Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias

Acute leukemias (ALs) are heterogeneous diseases. Functional polymorphisms in the genes encoding detoxification enzymes cause inter-individual differences, which contribute to leukemia susceptibility. The CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 polymorphisms in ALL (n = 156) and AML (n = 94) patients and 140 healthy controls were genotyped by PCR and/or PCR-RFLP using blood or bone marrow samples. No association was observed between the GSTT1 gene deletion and patients (OR = 0.8, 95% CI = 0.4-1.7 for AMLs and OR = 0.9, 95% CI = 0.5-1.6 for ALLs). Patients with ALL and AML had a higher prevalence of the GSTM1 deletions compared to controls but only the difference among adult AML patients (OR = 2.1, 95% CI = 1.0-4.2) was statistically significant. The CYP2D6*3 variant allele frequency was lower in the overall acute leukemia patients (0.6%) compared to controls (P = 0.03). CYP2D6*1/*3 genotype frequency also showed a protective association in AML patients (OR = 0.09, 95% CI = 0.01-1.7; P = 0.04). We also found a risk association for CYP2E1*5 in ALL and AML (OR = 3.6, 95% CI = 1.4-9.4 and OR = 3.9, 95% CI = 1.4-10.5, respectively). No association was found for the studied CYP2D6*4, CYP1A1*2A, and GSTT1"null" variants and the risk of acute leuke-mia (ALL or AML). This case-control study suggests a contribution of CYP2E1, CYP2D6, and GSTM1 "null" variants to the development of acute leukemias.     

Combined GSTM1 and GSTT1 null genotypes are associated with a lower risk of papillary thyroid cancer

Individual susceptibility to cancer is influenced by polymorphisms of genes encoding drug-metabolizing enzymes such as the glutathione S-transferases (GST). The null polymorphisms of the GSTM1 and GSTT1 genes have been associated to a modified risk of several cancers but studies of thyroid cancer have produced conflicting results. The aim of this study was to investigate the relationship between these polymorphisms and the risk of papillary thyroid cancer (PTC). A total of 188 patients with PTC and 247 controls were genotyped using a PCR-based assay. Odds ratios (OR) and 95% confidence intervals (CI) for each homozygous null genotype were determined. The frequency of each of the GSTM1 and GSTT1 null genotypes did not differ significantly between patients and controls (OR=0.83, 95%CI: 0.56-1.21; p=0.328; and OR=0.66, 95%CI: 0.39-1.12; p=0.123, respectively), but the frequency of individuals that had the combined GSTM1 null/GSTT1 null genotypes was significantly lower in the patient group (OR=0.50, 95%CI: 0.26-0.97; p=0.040). The GSTM1 null genotype was associated with a lower risk of advanced cancer stages (III/IV) (OR=0.50, 95%CI: 0.26-0.96; p=0.036) and the GSTT1 null genotype was associated with a lower risk of the follicular variant of PTC (OR=0.31, 95%CI: 0.10-0.97; p=0.044). These results suggest that GSTM1 and GSTT1 null genotypes are weak, yet possible, modifiers of the risk of PTC. This protective effect may be due to a role of the GSTM1 and GSTT1 encoded enzymes in the metabolic activation of putative thyroid carcinogens or in other pathways involved in thyroid carcinogenesis.     

Polymorphisms at GSTM1 and GSTT1 gene loci and susceptibility to cervical cancer in Indian population

Multiple allelism at loci encoding detoxifying enzymes is associated with cancer risk. Glutathione S-transferase (GSTs) catalyzes the conjugation of glutathione to numerous potentially genotoxic compounds. This study evaluates the influence of genetic polymorphisms of GST M1 and GST T1 on susceptibility to cervical cancer. A multiplex polymerase chain reaction method was used to detect the presence or absence of the GSTM1 and GSTT1 genes in genomic DNA isolated from cases with cervical cancer (n=142) and normal controls (n=96). The results showed that the frequency of homozygous GSTM1 null genotype was higher in cervical cancer cases (57.0%) as compared to controls (34.4%) and the differences were significant (p<0.05), OR=2.5, 95% CI: 1.4--4.5. The frequency of homozygous GSTT1 null genotype in cancer cases was 19.7% in comparison to 12.5% in controls, however, the difference was not statistically significant (OR=1.7, 95% CI: 0.8-3.8). Significant difference was found between the cases and controls in the distribution of the null genotype of GST M1 in individuals aged above 45 years (p=0.04), but this difference was not significant in individuals aged below 45 years (p=0.06). No significant differences were found in cervical cancer cases and controls when data were analyzed according to age group for GSTT1 null genotype. Further, the combined analysis of both GSTM1 null and GSTT1 null genotypes did not appear to influence the susceptibility to cervical cancer, suggesting that polymorphisms of other detoxifying enzymes may play a significant role in cervical carcinogenesis.     

Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study

Glutathione S-transferases (GSTs) have been associated with outcome in human cancers treated with cytotoxic chemotherapy. In a case-control study, we investigated the association between polymorphisms within the GSTM1, GSTT1, and GSTP1 genes and risk of relapse in childhood acute lymphoblastic leukemia (ALL). Cases were relapsed patients. Controls were successfully treated patients with a minimum follow-up of 5 years. The null genotype (absence of both alleles) for GSTM1 or GSTT1 conferred a 2-fold (OR = 0.5, 95% CI = 0. 23-1.07, P =.078) and 2.8-fold (OR = 0.36, 95% CI = 0.13-0.99, P =. 048) reduction in risk of relapse, respectively, relative to the presence of the GSTM1 or GSTT1 gene. The GSTP1 Val(105)/Val(105) genotype showed a 3-fold decrease in risk of relapse (OR = 0.33, 95% CI = 0.09-1.23, P =.099) in comparison to the combined category of Ile(105)/Val(105) and Ile(105)/Ile(105 )genotypes. No particular associations with relapse were observed for the GSTP1 polymorphism at codon 114. The risk of relapse when having 1 of the low-risk genotypes (GSTM1 null, GSTT1 null, GSTP1 Val(105)/Val(105)) decreased 1.9-fold (OR = 0.53, 95% CI = 0.24-1.19, P =.123), and the risk when having 2 or 3 low-risk genotypes 3.5-fold (OR = 0.29, 95% CI = 0.06-1.37, P =.118), compared with individuals having no low-risk genotype (P for trend =.005). Our results suggest that polymorphisms within genes of the GST superfamily may be associated with risk of relapse in childhood ALL. (Blood. 2000;95:1222-1228)     

Interaction models of CYP1A1, GSTM1 polymorphisms and tobacco smoking in intestinal gastric cancer

AIM: To explore the interaction models of the cytochrome P-450 (CYP) 1A1 Val variant and glutathione S-transferase (GST) M1 null polymorphisms with tobacco smoking in the occurrence of intestinal gastric cancer. METHODS: A community-based case-control study was conducted in Yangzhong. Subjects included 114 intestinal types of gastric cancer with endoscopic and pathological diagnosis during January 1997 and December 1998, and 693 controls selected from their spouse, siblings or siblings-in-law who had no history of digestive system cancer. Logistic regression was used to estimate the interaction models. RESULTS: The frequency of the CYP1A1 Val variant allele in cases did not differ from that in controls. The OR of GSTM1 null genotype was 2.0 (95% confidence interval (95%CI): 1.2-3.1, P<0.01). It showed a significant type 2 form of interaction model when both CYP1A1 Val variant allele and former tobacco smoking existed (i.e., among the multiplicative effects, the disease risk is increased by the tobacco exposure alone but not by the CYP1A1 variant alone). The interaction index gamma was 2.8, and OR(eg) (95%CI) was 5.0 (1.9-13.4). GSTM1 null genotype and former tobacco smoking were significant in a type 4 interaction model (i.e., the disease risk is increased by GSTM1 null genotype or tobacco exposure alone among the multiplicative effects). The interaction index gamma and OR(eg) (95%CI) were 3.4 and 8.4 (3.4-20.9), respectively. CONCLUSION: Different interaction models of CYP1A1 Val variant allele and GSTM1 null genotype with tobacco smoking will contribute to understanding carcinogenic mechanism, but there is a need to further investigate in larger scale studies.     

Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia

The involvement of phase I and II enzymes is well documented in the metabolism of a wide range of drugs and xenobiotics. Single-nucleotide polymorphisms (SNPs) of these enzymes are also known to alter their protein expression and function. Moreover, genetic susceptibility and environmental exposure have been proposed to be an etiology of cancer. We hypothesized that polymorphisms of these enzymes might affect the risk of childhood acute lymphoblastic leukemia (ALL). CYP 1A1, CYP 3A4*1B, CYP 3A5*3, CYP 3A5*6, GSTM1, and GSTT1 polymorphisms were genotyped by using PCR-RFLP in 107 children with ALL and 320 healthy controls. Allele and genotype frequencies of each of the SNPs were compared between two groups. It was found that the allele frequencies of CYP 1A1*1, *2A, *2B, and *4 were not different between cases and controls. CYP 3A4*1B allele frequency was only 0.8% and 0.9% in ALL and controls, respectively. CYP 3A5*1/*1, *1/*3, and *3/*3 genotype frequencies showed no statistically significant difference between patients and controls. CYP 3A5*6 was not detected in our population. The GSTM1 null genotype was significantly increased in children with ALL (OR 1.7; 95% CI, 1.0, 2.7). In contrast, the GSTT1 null genotype did not show this effect. Our data thus demonstrate that the GSTM1 null genotype might increase the risk of childhood ALL in a Thai population.     

GSTM1, GSTT1, GSTP1 and CYPIA1 genetic polymorphisms and susceptibility to esophageal cancer in a French population： Different pattern of squamous cell carcinoma and adenocarcinoma

AIM: To evaluate the association between CYPIA1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinorna (ADC) in a high risk area of northwest of France.METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles, GSTM1 *2/*2 and GSl-l-l*2/*2 null genotypes). A total of 79 esophagealcancer cases and 130 controls were recruited. RESULTS: GSTM2*2/*2 and CYP1A1*1A/*2C genotype frequencies were higher among squamous cell cardnomas at a level close to statistical significance (OR = 1.83, 95% CI0.88-3.83, P= 0.11; OR = 3.03, 95% CI 0.93-9.90, P= 0.07,respectively). For GSTP1 polymorphism, no difference wasfound between controls and cases, whatever their histological status. Lower frequency of GST/-1 deletion was observed in ADC group compared to controls with a statistically significant difference (OR=13.31, 95% CI 1.66-106.92, P&lt;0.01).CONCLUSION: In SCC, our results are consistent with the strong association of this kind of turnout with tobacco exposure. In ADC, our results suggest 3 distinct hypotheses:(1) activation of exogenous procarcinogens, such as small halogenated compounds by GSTTI‘, (2) contribution of GSTT1 to the inflammatory response of esophageal mucosa, which is known to be a strong risk factor for ADC,possibly through leukotriene synthesis; (3) higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.     

Characterization of MTHFR,GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia

The role of methylenetetrahydrofolate reductase (MTHFR C677T), glutathione S-transferases (GSTM1 and GSTT1 null, GSTP1 Ile105Val), and cytochromes p450 (CYP1A1*2A) genotypes in the etiology of childhood leukemia was simultaneously investigated. 144 Turkish children with acute lymphoblastic leukemia (ALL) and 33 with acute nonlymphoblastic leukemia (ANLL) were studied and compared with 185 healthy pediatric controls. The frequency of MTHFR genotype was insignificantly higher in ALL (7.7%) and ANLL (6.3%) than in controls (4.4%). Equal distribution of the GSTM1 null genotype was detected between ALL patients and controls (55%), while its incidence was slightly higher in ANLL patients (61.3%). Although GSTT1 null genotype was insignificantly lower in ALL patients (20.9%) than controls (22.7%), it was significantly underrepresented in ANLL patients (6.5%) (P = 0.05, OR 0.24, 95% CI 0.05-1.03). The homozygous frequency of GSTP1 genotype did not differ significantly between groups of ALL (3.7%), ANLL patients (9.1%) and controls (4.9%). Homozygous CYP1A1*2A genotype was underrepresented in ALL patients (1%) as compared to control (4.8%) but the differences did not reach to statistical significance (OR 0.21; 95% CI 0.03-1.72). Homozygosity for this genotype was not detected in ANLL patients. No particular association was noted between different combinations of combined genotypes and risk of development of childhood ALL and ANLL. These results suggested that there are no significant associations between the studied genotypes and the risk of developing either form of acute leukemia except GSTT1 null and homozygosity for CYP1A1 genotypes that may play protective roles in the development of ANLL in Turkish children.     

谷胱甘肽S-转移酶M1、T1基因多态与散发性大肠腺癌遗传易感性

目的　探讨谷胱甘肽S 转移酶 (GST)M1、T1基因多态与散发性大肠腺癌 (SCRAC)遗传易感性的关联。方法　应用多重聚合酶链反应 (PCR)技术 ,对经病理组织学确诊的 10 4例SCRAC患者及同期在本院体检的无血缘关系的 10 1例健康人 ,检测其GSTM1和GSTT1基因多态性。结果　 (1)在健康人和SCRAC患者 ,GSTM1、GSTT1空白基因型的频率差异均无显著性 (前者 4 6 5 % :5 6 7% ,χ2 =2 13,P >0 0 5 ;后者 4 7 5 % :6 0 6 % ,χ2 =3 5 2 ,P >0 0 5 )。 (2 )GSTM1空白基因型频率在近端与远端SCRAC患者间、在老年与非老年SCRAC间的频率差异均无显著性 ;而GSTT1空白基因型的频率差异有显著性 (前者 4 4 4 % :6 6 2 % ,χ2 =3 97,P <0 0 5 ;后者 70 9% :4 9 0 % ,χ2 =5 2 1,P <0 0 5 )。 (3)GSTM1、GSTT1均为空白基因联合型的个体患SCRAC的危险性升高 4 33倍 (9 6 % :2 6 9% ,χ2 =7 89,ν =3,P <0 0 5 )。结论　单独的GSTM1或GSTT1空白基因型与SCRAC遗传易感性无关 ,但GSTT1空白基因型与远端SCRAC遗传易感性有关 ,且多见于老年患者。GSTM1、GSTT1均为空白基因的联合基因型是SCRAC的易感基因型。     

Associations analysis of GSTM1, T1 and P1 Ile105Val polymorphisms with carpal tunnel syndrome

Oxidative stress was related with carpal tunnel syndrome (CTS). We aimed to clarify the associations between glutathione S-transferase (GST)M1, GSTT1 and GSTP1-Ile105Val polymorphisms and CTS. One hundred-forty patients with CTS and 97 healthy controls were enrolled in this study. Tinel and Phalen signs were noted as positive or negative. Functional and clinical status of patients was evaluated by the Boston Questionnaire. The intensity of hand and/or wrist pain was evaluated on 10 cm visual analog scale (VAS). We applied the polymerase chain reaction (PCR) to determine the polymorphisms of the GSTM1 and GSTT1 and the PCR-restriction fragment length polymorphism method for detecting the GSTP1-Ile105Val polymorphism. The M1 null genotype was significantly higher in patients with CTS compared to healthy controls, and the M1 null genotype seemed to increase the risk of CTS approximately two-fold (P?=?0.011; odds ratio (OR)?=?1.98; 95 % confidence interval (CI) 1.17–3.36). The M1 null, T1 present combined genotype was significantly higher in patients with CTS compared to healthy controls (P?=?0.043); however, it seemed not to increase the risk of CTS (P?=?0.14; OR?=?0.62; 95 % CI 0.33–1.76). We found significantly higher levels of the VAS, Boston Symptom Severity Scale and Phalen sign in patients with the Ile/Val or the Val/Val genotypes compared to those in patients with the Ile/Ile genotype (P?=?0.003, 0.004 and 0.044, respectively). We proposed that genes involved in the protection from oxidative stress may influence the susceptibility, clinical and functional status of CTS. The GSTM1 null genotype may be related with the development of CTS, whereas the Val allele of GSTP1-Ile105Val polymorphism may be associated with worse functional and clinical status in CTS.     

Polymorphisms in xenobiotic-metabolizing genes and the risk of chronic lymphocytic leukemia and non-Hodgkin's lymphoma in adult Russian patients

Polymorphisms in genes coding xenobiotic-metabolizing enzymes are considered as risk factors modifying susceptibility to cancer. We developed a biochip for the analysis of 18 mutations in 10 genes of metabolizing system: CYP1A1, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, CYP2C9, CYP2C19, and NAT2. Using allele-specific hybridization on the biochip 76 T-cell non-Hodgkin's lymphoma (NHL) patients, 83 B-cell chronic lymphocytic leukemia (B-CLL) patients, and 177 healthy donors were tested. Polymorphic CYP1A1 alleles were more frequent in B-CLL patients relative to normal controls, for example, a combination of polymorphic variants 4887C > A, 4889A > G, and 6235T > C (OR = 1.76, 95% CI = 1.0-3.1). The GSTM1 null genotype was more frequent in NHL patients relative to controls (OR = 1.82, 95% CI = 1.1-3.1). The combination of unfavorable polymorphic CYP1A1 variants and GSTM1 null genotype was found more frequently in B-CLL patients relative to controls (OR = 2.52, 95% CI = 1.3-4.9). In addition, male B-CLL patients demonstrated a significantly increased occurrence of heterozygous and homozygous allele *2 of CYP2C9 gene (OR = 2.38, 95% CI = 1.1-5.2) as well as a combination of alleles *2 and *3 of the gene (OR = 2.09, 95% CI = 1.1-3.9). Thus, our findings show the association between polymorphic alleles of CYP1A1, GSTM1, and CYP2C9 genes and the risk to develop NHL or B-CLL. The developed biochip can be considered as a convenient analytical tool for research studies and predictive analysis in oncohematology.     

Glutathione-S-transferase （GSTM1, GSTrl） and the risk of gastrointestinal cancer in a Korean population

AIM: To evaluate the association of glutathione S-transferase mu (GSTM1) and glutathione S-transferase theta (GSTT1) null genotypes with the risk of gastric cancer (GC) and colorectal cancer (CRC) in a South Korean population.METHODS: We conducted a population-based, large-scale case-control study including 2213 GCs, 1829 CRCs, and 1699 controls. Null and non-null genotypes of GSTM1 and GSTT1 were determined using real-time PCR.RESULTS: The null genotypes of GSTM1 and GSTT1 were not significantly associated with elevated risk of gastric (OR = 1.070, 95% CI = 0.935-1.224; OR = 1.101, 95% CI = 0.963-1.259, respectively) or colorectal cancer (OR = 1.065, 95% CI = 0.923-1.228; OR = 1.041, 95% CI = 0.903-1.200, respectively). The frequency of the combined null GST genotype was not different between the two cancer groups and controls. Moreover, smoking, drinking, and age did not modify the association between these genotypes and the risk of gastric or colorectal cancer.CONCLUSION: GSTM1 and GSTT1 null genotypes were not associated with increased risk of GC or CRC in Koreans.     

Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury

BACKGROUND/AIMS: Drug metabolizing enzymes may be related to drug-induced liver injury (DILI). Manganese superoxide dismutase (MnSOD), NAD(P)H:quinone oxidoreductase (NQO1), and glutathione S-transferase (GST) are important drug metabolizing enzymes. We aimed to elucidate the relationship between genetic polymorphisms of these enzymes and the susceptibility to DILI. METHODS: A total of 115 patients with DILI and 115 drug-, sex-, and age-matched controls were enrolled. Their genetic polymorphisms of MnSOD, NQO1, GSTM1, and GSTT1 were assayed. RESULTS: Sixty-three (54.8%) of DILI patients were incriminated to anti-tuberculosis drugs. Subjects with a mutant C allele (T/C or C/C genotype) of MnSOD had a higher risk of DILI than those with MnSOD T/T genotype, both in overall drugs studied (adjusted OR: 2.44, 95% C.I.: 1.38-4.30, P=0.002), and in sub-category of anti-tuberculosis drugs (adjusted OR: 2.47, 95% C.I.: 1.13-5.39, P=0.02). In addition, subjects carrying GSTM1 null genotype had increased risk of anti-tuberculosis DILI (adjusted OR: 2.23, 95% C.I.: 1.07-4.67, P=0.03). CONCLUSIONS: The MnSOD mutant C allele may increase the susceptibility to DILI, and GSTM1 null genotype may be related to anti-tuberculosis drug-induced hepatotoxicity. Determination of the MnSOD and GSTM1 genotypes may help identify patients at high risk for DILI.     

Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population

AIM: To evaluate the association of glutathione S-transferase mu (GSTM1) and glutathione S-transferase theta (GSTT1) null genotypes with the risk of gastric cancer (GC) and colorectal cancer (CRC) in a South Korean population.METHODS: We conducted a population-based, largescale case-control study including 2213 GCs, 1829CRCs, and 1699 controls. Null and non-null genotypes of GSTM1 and GSTT1 were determined using realtime PCR.RESULTS: The null genotypes of GSTM1 and GSTT1 were not significantly associated with elevated risk of gastric (OR = 1.070, 95% CI = 0.935-1.224; OR = 1.101, 95% CI = 0.963-1.259, respectively) or colorectal cancer (OR = 1.065, 95% CI = 0.923-1.228; OR = 1.041, 95% CI = 0.903-1.200, respectively). The frequency of the combined null GST genotype was not different between the two cancer groups and controls.Moreover, smoking, drinking, and age did not modify the association between these genotypes and the risk of gastric or colorectal cancer.CONCLUSION: GSTM1 and GSTT1 null genotypes were not associated with increased risk of GC or CRC in Koreans.     

Glutathione S-transferase M1 and T1 polymorphisms and cervical cancer risk: a meta-analysis

There were some studies on the associations between Glutathione S-transferase M1 (GSTM1) and Glutathione S-transferase T1 (GSTT1) polymorphisms and cervical cancer (CC) risk, but the results were inconsistent. Thus, a meta-analysis was performed. The electronic databases PubMed, Science Direct, CBM, and CNKI were searched for possible studies. Finally, 16 studies (1,627 cases and 2,161 controls) were included. For the GSTM1 and GSTT1 polymorphisms, the unadjusted odds ratios (OR) and 95% confidence intervals (95% CI) from each study were used to estimate summary OR. Subgroup analyses by ethnicity and histological type of CC were also performed. For the GSTM1 polymorphism, the null genotype of GSTM1 was associated with an increased CC risk in total population (OR=1.32, 95% CI=1.06-1.66). Similar association was found in Asians (OR=1.47, 95% CI=1.11-1.94), but not in Caucasians (OR=0.96, 95% CI=0.73-1.27). For the GSTT1 polymorphism, the null genotype of GSTT1 was not statistically significantly associated with CC risk in total population (OR=1.36, 95% CI=0.97-1.90). This result was also found in Asians (OR=1.27, 95% CI=0.87-1.85) and Caucasians (OR=1.09, 95% CI= 0.66-1.79), but not in Latinos (OR=4.58, 95% CI= 2.04-10.28). For the GSTM1/GSTT1 interaction analysis, the dual null genotypes of GSTM1/GSTT1 were significantly associated with increased CC risk in total population (OR=1.77, 95% CI= 1.14-2.75), and all the six studies were from Asia. For subgroup analyses by histological type of CC, the three aspects of the analyses above were all not significantly associated with CC risk in squamous cell carcinoma and adenocarcinoma, respectively. The null genotype of GSTM1 and the dual null genotypes of GSTM1/GSTT1 were risk factors in CC, and the null genotype of GSTT1 was not associated with CC risk.     

Genetic polymorphism at GSTM1 and GSTT1 gene loci and susceptibility to oral cancer

GSTs are phase II enzymes which are involved in the detoxification of active metabolites of many potential carcinogens from tobacco smoke and therefore may play an important role in modulating susceptibility to tobacco related cancers. This study evaluates the influence of genetic polymorphisms of GSTM1 and GSTT1 gene loci on susceptibility to oral cancer. The genotyping was based on multiplex PCR assay that identified the GSTM1 and GSTT1 null (-/-) genotypes but didn't distinguish homozygous wild type+/+ and heterozygous +/- individuals. Genomic DNA was isolated from cases with oral cancer (n=40) and normal controls (n=87). The prevalence of the GSTM1 null genotypes was 29/87 (33.3%) and 21/40 (52.5%) in controls and oral cancer cases, respectively but the differences were not significant (OR=2.2; 95%CI=0.96-5.1; p=0.06). The frequency of homozygous GSTT1 null genotype in cancer cases was 17/40 (42.5%) as compared to 13/87 (14.94%) in controls and the differences were highly significant (OR=4.2; 95%CI=1.64-10.9; p=0.0002). Oral cancer cases had higher proportion of both GSTM1 and GSTT1 null genotypes as compared to controls but the differences were not statistically significant (OR=2.9; 95%CI=0.71-11.9; p=0.17). When individuals were categorized into two groups, no differences were observed for GSTM1 null genotype frequencies in control and cancer cases (OR=2.9; 95%CI=0.9-9.6; p=0.08) (OR=1.6; 95%CI=0.44-6.1; p=0.58) in <=50 yrs and >50 yrs of age groups. Significant differences between control and cancer cases were observed for GSTT1 null genotypes both in <=50 yrs and >50 yrs of age groups (OR=4.0; 95%CI=1.1-15.0; p=0.03) (OR=4.5; 95%CI=0.97-22.29; p=0.05), respectively. The effect of smoking on GSTM1 null individuals was not found significant (OR=1.0; 95%CI=0.19-4.86; p=0.75) but it was significant in case of GSTT1 null individuals (OR=6.33; 95%CI=1.0-44.1; p=0.02). Our results thus suggest that GSTT1 gene polymorphisms modulate susceptibility to tobacco-related cancer of the oral cavity.     

Relationship of tobacco smoking CYP1A1 GSTM1 gene polymorphism and esophageal cancer in Xi'an

AIM: To analyze the association of tobacco smoking polymorphism of CYP1A1 (7th exon) and GSTM1 genotype and esophageal cancer(EC) in Xi'an. METHODS: A hospital based case-control study, with molecular epidemiological method, was carried out. Polymorphism of CYP1A1 and GSTM1 of samples from 127 EC cases and 101 controls were detected by PCR method. RESULTS: There were no significant difference of age and gender between cases and controls. Tobacco smoking was the main risk factor OR=1.97;95% CI=1.12-3.48 for EC in Xi'an. The proportions of CYP1A1 Ile/Ile, Ile/Val and Val/Val gene types in cases and controls was 19.7% 45.7% 34.6% and 30.7%,47.5%, 21.8% respectively(P=0.049).Individuals with CYP1A1 Val/Val genotype compared to those with CYP1A1 Ile/Ile genotype had higher risk for EC increased (OR=2.48, 95%CI=1.12-5.54). The proportions of GSTM1 deletion genotype in cases and controls were 58.3% and 43.6%(OR=1.81, 95%CI=1.03-3.18, P=0.028). Analysis of gene-environment interaction showed that tobacco smoking and CYP1A1 Val/Val genotype; tobacco smoking and GSTM1 deletion genotype had synergism interaction respectively. Analysis of gene-gene interaction did not find synergistic interaction between these two genes. But in GSTM1 deletion group there was significant difference of distribution of CYP1A1 genotype between cases and controls (P=0.011). CONCLUSION: CYP1A1 Val/Val and GSTM1 deletion genotypes are genetic susceptibility biomarkers for EC. The risk increases, when person with CYP1A1 Val/Val and/or GSTM1 deletion genotype. And these two-metabolic enzymes seem to have interactions with tobacco smoking, in which the mechanism still needs further study.     

Glutathione S-transferase M null homozygosity and risk of systemic lupus erythematosus associated with sun exposure: a possible gene-environment interaction for autoimmunity

OBJECTIVE: Multiple genetic factors modulate predisposition to systemic lupus erythematosus (SLE). The glutathione S-transferase (GST) genes GSTM1, GSTT1, and GSTP1 catalyze metabolic pathways for the excretion of reactive oxygen species that may be generated by cellular oxidative stress induced by ultraviolet radiation in sunlight. We hypothesized that risk of SLE associated with occupational sun exposure is modulated by GSTM1, GSTT1, and GSTP1 genotypes. METHODS: DNA samples and occupational history were collected from 243 cases and 298 controls in the Carolina Lupus Study, a population based case-control study of patients with recently diagnosed SLE. RESULTS: There was no independent association between SLE and presence of the homozygous null GSTM1 or GSTT1 genotype, the homozygous Val/Val or heterozygous Val/Ile GSTP1 genotype, or occupational sunlight exposure. The prevalence of Ro autoantibodies was significantly increased among Caucasians with the GSTM1 null genotype (OR 2.6, 95% CI 1.0, 6.8), but was somewhat weaker among African-Americans (OR 1.5, 95% CI 0.7, 3.5). In the combined analysis of occupational sunlight exposure and GSTM1 genotype, the effect of sun exposure among Caucasians varied depending on GSTM1 genotype. There was a 3-fold increased risk (OR 3.1, 95% CI 0.9, 10.8) of SLE associated with 24 or more months' occupational sun exposure among Caucasians with the GSTM1 null genotype, but sun exposure was not associated with risk among GSTM1 positive Caucasians (OR 0.6, 95% CI 0.3, 1.5). The interaction was statistically significant (p = 0.028). CONCLUSION: Our results suggest that GSTM1 homozygous null genotype may modify the effect of occupational sun exposure on the risk of SLE in caucasians.     

Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease

OBJECTIVE: The aim of this study was to determine whether null genotypes for glutathione transferase mu-1 (GSTM1) and theta-1 (GSTT1) influence the risk of development of advanced alcoholic liver disease. MATERIAL AND METHODS: GSTM1 and GSTT1 genotypes were identified on DNA through multiple analysis with polymerase chain reaction in 153 subjects diagnosed with advanced alcoholic liver disease and in 241 healthy controls. RESULTS: The frequency of the GSTM1 null genotype was not different between patients and controls (36.6% versus 41.1%, non-significant). The GSTT1 null genotype was more frequently found in patients than in controls (32% versus 22%, odds ratio 1.67, 95% CI 1.03-2.71, p =0.027). Moreover, patients were more likely to be simultaneous carriers of both GSTM1 and GSTT1 null genotypes (odds ratio 4.30, 95% CI 1.89-9.97, p =0.0003). CONCLUSIONS: The GSTT1 null genotype is more frequent among patients with advanced alcoholic liver disease than in controls. The coincidence of this genotype with the GSTM1 null genotype is four times more likely in patients. We suggest that polymorphisms affecting the activity of the glutathione S-transferase isoforms M1 and T1 may be associated with the risk of developing chronic severe ethanol liver damage.     

Glutathione S-transferase M1 and P1 metabolic polymorphism and lung cancer predisposition

Individual susceptibility to different environmental agents is expected to be associated with alterations in metabolism of xenobiotics. Thus, genetic polymorphism of glutathione S-transferase (GST) can be recognized as a potential risk modifier in lung cancer development. The distribution of GSTM1 and GSTP1 genotypes was studied in a group of 138 diagnosed lung cancer patients and in 165 controls living in central Poland and RFLP-PCR technique was applied. The frequency of GSTM1 null genotype and GSTP1 Val single and duplicated alleles was similar among patients and controls. GSTM1 homozygous deletion was most prevalent in small-cell carcinoma groups (adjusted odds ratio (OR): 2.32, 95% confidence interval (CI): 0.98-5.52). In patients and controls, GSTM1A genotype was most frequent (34.1% vs. 37.0%). The estimated lung cancer risk for GSTM1 null, GSTP1 Ile/Val and GSTP1 Val/Val combined genotype was 1.44 (95% CI: 0.73-2.83), suggesting the absence of modifying effect of defective GSTM1 and GSTP1 alleles on lung cancer predisposition.