解毒酶基因谷胱甘肽硫转移酶M1多态性与黄曲霉毒素B1相关性肝细胞癌易患性研究

目的探讨解毒酶基因谷胱甘肽硫转移酶M1(GSTM 1)多态性与黄曲霉毒素B1(AFB1) 相关性肝细胞癌(HCC)风险的相关性。方法应用聚合酶链反应技术对广西地区AFB1高污染区140 例HCC患者和536例对照人群的GSTM1基因多态性进行检测,进行以医院为基础的病例对照研究。结果(1)GSTM1-present基因型为HCC保护基因型,而GSTM1-null基因型为HCC风险基因型,其校正风险值OR(95%可信区间CI)为2.07(1.20-3.5 7);(2)在AFB1暴露中低度与高度两个层次, GSTM1基因多态性均增加HCC危险性,其校正OR(95%CI)分别为1.92(0.92-4.00)和1.80(0.77- 4.17)。结论解毒酶基因GSTM1多态性与HCC易患性相关,其缺失型增加患HCC风险;GSTM1在中低度和高度AFB1暴露时均与HCC易患性相关,但在中低度暴露时更明显。     

Susceptibility to hepatocellular carcinoma associated with null genotypes of GSTM1 and GSTT1

ALM In order to study the association between the null genotypes of GSTM1 and GSTT1 and the genetic susceptibility to hepatocellular carcinoma (HCC). METHODS The genotypes of GSTM1 and GSTT1 of 63 cases of HCC and 88 controls were detected with the multiple PCR technique. RESULTS The frequency of GSTM1 null genotype was 57.1% among the cases, and 42.0% among the controls, the difference being statistically significant (x2 = 3.35, P = 0.067),but X2 value approaching the significance level.The odds ratio was 1.84 (95% Cl=0.91 - 3.37).The frequency of GSTT1 non-null genotype was 87.3% among the cases and 62.5% among the controls, the difference being statistically significant (X2=11.42, P=0.0007274). The odds ratio was 4.13 (95% Cl = 1.64 - 10.70).According to the cross analysis, the GSTT1 nonnull genotype was more closely associated with HCC than GSTM1 null genotype, and these two factors play an approximate addlitive interaction in the occurrence of HCC. CONCLUSION The persons with GSTM1 nullgenotype and GSTT1 non-null genotype have the increased risk to HCC.     

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.     

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.     

Prognostic importance of DNA repair gene polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> Arg399Gln and <Emphasis Type="Italic">XPD</Emphasis> Lys751Gln in lung cancer patients from India

Purpose Inter individual variation in lung cancer susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the Base Excision Repair (BER) and nucleotide excision repair (NER) pathway. Two of the genetic polymorphisms, XRCC1Arg399Gln and XPD Lys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive. Methods In order to verify the role of the common variant alleles in the XPD gene, we have genotyped 211 lung cancer patients and 211 healthy controls using PCR-RFLP assays in a hospital based, case-control study in an Indian population. Logistic regression models were fit to examine the relationship between the log odds of lung cancer and each covariate. Overall Survival in relation to various genotypes and clinicopathological factors were analyzed using Kaplan Meier estimates and hazard ratios were calculated using Cox Regression analysis. Results The carriers of XRCC1 399 AA genotypes were at higher risk of lung cancer (OR = 2.1, 95% CI:1.224–3.669, P = 0.007) than carriers of GG genotype. Subjects carrying 751 AC genotype were at an increased risk of carcinoma of the lung (OR = 1.8; 95% CI:1.233–2.807, P = 0.003) than subjects with AA genotypes. Compared to the XRCC1 399 GG/ XPD 751 AA reference genotype, the combined variants, XRCC1 399 GG/ XPD 751 AC+CC (OR = 1.9, 95% CI: 1.037–3.481), P = 0.03), XRCC1 399 GA+AA/ XPD 751 AA (OR = 1.7, 95% CI: 1.020–2.833, P = 0.04), XRCC1 399 GA+AA/XPD 751 AC+CC (OR = 2.7, 95% CI: 1.582–4.864, P = 0.01), had significantly higher odds ratios. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival, the risk being significant for the XRCC1 gene polymorphism (P = 0.01 by log-rank test). The hazard of dying was significant for the XRCC1 399 AA genotype (HR = 3.04, 95%CI: 1.393–6.670, P = 0.005). Higher tumour stage also came out as significant predictors of patient death. Conclusions These findings suggest that genetic polymorphisms in the DNA repair genes may modulate overall lung cancer susceptibility and that pathological stage and XRCC1 Arg399Gln independently predicted overall survival among Indian lung cancer patients.     

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.     

DNA repair gene XRCC7 polymorphisms (rs#7003908 and rs#10109984) and hepatocellular carcinoma related to AFB1 exposure among Guangxi population, China

Aim: The X‐ray repair cross‐complementing group 7 (XRCC7) plays an important role in the repair of DNA double‐strand breaks by nonhomologous end‐joining repair (NEJR) pathway. However, the role of XRCC7 polymorphisms (rs#7003908 and rs#10109984) possibly influencing NEJR capacity in hepatocellular carcinoma (HCC) induced by aflatoxin B1 (AFB1) has not been well elaborated. Methods: This hospital‐based case‐control study, including 348 patients with newly diagnosed HCC and 597 controls without any evidence of liver diseases, was conducted to elucidate the association between these two polymorphisms and the risk of HCC related to AFB1 exposure among a Guangxi population from a high AFB1‐exposure area by means of TaqMAN‐polymerase chain reaction technique. Results: We observed that HCC patients featured higher AFB1 exposure than control group (odds ratios [OR] = 6.49 and 6.75 for exposure years and exposure levels, respectively). Furthermore, these individuals with the genotypes of XRCC7 rs#7003908 G alleles (namely XRCC7‐TG or ‐GG), compared the homozygote of XRCC7 rs#7003908 T alleles (XRCC7‐TT), faced increasing risk of HCC (OR, 3.45 and 5.04; 95% confidence intervals [CIs], 2.40–4.94 and 3.28–7.76, respectively). We also found some evidence that this polymorphism interacted with AFB1‐expousure years or levels in the process of HCC carcinogenesis. Additionally, XRCC7 rs#7003908 polymorphism was correlated with the levels of AFB1‐DNA adducts (r = 0.142, P < 0.001). XRCC7 rs#10109984 polymorphism, however, did not modify the risk of HCC related to AFB1 exposure (P > 0.05). Conclusion: These data suggest that XRCC7 rs#7003908 polymorphism may be one of the genetic modifiers for AFB1‐related HCC among Guangxi population.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

Glutathione S-transferase M1, T1, and P1 genotypes and rheumatoid arthritis

OBJECTIVE: To determine the effects of genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP on risk and severity of rheumatoid arthritis (RA) in a Korean population. METHODS: A total of 258 patients with RA and 400 disease-free controls were enrolled. GST genotypes were determined by RFLP-PCR. HLA-DRB 1 typing and further subtyping of all alleles was performed using sequence-specific oligonucleotide probe hybridization after PCR. Severity of RA among cases was assessed by Steinbrocker anatomical stage. Risk was assessed by calculating the age and sex adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The OR for risk of RA with the GSTM1-null genotype was 1.40 (95% CI 1.02- 1.92, p = 0.04), and 1.86 (95% CI 1.12- 3.09, p = 0.005) among individuals without the shared epitope (SE). Among patients with RA, the OR for risk of severe RA for the GSTM1-null genotype was 2.45 (95% CI 1.04- 5.77, p = 0.02). No association was observed between the GSTT1 or GSTP1 genotypes and either risk or severity of RA. CONCLUSION: These results suggest that the deletion polymorphism of GSTM1 is associated with increased susceptibility for RA, particularly among individuals who are not carriers of the HLA-DRB 1 SE.     

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.     

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)     

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.     

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.     

CYP1A1, GST gene polymorphisms and risk of chronic myeloid leukemia

PRINCIPLES: Associations between polymorphisms for genes encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the present study is to investigate the influence of cytochromes P450 (CYP450) 1A1*2C and Glutathione S-transferases (GSTs) (T1 and M1) gene polymorphisms in susceptibility to chronic myeloid leukaemia (CML). METHODS: The frequency of CYP1A1 Ile/Val alleles and of GSTT1 and GSTM1 homozygous deletions was examined in 107 patients with CML and 132 healthy controls by PCR and/or PCRRFLP methods using blood samples. RESULTS: The frequency of CYP1A1 Val allele was found to be 19.2% in CML patients and 4.4% for controls, indicating that persons carrying this allele had an increased risk of CML (OR = 5.10, 95% CI: 2.60-9.97). The frequency of individuals carrying the GSTT1 null genotype was higher among CML patients (40.2%) compared to controls (19.2%) (OR = 2.82, 95% CI: 1.58-5.05; p <0.001). Therefore, GSTT1 present genotype may be a protective factor for CML. Although GSTM1 null genotype frequency was slightly higher in the patient group (44.9%) than in the controls (42.3%), this difference was not statistically significant (OR = 1.11, 95% CI: 0.66-1.86; p = 0.693). Individuals with GSTM1 null genotypes without the T allele have a 5.981 higher risk for CML than those who have the T allele. CONCLUSIONS: This data suggests that polymorphic CYP1A1 and GSTT1 genes appear to affect susceptibility to CML.     

Polymorphism of glutathione S-transferase mu 1 and theta 1 genes and hepatocellular carcinoma in southern Guangxi, China

AIM: Glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genes are involved in the metabolism of a wide range of carcinogens, but deletions of the genes are commonly found in the population. The present study was undertaken to evaluate the association between GSTM1 and GSTT1 gene polymorphisms and hepatocellular carcinoma (HCC) risk. METHODS: The genetic polymorphisms were studied at an aflatoxin highly contaminated region in Guangxi, China. Pdymerase chain reaction (PCR) technique was used to detect the presence or absence of the GSTM1 and GSTT1 genes in blood samples. The case group was composed of 181 patients of HCC identified by the pathologists and the control group was composed of 360 adults without any tumor. RESULTS: The frequencies of GSTM1 and GSTT1 null genotypes in the control were 47.8% and 42.7%, while those in the HCC group were 64.6% and 59.7%, respectively. The differences between HCC group and control group were very significant (P<0.01). GSTM1 and GSTT1 combined null genotypes in HCC group and control group were 38.2% and 18.5% respectively, and the difference was significant (P<0.05). CONCLUSION: The GSTM1 and GSTT1 null genotypes are associated with an increased risk of HCC in a special geographic environment. Combination of the two null genotypes in an individual is substantially increased twice the risk of HCC.     

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.     

Human glutathione S-transferase A1, T1, M1, and P1 polymorphisms and susceptibility to prostate cancer in the Japanese population

Purpose: The incidence of prostate cancer is increasing in low-risk populations such as Japanese. One of the causes of this increase is considered to be associated with the Western diet, especially the high intake of red meat and fat. Glutathione S-transferase (GST) A1, T1, M1, and P1 are phase II enzymes that are important for activation and detoxification of chemical carcinogens.Methods: In this study, 190 Japanese male patients with prostate cancer and 294 healthy controls, frequency-matched for age, were compared for frequencies of GSTA1, GSTT1, GSTM1, and GSTP1 genotypes.Results: Among smokers, the frequency of the GSTA1*A/*B or *B/*B genotype in patients with prostate cancer (27.8%) showed a statistically significant increase compared with the control group frequency (18.2%; odds ratio [OR] =1.72; 95% CI, 1.01–2.94). In addition, the frequency of GSTT1 nondeletion genotype was associated with prostate cancer among smokers (OR =1.68; 95% CI, 1.06–2.68). The OR of carrying the combined genotyping of GSTA1*A/*B or *B/*B and GSTT1 nondeletion was 2.08 (95% CI, 1.14–3.80) with the combined genotyping of GSTA1*A/*A and GSTT1 null as a reference. On the other hand, no significant associations were observed for genotypes of GSTM1 and GSTP1 I105V.Conclusions: These findings suggest that the GSTA1 and GSTT1 polymorphisms are associated with prostate cancer susceptibility, especially among smokers.     

XPA、XPC、XPD、XRCC1基因单核苷酸多态性与急性淋巴细胞白血病易感性的关系

目的 研究中国人群DNA修复基因XPA A23G、XPC C499T和A939C、XPD T751G、XRCC1 G399A和C194T单核苷酸多态性与急性淋巴细胞白血病(ALL)遗传易感性的关系。方法 采用病例-对照研究方法,以Mass-ASSAY平台的基质辅助激光解吸电离飞行时间串联质谱(MALDI-TOF-MS)技术对114例确诊的ALL病例和169例年龄、性别相匹配的正常对照者进行多态性检测,比较不同基因型与ALL风险的关系。结果 与携带XPA 23AA基因型者相比,携带至少1个23G等位基因(即23GG和23AG基因型)的个体ALL风险是其2.02倍(95％CI1.08 ～3.78),而同时有XPAA23G和XPC C499T 2个位点突变者ALL风险是其5.60倍(95％ CI 1.57～19.90)。XPD T751G、XRCC1 G399A和C194T多态性与ALL易感性之间无显著相关性。结论 XPA A23G和ⅪC C499T 多态性可能与中国人群ALL遗传易感性有关,且存在显著的协同效应。     

Adenosine diphosphate ribosyl transferase and x-ray repair cross-complementing 1 polymorphisms in gastric cardia cancer

BACKGROUND & AIMS: Adenosine diphosphate ribosyl transferase (ADPRT) and x-ray repair cross-complementing 1 (XRCC1) are major DNA base excision repair proteins acting interactively in repair processes. This study examined the effects of ADPRT Val762Ala and XRCC1 Arg399Gln polymorphisms on ADPRT-XRCC1 interaction in vitro in cells and their contributions to gastric cardia adenocarcinoma (GCA) risk. METHODS: The ADPRT-XRCC1 interaction in cells transfected with ADPRT and XRCC1 variant complementary DNA (cDNA) constructs were examined by immunoprecipitation and immunoblotting analysis. Genotypes were analyzed in 500 patients and 1000 controls, and odds ratios (ORs) were estimated by logistic regression. RESULTS: Interactions between ADPRT-762Val and XRCC1-399Arg or XRCC1-399Gln were robust, but interactions between ADPRT-762Ala and either XRCC1-399Arg or XRCC1-399Gln were very weak. A case-control analysis showed ORs of 2.17 (95% CI, 1.55-3.04) and 1.61 (95% CI, 1.06-2.44) for GCA in the ADPRT Ala/Ala or XRCC1 Gln/Gln genotype carriers, respectively, compared with noncarriers. Gene-gene interaction of ADPRT and XRCC1 polymorphisms increased the OR of GCA in a multiplicative manner (OR for the presence of both ADPRT Ala/Ala and XRCC1 Gln/Gln genotypes, 6.43; 95% CI, 1.80-22.97). A supermultiplicative joint effect between the ADPRT polymorphism and smoking was observed. The ORs (95% CIs) of the Ala/Ala genotype for nonsmokers and smokers who smoked < or = 24 or > 24 pack-years were 1.44 (0.89-2.32), 2.00 (1.09-3.67), or 3.19 (1.59-6.42), respectively (Ptrend test = .008). CONCLUSIONS: The ADPRT and XRCC1 polymorphisms confer host susceptibility to GCA, which might result from reduced ADPRT-XRCC1 interaction and attenuated base excision repair capacity.     

GSTT1及GSTM1与急性髓系白血病疗效及预后的研究

目的探讨谷胱甘肽硫转移酶(GSTs)家族中GSTT1和GSTM1基因多态性与急性髓系白血病(AML)疗效,药物不良反应与预后的关系。方法AML患者180例,用多重PCR方法检测GSTT1和GSTM1基因型,比较不同基因型患者的诱导治疗完全缓解(CR)率,药物不良反应发生率,总体生存期,无复发生存期和复发率。结果(1)GSTT1和GSTM1基因双非缺失型(double-present型)患者一疗程CR率高于GSTT1,GSTM1任一基因缺失型(null型),二者差异有统计学意义(P=0.013),GSTT1/GSTM1的null基因型患者发生不CR的危险度是double-present型患者的8.736倍(95%CI1.146~66.574)。GSTT1present型一疗程CR率高于GSTT1null型,二者比较亦有统计学意义(P=0.021,OR=2.572,95%CI1.136~5.826);(2)GSTT1和GSTM1基因型分布与诱导治疗后中性粒细胞<0.5×109/L及PLT<20×109/L持续时间差异无统计学意义,GSTM1null型患者发生AST异常的危险度是GSTM1present型的2.593倍(P=0.016,95%CI1.176~5.717);(3)double-present型总体和无复发生存期较GSTT1/GSTM1的null型患者长(平均总体生存期为68.4、38.5个月,P=0.028;平均无复发生存期为73.5、34.9个月,P=0.014),GSTT1null型患者无复发生存期短于GSTT1present型患者(平均无复发生存期为26.7、64.3个月,P=0.038),但二者总体生存期无统计学意义(P=0.653)。double-present型患者复发率显著低于GSTT1/GSTM1的null型患者(13.3%、35.6%,P=0.019)。结论GSTT1,GSTM1基因型与AML患者治疗CR率、复发率、化疗的不良反应及预后均有显著相关性,GSTT1和GSTM1基因型有助于指导AML患者个体化治疗方案的制定。