Genetic polymorphism of lysyl oxidase,glutathione S-transferase M1, glutathione-S-transferase T1, and glutathione S-transferase P1 genes as risk factors for lung cancer in Egyptian patients

Lung cancer is a lethal malignancy and is affected by genetic polymorphisms that contribute to an individual’s susceptibility to developing the disease. Several studies on lung cancer showed conflicting results. The aim of this study is to investigate whether individual or combined modifying effects of LOX G/A, GSTM1 active/null, GSTT1 active/null and GSTP1 Ile/Val polymorphisms are related to the risk of lung cancer in relation to smoking in the Egyptian population. This study is a hospital-based case control study that included 200 patients and 200 control subjects. Genotyping of the 4 studied genes was determined by Multiplex PCR for GSTM1 and GSTT1 and Taq man SNP assay for GSTP1 and LOX genes. The LOX G/A and GSTP1 Ile/Val in both homozygous and heterozygous variants, and the GSTM1 and GSTT1 null genotype showed significant association with lung cancer. Combination between gene polymorphism and smoking increased the risk of developing cancer by 2.7 fold in the LOX GA+AA variant, 1.9 fold in the GSTM1 null variant, 4.8 fold in the GSTT1 null variant and 4.3 fold in the GSTP1 Ile/Val+Val/Val variant. The genetic combination (LOX GA+AA/GSTT1 active, LOX GG/GSTT1 null, LOX GA+AA/GSTT1 null, LOX GA+AA/GSTP1 Ile/Ile, LOX GG/GSTP1 Ile/Val+Val/Val and LOX GA+AA/GSTP1 Ile/Val+Val/Val) led to a higher lung cancer risk, compared to the reference group. The LOX GA/AA, GSTM1 null, GSTT1 null and GSTP1 Ile/Val, Val/Val genotypes contributed to increased lung cancer susceptibility. To the best of our knowledge, this is the first study of LOX genotyping in the Egyptian population. The combination of genotypes increased the risk of cancer, indicating the importance of gene–gene interaction and giving a targeted preventive approach.

     

Relation of glutathione S-transferase T1, M1 and P1 genotypes and breast cancer risk

The aim of this study was to investigate associations between genetic variability in specific Glutathione S-transferases (GST) genes (GSTM1, GSTT1 and GSTP1) and susceptibility to breast cancer. Genotypes of blood specimen DNA were determined for 65 women with incident cases of breast cancer and 108 control subjects. Associations between specific genotypes and the development of breast cancer were examined by the use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Neither GSTT1 nor GSTM1 homozygous null genotype was associated with a significant increased risk of developing breast cancer. The presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The risk of breast cancer associated with a combined GSTT1 and GSTM1 null genotype was 3.37 (95% CI = 0.76-2.95, p = 0.115). The only significant association between increased risk of breast cancer development and GSTs polymorphisms was found when GSTT1 null, GSTM1 null and the presence of valine in GSTP1 in codon 105 were combined (p < 0.048, OR = 3.75, 95% CI = 1.01-13.90). Our findings suggest that combined genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.     

Effects of glutathione S-transferase T1 and M1 deletions on advanced carotid atherosclerosis, oxidative, lipid and inflammatory parameters

Glutathione S-transferases (GSTs) carry out a wide range of functions in cells, such as detoxification of endogenous compounds, removal of reactive oxygen species, and even catalysis of reactions in metabolic pathways beyond detoxification. Based on previous research, GSTM1 and GSTT1 might modify the risk of atherosclerosis. The aim of our study was to analyze the possible association of GSTM1 and GSTT1 gene polymorphisms with the occurrence of carotid plaque (CP); and biochemical parameters of oxidative stress, lipid profile and inflammation, in 346 consecutive patients with advanced atherosclerosis that underwent endarterectomy. A multiplex polymerase chain reaction (PCR) method was used to detect the deletions in GSTM1 and GSTT1 genes in the genomic DNA in 346 patients and 330 controls. The adjusted OR for CP presence (adjusted for age, gender, smoking, hypertension, BMI, HDLC, TG) was 0.24, 95 %CI 0.08–0.7, p < 0.01 for GSTT1 null and 1.13, 95 %CI 0.62–2.07, p = 0.7 for GSTM1 null genotype. We found significantly lower plasma lipoprotein (a) (Lp(a)) levels in GSTT1 null compared to wild-type genotype carriers in patient group (20.68 ± 26.02 mg/dl vs. 40.66 ± 42.89 mg/dl, mean ± SD, p = 0.04). The serum interleukin-6 (IL-6) values were significantly influenced by both GST polymorphisms in patients with CP. Our results, showing the significant reduction of GSTT1 deletions in patients with CP, suggest involvement of GSTs in carotid atherosclerosis. This study shows additional view of the possible role of GSTs in advanced chronic inflammatory disease of vascular system, but the confirmation in a larger studies in different populations are needed.     

Modulation of hematology changes by polymorphism of glutathione S-transferase M1 and T1

Workers in the petroleum distribution trades experience relatively low-level exposures to gasoline vapors whose consequences have not been fully elucidated. The purpose of this study was to investigate changes in the hematological parameters among filling station workers who were occupationally exposed to gasoline. The target group for the study consisted of 41 workers from eight filling stations of Shiraz (south of Iran). The control group consisted of 27 healthy subjects matched for age and sex from general population. The complete blood count analysis was done in one laboratory. Using PCR-based method, the genotypes of glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) were determined. Workers were divided into three exposure groups according to employment history: duration less than 1 year, 1-5 years, and more than 5 years. Comparison was performed using Kruskal-Wallis test. In the individuals with the presence of both GSTT1 and GSTM1 functional alleles, comparison between four exposure groups revealed no significant difference for studied hematological variables. There were statistically significant differences between study groups, with only one functional allele, either GSTT1 or GSTM1, for relative number of lymphocytes (chi(2)=9.147, df=3, P=0.027) and neutrophils (chi(2)=9.951, df=3, and P=0.019), and absolute number of lymphocytes (chi(2)=9.135, df=3, and P=0.028), and RBC (chi(2)=10.586, df=3, and P=0.014). These findings could indicate the possible protective effect of concurrent presence of GSTM1 and GSTT1 enzymes on the hematopoietic system of filling station workers.     

Association of glutathione S-transferase M1/T1 polymorphisms with susceptibility to vitiligo

Background

Some studies suggested that Glutathione S-transferases M1/T1(GSTM1/T1) null polymorphisms may be associated with the risk of vitiligo.

Aims

The purpose of this study is to further evaluate the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo.

Methods

We carried out a retrieval of studies in the databases. Odds ratios (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of this association. We analyzed the data using Stata 11.0.

Results

Six case–control studies including 1358 cases and 1673 controls were included in this meta-analysis. Our overall results showed the GSTM1 or GSTT1 null polymorphism was associated with vitiligo (GSTM1:OR = 1.59, 95% CI: 1.21–2.08, P = 0.001; GSTT1: OR = 1.30, 95% CI: 1.12–1.51, P = 0.001). In the subgroup analysis, the GSTM1 null polymorphism might be a genetic risk factor to vitiligo in East Asian (OR = 1.71, 95% CI: 1.12–2.63, P = 0.014) but not in the Mediterranean, however individuals with the GSTT1 null polymorphism in the Mediterranean (OR = 1.76, 95% CI: 1.15–2.71, P = 0.010) but not in East Asian have a greater predisposition to vitiligo. In addition there was also a significant trend toward an association with the combination of the GSTM1 null and GSTT1 null in either East Asians or Mediterraneans.

Conclusion

The GSTM1/T1 null polymorphisms may be associated with vitiligo. More studies are needed to confirm this conclusion.     

Cytochrome P4501A1, glutathione S-transferase M1 and T1 gene polymorphisms in chronic myeloid leukemia

Polymorphic variants of cytochrome P4501A1 (CYP1A1), glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) distribution was studied in patients with chronic myeloid leukemia (CML) and healthy individuals. It was shown that homozygotes for the GSTT1 gene deletion occur significantly more frequently in the CML patient group compared to the control group (13.17% versus 24.10% in CML patients, Chi2 = 4.40, p < 0.05; OR = 2.09; 95% CI = 1.10-3.99). In contrast, no significant difference was observed between the healthy individuals and CML patients in the frequency of polymorphic variants of GSTM1 and CYP1A1 genes (p > 0.05).     

Laryngeal and oropharyngeal cancer, and alcohol dehydrogenase 3 and glutathione S-transferase M1 polymorphisms

In this study the GSTμ phenotype and ADH genotype at the ADH3 locus were investigated in a group of 39 alcoholic men with upper respiratory/digestive tract cancer: 21 with oropharyngeal cancer and 18 with laryngeal cancer. The results are compared with those of a control group of 37 alcoholic men without alcohol-related medical complications. Of the control subjects, 48% were found to be GSTμ deficient [GSTμ(–)] and 19% carried the ADH₃ ¹/ADH₃ ¹ genotype. In the laryngeal cancer patients, a significantly elevated frequency of both the GSTμ(–) (78%) and ADH₃ ¹/ADH₃ ¹ genotype (56%) was observed, relative to the control group. On the basis of this result, the risk of laryngeal cancer associated with the GSTμ(–) and ADH₃ ¹/ ADH₃ ¹ genotypic combination within the population of alcoholics was estimated to be 12.9 with a 95% confidence interval of 1.8–92 (P < 0.01) relative to alcoholic individuals who have GSTμ [GSTμ(+)] and are not ADH₃ ¹/ADH₃ ¹. Thus, alcoholics who are GSTμ(–) and ADH₃ ¹/ADH₃ ¹ have at least an 80% greater risk of developing laryngeal cancer than alcoholics who are GSTμ(+) and who are not ADH₃ ¹/ ADH₃ ¹. In addition, the oropharyngeal cancer patients had excess frequencies of both GSTμ(–) (62%) and ADH₃ ¹/ ADH₃ ¹ (43%) relative to the control group, but these excess frequencies were not statistically significant. The GSTμ(–) and ADH₃ ¹/ADH₃ ¹ genotypic combination may be a constitutional risk factor for laryngeal cancer among alcoholics. Received: 5 July 1996 / Revised: 15 October 1996     

Association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer

The conclusions of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the risk of lung cancer are still debated. GSTP1 is one of the important mutant sites reported at present. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of lung cancer. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Forty-four reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and lung cancer susceptibility, consisting of 12,363 patients with lung cancer and 13,948 controls. The association between GSTPI G allele and lung cancer risk was found in this meta-analysis (OR 1.08, 95?% CI 1.02–1.15, P?=?0.01). However, the GG genotype and AA genotype were not associated with the susceptibility of lung cancer. Furthermore, there was no association between GSTP1 A/G gene polymorphism and the risk of lung cancer in Caucasians, and East-Asians. In conclusion, GSTP1 G allele is associated with the lung cancer susceptibility. However, more studies on the relationship between GSTP1 A/G gene polymorphism and the risk of lung cancer should be performed in the future.     

Glutathione S-transferase M1, T1 and P1 polymorphisms and bladder cancer risk in Egyptians

Previous studies suggest that bladder cancer risk may vary with GST genotype but these results are inconsistent. The aim of this study was to explore whether GSTM1, GSTT1 and GSTP polymorphisms were associated with increased bladder cancer risk in an Egyptian population. GSTM1, GSTT1 and GSTP1 genotype frequencies were determined in bladder cancer cases (n=72) and healthy controls with no history of malignancies (n=82) using PCR-based techniques. The GSTT1*2 genotype was particularly associated with increased risk (OR 2.71, 95%CI 1.27-5.73) and the GSTM1*2 genotype to a lesser extent (OR 1.63, 95%CI 0.85-3.10). 18.1% of cases but only 7.3% of controls were GSTP1*B*B homozygotes (OR 2.38, 95%CI 0.83-6.87). The presence of two or more a priori at-risk genotypes was associated with increased bladder cancer risk (OR 2.42; 95%CI 1.47-3.97). These results suggest that polymorphisms in the GST genes are associated with increased risk of bladder cancer among Egyptians.     

Delineation of xenobiotic substrate sites in rat glutathione S-transferase M1-1

Glutathione S-transferases catalyze the conjugation of glutathione with endogenous and exogenous xenobiotics. Hu and Colman (1995) proposed that there are two distinct substrate sites in rat GST M1-1, a 1-chloro-2,4-dintrobenzene (CDNB) substrate site located in the vicinity of tyrosine-115, and a monobromobimane (mBBr) substrate site. To determine whether the mBBr substrate site is distinguishable from the CDNB substrate site, we tested S-(hydroxyethyl)bimane, a nonreactive derivative of mBBr, for its ability to compete kinetically with the substrates. We find that S-(hydroxyethyl)bimane is a competitive inhibitor (K(I) = 0.36 microM) when mBBr is used as substrate, but not when CDNB is used as substrate, demonstrating that these two sites are distinct. Using site-directed mutagenesis, we have localized the mBBr substrate site to an area midway through alpha-helix 4 (residues 90-114) and have identified residues that are important in the enzymatic reaction. Substitution of alanine at positions along alpha-helix 4 reveals that mutations at positions 103, 104, and 109 exhibit a greater perturbation of the enzymatic reaction with mBBr than with CDNB as substrate. Various other substitutions at positions 103 and 104 reveal that a hydrophobic residue is necessary at each of these positions to maintain optimal affinity of the enzyme for mBBr and preserve the secondary structure of the enzyme. Substitutions at position 109 indicate that this residue is important in the enzyme's affinity for mBBr but has a minimal effect on Vmax. These results demonstrate that the promiscuity of rat GST M1-1 is in part due to at least two distinct substrate sites.     

Genetic polymorphism of glutathione S-transferase T1 and the risk of colorectal cancer: A meta-analysis

Background: Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and risk of colorectal cancer have reported conflicting results. In order to clarify the effect of GSTT1 polymorphism on the risk of developing colorectal cancer, we carried out a meta-analysis using published data to obtain more precise estimates of risk. Methods: Electronic searches of PubMed and EMBASE were conducted to select studies for this meta-analysis. Papers were included if they were observational studies investigating the association between GSTT1 polymorphism and colorectal cancer risk. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of colorectal cancer associated with GSTT1 null genotype. Results: We identified 30 eligible studies, which included 7635 cases and 12,911 controls. The combined results based on all studies showed that there was a statistically significant link between GSTT1 null genotype and colorectal cancer risk (OR = 1.20, 95% CI = 1.03–1.40). In the analysis of ethnic groups, we observed distinct differences associated with GSTT1 null genotype, the pooled odds ratios for the GSTT1 polymorphism were 1.32 in Caucasians (95% CI = 1.09–1.58) and 1.03 in Asians (95% CI = 0.81–1.32). As far as concerned the interaction between GSTT1 genotype and colorectal cancer risk in relation to smoking history, there was no increase in risk for smokers or nonsmokers with the GSTT1 null genotype (smokers: OR = 1.13, 95% CI = 0.80–1.60, nonsmokers: OR = 0.99, 95% CI = 0.71–1.38). When stratifying by the location of colorectal cancer, we found that there was a statistically significant link in rectal cancer (OR = 1.50, 95% CI = 1.09–2.07), but not in colon cancer (OR = 1.33, 95% CI = 0.94–1.88). No associations could be detected between null GSTT1 polymorphism and age, sex, tumor stage and differentiation. Conclusion: Our current study demonstrates that GSTT1 null genotype is associated with an increased risk of colorectal cancer, specifically, among Caucasians.     

Polymorphism of glutathione S-transferase genes M1 and T1 in patients with motor neuron disease from the city of Moscow

Comparison of the frequency distributions of alleles, genotypes, and genotype combinations of genes GSTM1 and GSTT1 did not show statistically significant differences between patients with motor neuron disease (MND) and a random sample from the Moscow population. Apparently, these genes are not involved in MND pathogenesis in these patients.     

Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) in selected populations of Afghanistan

Genetic polymorphisms in genes encoding glutathione S-transferase T1 (GSTT1, a member of class theta) and M1 (GSTM1, a member of class mu) have been defined. Previous studies have revealed that there was significant difference between populations for allelic frequency of several members of GSTs. In order to find the prevalence of null genotypes of GSTM1 and GSTT1 in Afghanis populations the present study was carried out. The total study subjects consisted of 656 unrelated healthy Afghanis refugees living in Fars province (southern Iran). From these 257, 217, 120, and 62 individuals were Pashtuns, Tajiks, Hazaras, and Uzbeks, respectively. Genetic polymorphisms for GSTT1 and GSTM1 were detected by multiplex PCR. The prevalence of null genotype of GSTM1 in Pashtuns, Tajiks, Hazaras, and Uzbeks was 42.4, 48.4, 52.5, and 40.3 %, respectively. There was no significant difference between these populations for the genotypic distribution of the GSTM1 polymorphism (χ(2) = 4.67, df = 3, P = 0.197). The frequency of GSTT1 null genotype in Pashtuns, Tajiks, Hazaras, and Uzbeks was 7.4, 25.3, 25.0, and 29.0 %, respectively. The observed difference between populations for prevalence of GSTT1 null genotype was statistically significant (χ(2) = 35.54, df = 3, P < 0.001). In comparison with European and Asian populations, Afghanistan populations like Iranian populations showed intermediate frequency for GSTT1 and GSTM1 null genotypes.     

The development of glutathione S-transferase and glutathione peroxidase activities in human lung

The development of glutathione S-transferase and glutathione peroxidase activities has been studied in human lung cytosols. Whilst no clear change in glutathione peroxidase activity was identified, expression of the acidic glutathione S-transferase isoenzyme decreased markedly after 15 weeks of gestation so that at birth the level of activity of this isoenzyme was only about 20% of that in samples obtained during the first trimester. Basic glutathione S-transferase isoenzymes were weakly expressed during development and usually comprised less than 10% of cytosolic activity. Ion-exchange studies identified several basic isoenzymes that may correspond to the alpha, beta, gamma, delta and epsilon set previously identified in liver. Weak expression of apparently near-neutral isoenzymes was also detected; they were detected in only a few cytosols.     

Genetic polymorphisms of glutathione S-transferase M1 and bladder cancer risk: a meta-analysis of 26 studies

Studies investigating the association between glutathione S-transferase M1 (GSTM1) polymorphism and bladder cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. We performed a systematic search of the National Library of Medline and Embase databases. This meta-analysis included 26 case-control studies, which included 5029 bladder cancer cases and 6680 controls. The combined results based on all studies showed that the GSTM1 null genotype was associated with an increased risk of bladder cancer (OR = 1.46, 95% confidence interval [CI] = 1.35, 1.57). When stratifying for race, results were similar among Asians (OR = 1.60, 95% CI = 1.27, 2.01) and Caucasians (OR = 1.44, 95% CI = 1.33, 1.57) except Africans (OR = 1.25, 95% CI = 0.76, 2.06). When stratifying by the smoking, stage, grade, and histological type of bladder cancer, we found no statistical association. Our meta-analysis suggests that the GSTM1 null genotype is associated with a modest increase in the risk of bladder cancer.     

Glutathione S-transferase M1 and T1 genotypes and myocardial infarction

Myocardial infarction (MI), which is the most important manifestation of coronary artery disease, is the leading cause of morbidity and mortality in the world. Glutathione S transferases (GSTs) are enzymes responsible for the metabolism of numerous xenobiotics and are known to be polymorphic in humans. We investigated the association between the GSTM1 and GSTT1 gene polymorphisms and MI. The study consists of 296 healthy controls and 324 consecutive patients who had undergone coronary angiography for suspicion of coronary artery disease and with a past history of myocardial infarction. DNA was extracted from whole blood of patient and control. GSTM1 and GSTT1 gene polymorphisms were examined using multiplex PCR. We found that the null GSTM1 was associated with protective effect on MI, although this increase was not significant for GSTM1 (p < 0.054). However, GSTT1 genotype was associated with an increase in the risk of developing MI. In addition to after adjusting other all coronary risk factors, the interactive effect of GSTT1 null genotype remained statistically significant (p < 0.001) for MI disease but GSTM1 null genotype was not statistically significant. Patients, who smoke having the null genotypes of GSTM1, were at a higher risk for developing MI (p < 0.001, OR = 0.41, 95 % CI = 0.240–0.207). There was an effect of interaction of GSTM1 null genotype and smoking on MI development between patient and control groups (p < 0.001). Our results showed that individuals with the null genotypes for GSTM1 had protective effect, while GSTT1 was at a higher risk for MI disease. In addition, there was additional effects of smoking when smoking and non-smoking groups were compared.     

Glutathione S-transferase M1 and T1 polymorphisms in Brazilian African descendants

The glutathione S-transferase gene family has an important role in the biotransformation and detoxification of different xenobiotics and endogenous compounds. Two polymorphic genes of this family, GSTM1 and GSTT1, present null alleles that consequently do not produce the respective enzyme when the genotype is homozygous. These polymorphisms are also interesting for population dynamics studies because they have great frequency variations among different ethnic groups and have been reported worldwide. The distribution of these alleles in urban and Amerindian populations in Brazil has been described, but none of those studies reported on African-descended rural populations. The aim of this study was to analyze the genotype frequency distribution of the GSTM1 and GSTT1 null alleles in an urban sample from the Federal District (n = 91) and in four semi-isolated African-descended populations: Mocambo (n = 55), Rio das R?s (n = 117), Riacho de Sacutiaba (n = 34), and Kalunga (n = 68). The GSTM1 and GSTT1 null genotype frequencies in these populations range from 17% to 35% for GSTM1 and from 22% to 44% for GSTT1. These values are similar to those described in other African and African-descended populations. Despite this range, there is no distribution difference among the analyzed populations. Combined GSTM1 and GSTT1 null genotype frequencies range from 6% to 13% and are similar to European-derived populations, suggesting admixture with this ethnic group. This can be interpreted as a European contribution to these African-descended populations. Regarding the urban population in the Federal District, our results suggest an important African and European contribution.