 0.38). NSCLC risk with GSTT1 mutant genotype showed a similar trend of risk in both smokers (OR: 4.1) and non-smokers (OR: 3.8). ConclusionThe effect of CYP1B1 mutant appears to be a risk modifier in tobacco smokers, whereas deletions in GSTT1 (−/−) increases the risk of NSCLC in both smokers and non-smokers. A marked synergistic risk was evident when both mutations were present.

Association of Genetic Polymorphisms in GSTP1, GSTM1, and GSTT1 Genes with Vesicoureteral Reflux Susceptibility in the Children of Southeast Iran.

Background:Vesicoureteral reflux (VUR) disease is the most common type of urinary tract anomalies in children. Genetic risk factors may be associated with the etiology of VUR. The role of the Glutathione S-transferases (GSTs) as multifunctional enzymes is cellular oxidative stress handling. This is the first study aimed at evaluating the relative risk of GSTP1, GSTM1, and GSTT1 polymorphisms in VUR susceptibility in children and provides new important insights into the genetics of affected children.Methods:The study was done in 2013 in Sistan and Baluchestan University, eastern Iran. Genotyping of three GSTP1, GSTM1, and GSTT1 genes were determined using the multiplex polymerase chain reaction assay in 216 reactions for 72 VUR children and 312 reactions for 104 healthy controls.Results:The presence of GSTT1 deletion was associated with high risk of VUR in children, whereas GSTP1 and GSTM1 genotypes did not show the same effect. Furthermore, the combination of GSTT1/GSTM1 and GSTT1/ GSTP1 genotypes showed a significant influence on lower risk of VUR in children.Conclusion:Deletion of GSTT1 functional gene is a genetic risk factor causing VUR in children. Interestingly, the combination of GSTM1 and GSTP1 null genotypes with GSTT1 has shown a protective role against risk of GSTT1 deletion.

Women with polycystic ovary syndrome and other causes of infertility have a higher prevalence of GSTT1 deletion

Research questionIs GSTM1 and GSTT1 deletion associated with the development of polycystic ovary syndrome (PCOS)? DesignA case-control study was designed to investigate the association between GSTM1 and GSTT1 gene polymorphisms with PCOS. Blood samples from 201 women diagnosed with infertility were taken, of which 69 women were diagnosed with PCOS. Genomic DNA was extracted, and genotyping analyses were conducted by polymerase chain reaction-based methods. Odds ratios and 95% confidence intervals were calculated by unconditional logistic regression. ResultsAn increased risk of PCOS was found to be associated with GSTT1 null genotype (OR 4.890, 95% CI 2.261 to 9.122; P < 0.001). A strong association between GSTT1 null genotype was found with female infertility, regardless of the associated cause (OR 5.300, 95% CI 3.238 to 8.675; P < 0.001) as well as with the GSTM1 null genotype (OR 1.620, 95% CI 1.067 to 2.459; P = 0.026). A statistically significant association with the development of infertility was also found when carriers of the combined genotype GSTT1+/GSTM1+ was compared with carriers of the combined genotype GSTT1–/ GSTM1+ (OR 3.600 95% CI 1.864 to 6.956; P < 0.001). The two-way combination of GSTT1 and GSTM1 null genotypes resulted in an increased susceptibility to infertility development (OR 11.136; 95% CI 5.035 to 24.629; P < 0.001). ConclusionsCarriers of GSTT1 null genotype seem to have higher susceptibility to developing PCOS and infertility from other causes. Also, GSTT1 null genotype, alone or in association, are related with increased susceptibility to infertility development, independently of its cause. GSTM1 null genotype is only associated with all cause of infertility when the GSTT1 is null.

Hepatic Injury and Glutathione s-transferase Deletion Related to Antituberculosis Use: An Observational Study in Balinese Population, Indonesia

BACKGROUND: Glutathione S-transferase (GST), together with other drug-metabolizing enzymes (N-acetyltransferase and cytochrome P450), plays a crucial role in the metabolism of isoniazid (isonicotinic acid hydrazide). Among five isoforms of GST, GSTM1, and GSTT1 had been proved to involve in isoniazid metabolism.&#x0D; AIM: We aimed to investigate association between GST deletion and hepatic injury in the Indonesian population.&#x0D; METHODS: This is a cross-sectional study. The total participants’ number was 70. Our whole blood samples were collected from adult pulmonary tuberculosis patients who received antituberculosis treatment category one in Bali. Detection for GSTM1 and GSTT1 deletion performed with the polymerase chain reaction technique using internal standard β-globin. Data analysis performed with the Chi-square test.&#x0D; RESULTS: The proportion of GSTM1 null was 71.4% whereas the GSTT1 null was 34.3%. The proportion of combined GSTM1 null and GSTT1 null was 22.9%. There was no significant difference in liver damage incidence between GSTM1 null and wild-type (p &gt; 0.005). There was also no significant difference in liver damage incidence between GSTT1 null and wild-type (p &gt; 0.005).&#x0D; CONCLUSIONS: Neither GSTM1 nor GSTT1 deletion proved to be associated with liver injury regarding antituberculosis use.

Detection of glutathione S-transferases M1, T1 gene deletions among cancer patients in Mongolia

Various types of toxic xenobiotic and electrophilic compounds, which were formed from the glutathione S-transferases cell metabolism and the oxidation stress, are the group enzymes with detoxification roles that are involved in the metabolism phase II. During the GSTM1 and GSTT1 gene homozygous deletion, the above enzymes completely lose their activity and consequently somatic mutation is formed. Furthermore, it is considered that it might have increased the risk of cancer. Therefore, the research works which connected the GSTMI and GSTTI gene deletion with the cancer of kidney, lung, prostate, breast, stomach, esophagus, large and narrow intestines. In this study, two gene deletion distribution is detected for cancer patients. We collected the blood samples of 60 patients who have been diagnosed with cancer. The DNA was extracted and the GSTM1 and GSTT1 genes were amplified using multiplex PCR. According to our research, the above two gene deletion is predominant among patients who have cancer. The results showed that from the total 60 patients GSTM1 and GSTT1 both deletions, GSTM1 gene deletion - 35%, GSTM1 gene deletion - 25%, GSTT1 gene deletion - 26.7%, GSTM1 and GSTT1 both positive -13.3 %. Therefore, we think that in order to prevent tumor and cancer, these gene mutations must be revealed and it is important to bring the risky group under medical control and assist them in order to prevent them from this disease.

Polymorphism of glutathione S-transferase in the population of Polish patients with carcinoma of the prostate

The aim of the study was frequency analysis of GSTM1, GSTT1, and GSTP1 polymorphisms of glutathione S-transferase in the group of patients with prostate cancer and in a control group of healthy individuals. Genomic DNA was isolated; molecular analysis of glutathione S-transferase M1 and T2 polymorphisms was performed using multiplex PCR and RFLP methods. The products of the PCR reaction were then visualized in agarose gel, and a statistical analysis of the results was performed. No statistically significant differences were found in the frequency of glutathione S-transferase polymorphisms between 66 patients with prostate cancer and the control group (64 healthy volunteers). The GSTM1 gene deletion was found in ca. 47% of patients with prostate cancer and in ca. 55% of the controls. The GSTT1 deletion was found in approximately 17% of patients and 14% of the controls. The distribution of GSTP1 Ile/Ile, Ile/Val, and Val/Val polymorphisms was ca. 51.5%, 39%, and 9% in the group of patients and 61%, 34%, and 5% in the control group, respectively. The results indicate that there is no relationship between glutathione S-transferase polymorphisms and prostate cancer in the study group, which is a novelty when compared with the previous work on the role of these genetic variants in the etiology of cancer.

Glutathione S-transferase M1 and T1 genes deletion polymorphisms and risk of developing essential hypertension: a case-control study in Burkina Faso population (West Africa)

BackgroundGlutathione S-transferases play a key role in the detoxification of persistent oxidative stress products which are one of several risks factors that may be associated with many types of disease processes such as cancer, diabetes, and hypertension. In the present study, we characterize the null genotypes of GSTM1 and GSTT1 in order to investigate the association between them and the risk of developing essential hypertension.MethodsWe conducted a case-control study in Burkina Faso, including 245 subjects with essential hypertension as case and 269 control subjects with normal blood pressure. Presence of the GSTT1 and GSTM1 was determined using conventional multiplex polymerase chain reaction followed by gel electrophoresis analysis. Biochemical parameters were measured using chemistry analyzer CYANExpert 130.ResultsChi-squared test shows that GSTT1-null (OR = 1.82; p = 0.001) and GSTM1-active/GSTT1-null genotypes (OR = 2.33; p < 0.001) were significantly higher in cases than controls; the differences were not significant for GSTM1-null, GSTM1-null/GSTT1-active and GSTM1-null/GSTT1-null (p > 0.05). Multinomial logistic regression revealed that age ≥ 50 years, central obesity, family history of hypertension, obesity, alcohol intake and GSTT1 deletion were in decreasing order independent risk factors for essential hypertension. Analysis by gender, BMI and alcohol showed that association of GSTT1-null with risk of essential hypertension seems to be significant when BMI < 30 Kg/m2, in non-smokers and in alcohol users (all OR ≥ 1.77; p ≤ 0.008). Concerning GSTT1, GSTM1 and cardiovascular risk markers levels in hypertensive group, we found that subjects with GSTT1-null genotype had higher waist circumference and higher HDL cholesterol level than those with GSTT1-active (all p < 0.005), subjects with GSTM1-null genotype had lower triglyceride than those with GSTM1-active (p = 0.02) and subjects with the double deletion GSTM1-null/GSTT1-null had higher body mass index, higher waist circumference and higher HDL cholesterol than those with GSTM1-active/GSTT1-active genotype (all p = 0.01).ConclusionOur results confirm that GSTT1-null genotype is significantly associated with risk of developing essential hypertension in Burkinabe, especially when BMI < 30 Kg/m2, in non-smokers and in alcohol users, and it showed that the double deletion GSTM1-null/GSTT1-null genotypes may influence body lipids repartition.

GSTP1 rs1138272 Polymorphism Affects Prostate Cancer Risk.

Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89–8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19–2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56–11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55–8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05–44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene–gene interactions in human susceptibility to this cancer.

Iron intake, oxidative stress-related genes and breast cancer risk.

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case-control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER-/PR- breast cancer risk (all ptrend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR>18 vs. 0 mg/day = 0.68, 95% CI: 0.51-0.91), and dietary heme iron was associated with an increased risk, particularly the ER-/PR- subtype (ORhighest vs. lowest quintile = 1.69, 95% CI: 1.16-2.47; ptrend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (pinteraction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.

Genomics of Detoxification: How Genomics can be Used for Targeting Potential Intervention and Prevention Strategies Including Nutrition for Environmentally Acquired Illness

Due to their genomic variants, some individuals are more highly affected by toxicants than others. Toxicant metabolizing and activating variants have been linked with a wide variety of health issues including an increased risk of miscarriages, birth defects, Alzheimer’s, benzene toxicity, mercury toxicity and cancer. The study of genomics allows a clinician to identify pathways that are less effective and then gives the clinician the opportunity to counsel their patients about diet, supplements and lifestyle modifications that can improve the function of these pathways or compensate to some extent for their deficits. This article will review a few of these critical pathways relating to phase I and phase 2 detox such as GSTP1, GPX1, GSTT1 deletions, PON1 and some of the CYP 450 system as examples of how an individual's genomic vulnerabilities to toxicants can be addressed by upregulating or downregulating specific pathways via genomically targeted use of foods, supplements and lifestyle changes.

MOLECULAR GENETIC ASPECTS OF BRONCHIAL HYPERREACTIVITY IN CHILDREN - RESIDENTS OF RADIOACTIVELY CONTAMINATED AREAS.

to determine the relationship between polymorphisms of glutathione S-transferase gene family andbronchial hyperreactivity in children living in radioactively contaminated areas. School age children-residents of radioactively contaminated areas (RCA), without clinicalsigns of respiratory pathology were examined. Molecular genetic studies were carried out by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) for further analysis. The GSTT1, GSTM1 gene deletion polymorphism was investigated using multiplex PCR. PCR and PCR-RFLP analyses were performed in the studyof the GSTP1 gene A313G polymorphism. The ventilation lung capacity was examined by the pneumotachographicmethod according to the analysis of «the flow-volume» loop. The pharmacologic inhalation test with bronchodilator drug, affecting the β2-adrenergic lung receptors was used to detect the early changes in the ventilation lungcapacity - the bronchial hyperreactivity (latent and nonlatent bronchospasm). Molecular genetic studies showed that the GSTM1 gene deletion genotype and the GSTP1 gene A313G polymorphism were found significantly more often in the subgroup of children with bronchial hyperreactivity living inRCA than in children without bronchial hyperreactivity and children of the control group. The frequency of GSTT1deletion polymorphism did not have a statistically significant difference in all subgroups. The GSTM1 gene deletion polymorphism and the GSTP1 gene A313G genotype may be a risk factor fordeveloping bronchial hyperreactivity in children living under adverse environmental conditions, including radioactively contaminated areas.

Association between genetic polymorphisms of glutathione S-transferase M1/T1 and psoriasis in a population from the area of the strict of messina (Southern Italy)

Glutathione S-transferases (GST) are antioxidant enzymes with frequent genetic polymorphisms. Homozygosis for gene deletion (“null” genotype) of GSTM1 and GSTT1, causing decrease of the antioxidant potential of the organism, is frequent, with variable frequency in different ethnic contexts. Although oxidative stress notoriously plays a role in the pathogenesis of psoriasis, few studies exist on the association between GSTM1/GSTT1 genotype and psoriasis, with different results. We aimed to assess the frequency of GSTM1/GSTT1 polymorphisms in Southern Italian psoriatic patients and controls and investigate the association of the GSTM1/GSTT1 genotype with individual and disease parameters. To this aim, the GSTM1/GSTT1 genotype of 148 psoriatic patients and 148 age- and sex-matched controls was defined by PCR on oral mucosa cells. GSTT1 null was associated with psoriasis (55.4% of patients vs. 25% of controls, p = 9.58 × 10−8, odds ratio 3.73), while GSTM1 null was not. The GSTM1/GSTT1 “double null” genotype conferred an even higher odds ratio for psoriasis (5.94). The association between psoriasis and GSTT1 null was stronger in women (54.1% of patients vs. 19.7% of controls, p = 8.13 × 10−5) than in men (56.3% of patients vs. 28.7% of controls, p = 0.0002). No association was found between GSTM1/GSTT1 genotype and psoriasis severity, age of onset or comorbidities (psoriatic arthritis, metabolic syndrome). The remarkable differences among the few available data on the association between GSTM1/GSTT1 polymorphisms and psoriasis suggest the need for further studies, on different and larger populations, to improve knowledge on the pathogenesis of psoriasis and possibly provide more precise and personalised prevention and treatment in the future.

Gene-environment interactions between GSTs polymorphisms and targeted epigenetic alterations in hepatocellular carcinoma following organochlorine pesticides (OCPs) exposure

Exposure to environmental pollutant organochlorine pesticides (OCPs) and the role of tumour suppressor GSTs gene polymorphisms as well as epigenetic alterations have all been well reported in hepatocarcinogenesis. However, the interplay between environmental risk factors and polymorphic tumour suppressor genes or epigenetic factors in hepatocellular carcinoma (HCC) development remains ambiguous. Herein, we investigated the relationship of three GSTs polymorphisms (GSTT1 deletion, GSTM1 deletion, GSTP1 rs1695) as well as GSTP1 promoter region DNA methylation and HCC risk with a particular focus on the interaction with OCPs exposure among 90 HCC cases and 99 controls in a Chinese population. Serum samples were analysed for OCPs exposure employing gas chromatography coupled with mass selective detector (GC-MS). GSTs polymorphisms and epigenetic alterations were determined using high-resolution melting PCR (HRM PCR) and DNA sequencing. After adjusting for confounders (HBV infection, smoking, alcohol consumption, BMI, age, gender), OCPs exposure and GSTP1 methylation is significantly associated with elevated risk of HCC, while no significance is observed for GSTs polymorphisms. Moreover, the effects of OCPs exposure on HCC risk are more pronounced amongst GSTP1 (Ile/Val + Val/Val) and GSTP1 promoter methylation subjects than those who were GSTP1 (Ile/Ile) and unmethylated subjects. The interactions between OCPs exposure and GSTP1 genotype as well as GSTP1 epigenetic status are statistically significant. The current study demonstrates the importance of gene-environment interactions in the multifactorial development of HCC.

Relationship of anti-tuberculosis drug-induced liver injury and genetic polymorphisms in CYP2E1 and GST

SettingTreatment of tuberculosis (TB) can result in Drug-Induced Liver Injury (DILI) since hepatotoxic metabolites are formed during the biotransformation of isoniazid (INH).DILI can be related to the genetic profile of the patient. Single nucleotide polymorphisms in the CYP2E1 gene and GSTM1 and GSTT1 deletion polymorphisms have been associated with adverse events caused by INH. ObjectiveTo characterize the genetic polymorphisms of CYP2E1, GSTT1 and GSTM1 in TB carriers. DesignThis is an observational prospective cohort study of 45 patients undergoing treatment of TB. PCR-RFLP and multiplex-PCR were used. ResultsThe distribution of genotypic frequency in the promoter region (CYP2E1 gene) was: 98% wild genotype and 2% heterozygous. Intronic region: 78% wild genotype; 20% heterozygous and 2% homozygous variant. GST enzyme genes: 24% Null GSTM1 and 22% Null GSTT1. Patients with any variant allele of the CYP2E1 gene were grouped in the statistical analyses. ConclusionPatients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI (p=0.09; OR: 4.57; 95% CI: 0.75–27.6). Individuals with both genotypes had no increased risk compared to individuals with one genotype.

Abstract 4610: Prognostic impact of KRAS driver mutations and GSTT1 expression in colorectal cancer to FOLFOX treatment

Abstract Colorectal cancer (CRC) is one of the most common cancer and the leading causes of cancer-related death worldwide. CRCs are neoplasms which have high propensity for metastasis, especially spreading to liver and lung. Liver metastasis accounts for around 50% of CRC patients, usually associated with cancer relapse and worse prognosis of the patient. The combination chemotherapy FOLFOX including 5-flurouracil, oxaliplatin and leucovorin is one of the most common and standard first-line chemotherapy utilized for adjuvant and/or neoadjuvant treatment of patients with CRC, which can reduce the risk of cancer relapse. However, a number of studies reported that chemotherapy alone cannot completely eradicate all the cancer cells, especially metastatic cells. Moreover, the mutations of oncogenes such as KRAS, existed in more than 40% of CRC patients, are often associated with poor response of anti-EGFR therapy either as single agent or in combination with FOLFOX. There is still no direct evidence on the association of KRAS or other oncogenic drivers with the resistance to FOLFOX. To understand if any of the potential biomarkers have the predictive value of FOLFOX treatment for CRC patients, especially later stage diseases, we have selected 16 CRC PDX models derived from patients who are in stage II or later where most of patients’ tumors present invasion and metastatic features. We have evaluated the drug efficacy of FOLFOX treatment in vivo for these 16 CRC PDX models and found that 6 of them were sensitive to FOLFOX and 10 models have poor responses. To study the potential biomarkers which affect the efficacy of FOLFOX in CRC PDX models, we analyzed the correlation of tumor growth inhibition (TGI) with the genomic background of these PDX models and identified the genes with significant correlation. Through filtering the genes by their functional relevance to FOLFOX treatment, we found that low expression of GSTT1 was highly related to FOLFOX resistance in these CRC PDX models. GSTT1 deletions was found to enhance the resistance to chemotherapy and a shorter survival in AML patients, which is consistent with our observation. Furthermore, we have also run the driver mutation analysis for these 16 PDX models, and found that models without KRAS driver mutations are more sensitive to FOLFOX treatment. Interestingly, in 32 CRC patients treated with FOLFOX, we found the sensitivity of FOLFOX is correlated with wild type KRAS and high expression of GSTT1, similar to our findings in PDX studies. In conclusion, our studies demonstrated that KRAS driver mutations or low expression of GSTT1 gene may render higher chances of resistance to FOLFOX treatment, these biomarkers may be beneficial for clinicians to choose effective therapies for advance CRC patients. Citation Format: Jessie Jingjing Wang, Binchen Mao, Sheng Guo, Davy Xuesong Ouyang, Henry Qixiang Li. Prognostic impact of KRAS driver mutations and GSTT1 expression in colorectal cancer to FOLFOX treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4610.

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants.

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio (LME p = 0.041) and 30% decrease in clinical efficacy (LME p = 0.0031). GSTA1 variant (12.8% of patients) showed a trend (p = 0.046, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.