Genetic polymorphism of glutathione S-transferase T1 gene and susceptibility to idiopathic azoospermia or oligospermia in northwestern China

Aim： To investigate the association of glutathione S-transferase T1 （GSTT1） gene polymorphism in patients with idiopathic azoospermia or oligospermia in the northwestern China population. Methods： In the case-control study, GSTT1 genotypes were identified by multiplex polymerase chain reaction （PCR） with peripheral blood DNA samples from 78 patients with idiopathic azoospermia, 103 patients with idiopathic oligospermia and 156 age-matched controls with normal sperm concentration and motility, according to the criteria adapted from World Health Organization guidelines. All of the patients and controls were from northwestern China. Results： There is a significant association between GSTT1 null genotype with idiopathic azoospermia risk （odds ratio [OR]： 2.36, 95% confidence interval [CI]： 1.33-4.20, P = 0.003） or idiopathic oligospermia risk （OR： 2.00, 95% CI： 1.17-3.27, P = 0.010）. Conclusion： GSTT1 null genotype is a predisposing risk factor for sporadic idiopathic azoospermia or oligospermia in northwestern China. （Asian J Androl 2008 Mar; 10： 266-270）

Genetic dissection of glutathione S-transferase omega-1:identification of novel downstream targets and Alzheimer's disease pathways

Alzheimer's disease(AD)is affected by genetic factors.Polymorphisms in the glutathione S-transfe rase omega-1(Gsto1)gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD.Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to chara cterize the mechanisms underlying regulation of Gstol variation regulation and to identify network membe rs that may contribute to AD risk or progression.Allele-specific assays confirmed that variation in Gstol expression is controlled by cis-expression quantitative trait loci.We found that Gstol mRNA levels were related to several central nervous system traits,such as glial acidic fibrillary protein levels in the caudate putamen,co rtical gray matter volume,and hippocampus mossy fiber pathway volume.We identified 2168 genes whose expression was highly correlated with that of Gsto1.Some genes were enriched for the most common neurodegenerative diseases.Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD,such as APP,Grin2 b,Ide,and Psenen.To evaluate the relationships between Gstol and candidate network members,we transfected astrocytes with Gstol siRNA and assessed the effect on putative downstream effecto rs.We confirmed that knockdown of Gstol had a significant influence on Pa2g4 expression,suggesting that Pa2g4 may be a downstream effector of Gstol,and that both genes intera ct with other genes in a network during AD pathogenesis.

Association of polymorphisms in glutathione S-transferase genes （GSTM1, GSTT1, GSTP1） with idiopathic azoospermia or oligospermia in Sichuan, China

The reported effects of the glutathione S-transferase （GSTs） genes （GSTM1, GSTTI, and GSTP1） on male factor infertility have been inconsistent and even contradictory. Here, we conducted a case-control study to investigate the association between functionally important polymorphisms in GST genes and idiopathic male infertility. The study group consisted of 361 men with idiopathic azoospermia, 118 men with idiopathic oligospermia, and 234 age-matched healthy fertile male controls. Genomic DNA was extracted from the peripheral blood, and analyzed by polymerase chain reaction and restriction fragment length polymorphism analysis. There was a significant association between the GSTP1 variant genotype （lle/Val ＋ Val/Val） with idiopathic infertility risk （odds ratio [OR]： 1.53; 95% confidence interval [CI]： 1.11-2.11; P = 0.009）. Similarly, a higher risk of infertility was noted in individuals carrying a genotype combination of GSTTI-null and GSTP1 （lle/Val ＋ ValNal） （OR： 2.17; 95% Cl： 1.43-3.31; P = 0.0002）. These results suggest an increased risk of the GSTPI variant genotype （lle/Val ＋ Val/Val） for developing male factor infertility. Our findings also underrate the significance of the effect of GSTM1 and/or GSTT1 （especially the former） in modulating the risk of male infertility in males from Sichuan, southwest China.

Relationship between polymorphisms of genes encoding microsomal epoxide hydrolase and glutathione S-transferase P1 and chronic obstructive pulmonary disease

Background Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD) However, only 10%-20% of chronic heavy cigarette smokers develop symptomatic disease COPD is most likely the result of complex interactions between environmental and genetic factors Genetic susceptibility to COPD might depend on the variations in enzyme activities that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) In this study, we investigated the relationship between polymorphisms in the genes encoding mEH and glutathione S-transferase P1 (GSTP1) and COPD in a Chinese population Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to find mEH polymorphism in exon 3 (Tyr113→His), exon 4 (His139→Arg) and GSTP1 polymorphism in exon 5 (Ile105→Val) in 100 COPD patients and 100 age- and sex-matched healthy controls Results The proportion of mEH exon 3 heterozygotes was significantly higher in patients with COPD than that in the control subjects (42% vs 32%) The odds ratio ( OR ) adjusted by age, sex, body mass index (BMI) and cigarette years was 2 96 (95% CI 1 24-7 09) There was no marked difference in very slow activity genotype versus other genotypes between COPD patients and the controls When COPD patients were non-smokers, the OR of very slow activity genotype versus other genotypes was more than 1 00; and when COPD patients were smokers (current smokers and ex-smokers), the OR was less than 1 00 There was no significant difference in GSTP1 polymorphism adjusted by age, sex, BMI and smoking between COPD patients and the controls Conclusions mEH exon 3 heterozygotes might be associated with susceptibility to COPD in China The interaction might exist between mEH genotype and smoke The gene polymorphism for GSTP1 might not be associated with susceptibility to COPD in the Chinese population

Glutathione S-transferase P1 IlelO5Val Polymorphism and Male Infertility Risk： An Updated Meta-analysis

Background： Several studies concerning the association between glutathione S-transferase P1 （GSTP1） Ilel05Val polymorphism and male infertility risk have reported controversial findings. The present study was aimed to explore this association using a recta-analysis. Methods： The PubMed, EMBASE, China National Knowledge Infrastructure （CNKI）, and Wanfang databases were searched. Odds ratios （ORs） with 95% confidence intervals （C/s） were calculated to estimate the strength of the association. Results： A total of 3282 cases and 3268 controls in nine case-control studies were included. There was no significant association between GSTP1 llel05Val polymorphism and male infertility in the overall population, but significant associations were lbund under the dominant （OR = 1.23, 95% CI = 1.04-1.46, F = 32.2%） and heterozygote （OR = 1.29, 95% C1 - 1.08-1.53, F = 26.8%） models after excluding studies for which the data did not satisfy Hardy-Weinberg equilibrium （HWE）. Similarly, subgroup analyses revealed no significant association in Asians or Chinese population although a significant association was apparent among Chinese population in studies with HWE under the heterozygote model （OR = 1.25, 95% CI = 1.03-1.52, F = 44.1%）. Significant heterogeneity could be observed in some genetic models, but this heterogeneity was not significant when stratified by HWE. No evidence for publication bias was found. Conclusions： The GS-FP1 lle105Val polymorphism might not be associated with male infertility risk, and thus additional well-designed studies with larger sample size are warranted.

Genetic polymorphisms of GSTM1,GSTP1 and GSTT1 genes and lung cancer susceptibility in the Bangladeshi population

Objective:To verify possible associations between polymorphisms of glutathione S-transferase Mu(GSTM1),glutathione S-transferase θ(GSTT1) and glutathione S-transferase Pi(GSTP1)genes and susceptibility to lung cancer.Methods:A total of 106 lung cancer patients and 116 controls were enrolled in a case-control study.The GSTM1 and GSTT1 were analyzed using PCR while GSTP1 was analyzed using PCR-restriction fragment length polymorphism.Risk of lung cancer was estimated as odds ratio at 95%confidence interval using unconditional logistic regression models adjusting for age,sex,and tobacco use.Results:GSTM1 null and GSTT1 null genotypes did not show a significant risk for developing lung cancer.A significandy elevated lung cancer risk was associated with GSTP1 heterozygous,mutant and combined heterozygous+mutant variants of rs1695.When classified by tobacco consumption status,no association with risk of lung cancer was found in case of tobacco smokers and nonsmokers carrying null and present genotypes of GSTM1 and GSTTL There is a three-fold(approximately) increase in the risk of lung cancer in case of both heterozygous(AG) and heterozygous+mutant homozygous(AG+GG) genotypes whereas there is an eightfold increase in risk of lung cancer in cases of GG with respect to AA genotype in smokers.Conclusions:Carrying the GSTM1 and GSTT1 null genotype is not a risk factor for lung cancer and GSTP1Ile105 Val is associated with elevated risk of lung cancer.

GENETIC DELETION OF DETOXIFIC ENZYME GSTM1 AND GSTT1 AS A HOST SUSCEPTIBLE FACTOR FOR NASOPHARYNGEAL CARCINOMA

Objective: To study the gene polymorphisms of GSTT1 and GSTM1 in nasopharyngeal carcinoma (NPC) patients and controls in an incidental area to evaluate the relationship between specific genotype and genotype combinations of these polymorphisms with the risk of NPC. Methods: Cases and controls all came from the Southwestern Guangxi. DNAs were extracted from their WBC. PCR technique was used to calculate the deletion rate of the two detoxific enzyme genes. Results: In this high risk area of NPC, the residents had high level deletion rates of 47.4% (64/135) M1 and T1 40.7% (55/135). The deletion rates were even higher in NPC patients, 61.5% (56/91) for M1 and 59.3% (54/91) for T1 respectively. There were statistical significances compared with control, P<0.05 and P<0.01 for M1 and T1 respectively. The difference was more significant in terms of combined M1 and T1 deletion between patients and controls x2=12.533, P=0.002. Conclusion: The combined deletion of detoxific enzyme genes GSTM1 and GSTT1 may be an important genetic susceptible factor for NPC in Guangxi.

Relationship of GSTM1 and GSTT1 genetic variant and markers of oxidative stress and inflammation in smokers with coronary artery disease

Objective： To investigate the role of glutathione S-transferase （GST） genetic variants and markers of oxidative stress and inflammation in smokingrelated coronary artery disease （CAD） patients. Methods： Five hundred and thirty-five Chinese CAD patients were successfully genotyped. Plasma total antioxidant status （TAOS）, glutathione, C-reactive protein （CRP）, fibrinogen（FIB） and white blood cell count （WBC） were determined to evaluate the oxidative stress and inflammatory response. Results： GSTM1-0/ GSTT1-0 subjects had a higher CRP, FIB, WBC and GSH and a lower TAOS compared to patients with wild-type GSTM1/GSTT1 genes, but there was significant difference only with regards to TAOS. Smokers with the null genotype of GSTT1 had the highest CRP and the lowest TAOS and GSH when compared to the GSTTI-1 genotype with smoking status, or the GSTT1-0 genotype with non-smoking status, or the GSTTI-I genotype with non-smoking status. However, we found no significant difference between these groups. Also, no significant interaction was observed between genotypes and smoking status in determining CRP levels. Conclusion： Our results suggest that GST polymorphisms do not modify the effect of smoking on markers of oxidative stress and inflammation in Chinese CAD patients.

GSTP1、XPG基因多态性与晚期非小细胞肺癌患者铂类药物化疗疗效及生存期的关系

背景与目的:本文旨在探讨谷胱甘肽S转移酶P1(glutathione S-transferase P1,GSTP1)基因A105G和人着色性干皮病G组(xeroderma pigmentatosum group G,XPG)基因C46T多态性与晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者对以铂类药物为主方案的化疗疗效及生存期的关系。方法:经病理学确诊的晚期NSCLC患者85例,化疗前取静脉血采用DNA测序法检测GSTP1 A105G和XPG C46T多态性,给予以铂类药物为主方案的化疗,2个周期后进行临床疗效评价(RECIST标准)并统计疾病进展时间(time to progression,TTP)和总生存时间(overall survival,OS),分析GSTP1 A105G和XPG C46T多态性与化疗疗效及生存期的关系。结果:85例晚期NSCLC患者中,GSTP1 A/G+G/G基因型和A/A基因型患者化疗有效率分别为43.59%和19.57%,差异有统计学意义(χ2=5.738,P<0.05);XPG C/C基因型和C/T+T/T基因型患者化疗有效率分别为42.86%和18.60%,差异有统计学意义(χ2=5.886,P<0.05);联合多态性分析显示,同时携带GSTP1 A/G+G/G和XPG C/C基因型患者化疗有效率最高为44.74%,组间比较差异有统计学意义(P<0.05)。至随访结束,81例患者中位TTP为6.5个月,其中GSTP1 A/G+G/G基因型为8.0个月,A/A基因型为6.0个月,差异有显著统计学意义(χ2=14.688,P<0.01);XPG C/C基因型为7.5个月,C/T+T/T基因型为6.0个月,差异有显著统计学意义(χ2=10.897,P<0.01);联合多态性分析显示,同时携带GSTP1 A/G+G/G和XPG C/C基因型患者的中位TTP最长为8.0个月,组间比较差异有显著统计学意义(P<0.01)。78例患者中位OS为9.0个月,其中GSTP1 A/G+G/G基因型为11.0个月,A/A基因型为9.0个月,差异有显著统计学意义(χ2=14.522,P<0.01);XPG C/C基因型为10.5个月,C/T+T/T基因型为9.0个月,差异有显著统计学意义(χ2=12.136,P<0.01);联合多态性分析显示,同时携带GSTP1 A/G+G/G和XPG C/C基因型患者的中位OS最长为11.0个月,组间比较差异有显著统计学意义(P<0.01)。结论:GSTP1 A105G和XPG C46T多态性可单独及联合用于预测晚期NSCLC患者对以铂类药物为主方案的化疗疗效及生存期,初步提示可以根据患者基因型来指导个体化治疗。

GSTP1基因多态性与新疆维、汉肺癌易感性的关系

目的探讨谷胱甘肽S转移酶P1基因（glutathione S-transferase P1,GSTP1）rs1695位点多态性与新疆地区维吾尔族（维族）和汉族肺癌患者的相关性。方法采用病例—对照研究方法,选取维族、汉族肺癌患者各80例作为病例组,另以维族、汉族健康人群各80例为对照组,运用限制性片段长度多态性聚合酶链反应（PCRrestriction fragment length polymorphism,PCR-RFLP）技术检测GSTP1基因Ile105Val多态性,分析其基因型频率在2个民族间分布的差异。结果 （1）GSTP1基因rs1695位点多态性在对照组与病例组中的分布均符合HardyWeinberg平衡;（2）在维族人群中,GSTP1基因rs1695位点基因型在病例组与对照组中的分布频率差异无统计学意义（P〉0.05）。在汉族人群中,携带G等位基因者发生肺癌的风险增加（OR=2.170,95%CI：1.146~4.107,P〈0.05）;（3）维族人群突变型杂合子AG和纯合子GG基因型频率均高于汉族,其中在对照组中维族GSTP1（GG）基因型频率较汉族高1.3倍（8.8%vs 3.8%）,但差异均无统计学意义（均P〉0.05）。结论 GSTP1基因rs1695多态性与汉族人群肺癌发病风险相关,与维吾尔族人群无关,其相关性具有民族差异。

Impact of SNP-SNP interactions of DNA repair gene ERCC5 and metabolic gene GSTP1 on gastric cancer/atrophic gastritis risk in a Chinese population

AIM To investigate the interactions of the DNA repair gene excision repair cross complementing group 5(ERCC5) and the metabolic gene glutathione S-transferase pi 1(GSTP1) and their effects on atrophic gastritis(AG) and gastric cancer(GC) risk.METHODS Seven ERCC5 single nucleotide polymorphisms(SNPs)(rs1047768, rs2094258, rs2228959, rs4150291, rs4150383, rs751402, and rs873601) and GSTP1 SNP rs1695 were detected using the Sequenom MassA RRAY platform in 450 GC patients, 634 AG cases, and 621 healthy control subjects in a Chinese population.RESULTS Two pairwise combinations(ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) influenced AG risk(P_(interaction) = 0.008 and 0.043, respectively), and the ERCC5 rs2094258-GSTP1 rs1695 SNP pair demonstrated an antagonistic effect, while ERCC5 rs873601-GSTP1 rs1695 showed a synergistic effect on AG risk OR = 0.51 and 1.79, respectively). No pairwise combinations were observed in relation to GC risk. There were no cumulative effects among the pairwise interactions(ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) on AG susceptibility(P_(trend) > 0.05). When the modification effect of Helicobacter pylori(H. pylori) infection was evaluated, the cumulative effect of one of the aforementioned pairwise interactions(ERCC5 rs873601-GSTP1 rs1695) was associated with an increased AG risk in the case of negative H. pylori status(P_(trend)= 0.043).CONCLUSION There is a multifarious interaction between the DNA repair gene ERCC5 SNPs(rs2094258 and rs873601) and the metabolic gene GSTP1 rs1695, which may form the basis for various inter-individual susceptibilities to AG.

Proteome analysis and tissue array for profiling protein markers associated with type B thymoma subclassification

Background The prognostic relevance of World Health Organization （WHO） subtypes within type B thymomas is still controversial. Understanding of the molecular characteristics of the different histologic types of thymomas will provide meaningful information for diagnosis and therapeutic management in type B thymoma. Methods Proteins extracted from twelve type B thymoma tissue specimens （six type B1 and six type B2） were analyzed by two-dimensional electrophoresis （2-DE） coupled with MALDI-TOF-MS. Differentially expressed proteins were then assayed in sixty-nine type B thymoma tissues （including B1, B2 and B3） by tissue array analysis with immunohistochemistry staining. The relationship of their expression with clinicopathological parameters, such as tumor stage or WHO classification, was estimated by Spearman＇s Rank Correlation Test. Results Sixteen differentially expressed proteins between type B1 and B2 thymoma tissues were identified. The differential levels of ezrin and glutathione S-transferase pi （GSTP1） were validated using immunohistochemistry staining. A statistically significant difference was observed in the positive rate of ezrin expression between type B1 thymoma and type B3 thymoma （Z= -2.963, P 〈0.01）. Ezrin showed a tendency to be expressed in higher classification tumors from type B1 to B3. A statistical analysis demonstrated that type B2 and B3 tumors had significantly higher positive expression of GSTP1 than the B1 group （type B2 vs. BI： Z= -2.582, P 〈0.01; type B3 vs. BI： Z= -4.012, P 〈0.001）. The results also showed a strong correlation between GSTP1 and WHO type staging of B1 to B3 tumors （Spearman＇s correlation coefficient： 0.633, P 〈0.001）. Statistical analysis showed that there was close correlation between GSTP1 and ezrin expression with the clinical stage （Spearman＇s correlation coefficients, ezrin： 0.481, P 〈0.05; GSTPI： 0.484, P 〈0.01）. Conclusions Differentially expressed proteins between type B1 and B2 thymoma tissues were analyzed by comparative proteomic analysis. The techniques of proteomic analysis and tissue array provide a potential tool for screening of key molecules in type B thymoma histological sub-classifications. The statistical analysis of ezrin and GSTP1 expression by immunohistochemistry, especially GSTP1, may be a useful approach for type B thymoma classification.