Glutathione S-transferase P1 Gene Research Articles

Association of Glutathione S-Transferase P1 (GSTP1) Gene Polymorphism with the Response to Platinum Based Chemotherapy in Patients with Non-Small Cell Lung Cancer

Abstract Background Lung cancer is one of the most commonly diagnosed cancers and despite therapeutic advances, mortality remains high. Platinum based chemotherapy remains the mainstay of adjuvant or first line chemotherapy in non small cell lung cancer (NSCLC) treatment, pathophysiological features along with genetic background significantly influence therapeutic efficacy of platinum-based chemotherapy. GSTP1 gene is a member of the cytosolic superfamily of glutathione-S-transferases, which is responsible for phase II detoxification enzymes that convert various reactive metabolites to more water-soluble and less harmful forms by conjugating them with glutathione. The genetic polymorphism GSTP1 rs1695 is associated with decreased substrate specific catalytic activity and the reduced enzyme activity which may reduces platinum detoxification, thus promoting better response rates to platinum-based chemotherapy. Aim of the Work In the present study was aimed to investigate the association of GSTP1 gene polymorphism with the response to platinum based chemotherapy in patients with NSCLC in order to prevent the non necessary exposure to the toxic effect of chemotherapy. Patients and Methods The study was a retrospective cross sectional study conducted on 50 NSCLC patients who were recruited from the Oncology clinic in Ain Shams University Hospitals, twenty of them were responders to platinum based chemotherapy and the other 30 were not responders according to RECIST criteria. All subjects underwent full medical history focusing on tobacco smoking and family history of cancers, thorough clinical examination, histological diagnosis of NSCLC and TNM classification, radiological studies: computed tomography of chest and abdomen and laboratory investigations in the form of: complete blood picture (CBC), liver function tests and kidney function tests. Detection of the GSTP1 rs1695 (A/G) polymorphism by real-time PCR was done for both the responders and the non responders group. Results There was no statistically significant difference between the responders’ and non responders’ groups regarding the genotypic distribution (p > 0.05). However, the G allele was significantly higher in the responders’ group compared to the non responders’ group with p value < 0.05. Conclusion The present study did not confirm the presence of significant association between the genotypic frequencies of the GSTP1 rs 1695 among the responders and the non responders group, but despite that it showed that the A allele was significantly higher in the non responders’ group compared to the responders’ group. However, the G allele was significantly higher in the responders’ group compared to the non responders’ group. Further studies with higher sample size are needed to clarify the association.

Flexible bioelectronic innovation for personalized health management

Flexible bioelectronic innovation for personalized health management

Association of GSTP1 and PLCE1 gene polymorphisms with primary esophageal cancer

To assess the association of polymorphisms of glutathione S-transferase P1 (GSTP1) and phospholipase C epsilon-1 (PLCE1) genes with the susceptibility of primary esophageal cancer and their interaction with environmental factors. 162 patients with primary esophageal cancer and 162 healthy controls were recruited in this cross-sectional study. Basic information such as gender, age, history of smoking and alcohol consumption and family history of esophageal cancer were collected. Single nucleotide polymorphisms at A105G locus of GSTP1 gene and rs3765524, rs2274223 and rs3781264 loci of PLCE1 gene were detected. A logistic regression model was established to analyze the risk factors of esophageal cancer and the interaction among the factors. The proportions of individuals with smoking history, family history of esophageal cancer and hot diet in esophageal cancer group were higher than those in the control group (P<0.05). Conditional Logistic regression analysis showed that smoking, family history of esophageal cancer and GG genotype at the rs2274223 locus of PLCE1 gene were the risk factors for esophageal cancer (P<0.05), and AG/GG genotypes at the A105G locus of GSTP1 gene were the protective factors for esophageal cancer (P<0.05). In the two-factor interaction model, both AA genotype at A105G locus of GSTP1 gene and GG genotype at rs2274223 locus of PLCE1 gene had an interaction with smoking, and the risk of esophageal cancer has increased by 83.6% and 85.7%, respectively (P<0.05). AA genotype at A105G locus of GSTP1 gene, GG genotype at rs2274223 locus of PLCE1 gene and smoking constituted the best three-factor interaction model, and the risk of esophageal cancer has increased by 244.0% (P<0.05). Four-factor interaction model analysis showed that the risk of esophageal cancer among individuals with AA genotype at A105G locus of GSTP1 gene, GG genotype at rs2274223 locus of PLCE1 gene, smoking and family history of esophageal cancer has increased by 264.4% (P<0.05). The AG and GG genotypes at the A105G locus of GSTP1 gene are protective factors for esophageal cancer, and the GG genotype at rs2274223 locus of PLCE1 gene is a risk factor, both of them may interact with smoking and affect the susceptibility to esophageal cancer.

Potential role of glutathione S-transferase P1 gene polymorphism and metabolic syndrome in lower urinary tract symptoms attributed to benign prostatic hyperplasia.

The aim of the study is to investigate the effects of glutathione S-transferase P1 (GSTP1) gene polymorphism and metabolic syndrome (MS) on lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH). This study included 195 patients diagnosed with LUTS secondary to BPH as case group, divided into simple BPH group (S-BPH group) and combined with MS group (MS-BPH group). Control group included 200 healthy elderly men without LUTS. Use peripheral blood samples detected the GSTP1 gene polymorphism (Ile 105 Val A → G polymorphism) by polymerase chain reaction-restriction fragment length polymorphism. Recorded age, GSTP1 gene polymorphism, international prostate symptom score (IPSS), prostate volume (PV), residual urine volume (RV), maximal urinary flowrate (Qmax), and prostate-specific antigen (PSA) to statistical analysis. Pairwise compared between control group, S-BPH group and MS-BPH, the PV (P < 0.001), PSA (P < 0.001), RV (P < 0.001), Qmax (P < 0.001), IPSS (P < 0.001), frequencies of GSTP1 gene (P < 0.05) were shown significant different, and MS-BPH group had larger PV, and more severe LUTS. In case group, variation genotypes (GSTP1 A/G + G/G) always had larger PV, higher PSA and IPSS, more RV and lower Qmax than homozygote (GSTP1 A/A) and the comparison were significant different (P < 0.05). Variation genotypes were positively correlated with PV (β = 0.092, P < 0.001), RV (β = 0.228, P = 0.004), IPSS (β = 0.274, P = 0.038), PSA (β = 1.243, P < 0.001) and negatively correlated with Qmax (β = -0.362, P = 0.025). In patients with BPH, GSTP1 variation genotypes and MS might be potential risk factors for faster progression of benign prostatic enlargement and LUTS, which might increase the surgical rate. ChiCTR-IPR-14005580.

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.

Pyrethroid exposure: as determinant of CYP1A1 and GSTP1 genetic variations in occupationally exposed Sindh farmers

Pyrethroid (PYR) is a class of pesticide which was frequently applied in agricultural fields of Sanghar in Pakistan. Consistent and over use of PYR may lead to health effects on workers who are occupationally exposed to pesticides every day. For assessment of PYR toxicity, Cytochrome-P450 (CYP1A1) and Glutathione–S-transferase P1 (GSTP1) code for xenobiotic metabolizing enzymes (XME) were investigated in Sanghar exposed studied population. To execute the case-control study, a total of 200 blood samples from PYR-exposed and control subjects were collected. Prior informed consent was taken from all the subjects. For determination of genetic variations, CYP1A1 (rs1048943) and GSTP1 (rs1695) regions were amplified using polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP). Resolved bands were visualized on 2 % agarose gel. Results indicated that in CYP1A1 polymorphism (rs1048943) there was no significant association between CYP1A1 genotypes AA, AG, GG and PYR toxicity (ϰ2= 2.03, p > 0.05) in exposed subjects. However, the impact of mutant allele G was further evaluated by genetic models, which demonstrated that G allele may show a risk for CYP1A1gene susceptibility to PYR exposure (OR: 8.608; CI: 1.056–70.172) p < 0.05 in dominant and in co-dominant model (OR:16.25; CI:1.94-135.84) p < 0.05 as well. In contrast, in GSTP1 (rs1695) polymorphism, a significant association was observed in genotypes AA, AG, GG (ϰ2= 8.03, p < 0.05) compared with control subjects. G allele may also exhibit a significant association with GSTP1 gene susceptibility and PYR-toxicity in co-dominant model (OR: 7.166; CI: 2.828–8.15) p < 0.001. This study may help to provide acquaintance about the pesticide hazardous effects.

Identification of circRNAs in the Liver of Whitespotted Bamboo Shark (Chiloscyllium plagiosum).

Whitespotted bamboo shark (Chiloscyllium plagiosum), a member of the cartilaginous fish family, has an extremely large liver and demonstrates a strong regeneration ability and immune regulation. Circular RNAs (circRNAs) is an important class of non-coding RNAs. Increasing evidences suggest that circRNAs are a kind of potential regulators. Recently, researchers have isolated and identified different circRNAs from various species, while few reports were on the circRNAs of C. plagiosum. In this study, we have identified a total of 4,558 circRNAs in the liver of C. plagiosum. This finding suggests that circRNAs are not evenly distributed in the chromosomes and follow the GT-AG rule during cyclization. Alternative back-splicing might exist in shark circRNAs as shown by the authenticity identification of predicted circRNAs. The binding strength of circRNAs (<2,000 bp) and the detected miRNAs in shark liver were simultaneously analyzed to construct an mRNA–miRNA–circRNA network for the Glutathione S-transferase P1 gene, and the circRNA authenticity was simultaneously verified. Our data provide not only novel insights into the rich existence of circRNAs in marine animals, but also a basis for characterizing functions of identified circRNAs in the liver homeostasis of C. plagiosum.

Association analysis of rs1695 and rs1138272 variations in GSTP1 gene and breast cancer susceptibility.

Background:The glutathione S transferases P1 (GSTP1) is one of the common type of the GSTs family. This gene has several genetic polymorphisms that the rs1695 and rs1138272 are the most common variations in this gene. This study aimed to examine the association of these genetic variations with breast cancer risk which was followed by bioinformatics analysis. Materials and Methods:In a case-control study, 200 participants including 100 women with breast cancer and 100 healthy women were enrolled. After blood sample collection and DNA extraction, the total genomic DNA was extracted from this sample. The SNPeffects online software was employed to evaluate the effects of rs1695 genetic variation on the GSTP1 protein structure. Results:Our data revealed that there is a significant association between rs1695 genetic variation and the risk of breast cancer in homozygote (OR= 3.1532, 95%CI= 1.1072 to 8.9798, p= 0.0315) and allelic (OR= 1.6098, 95%CI= 1.0577 to 2.4500, p= 0.0263) genetic comparisons. This despite the fact that the rs1138272 polymorphism was not associated with breast cancer risk. Our bioinformatics analysis based on WALTZ output showed that the rs1695 polymorphism reduces the amyloid propensity of the GSTP1 enzyme (dWALTZ= -228.00). Conclusions:Based on our findings, the rs1695 genetic variation is a genetic risk factor for breast cancer and it could be considered as a biomarker for screening of susceptible women.

Association between GSTP1 gave polymorphisms and susceptibility to noise-induced hearing loss

Objective: To investigate the association between the single nucleotide polymorphisms (SNPS) at rs1695 and rs6591256 in glutathione S-transferase P1 (GSTP1) gene and susceptibility to noise-induced hearing loss in Chinese Han workers exposed to noise. Methods: A 1: 2 matched nested case-control study was performed, which based on the cohort of 6297 workers exposed to noise in an iron and steel plant in Henan, China, who were followed up from January 1, 2006 to December 31, 2015. According to the criteria of binaural average high-frequency hearing threshold ≥40 dB, a total of 292 workers were enrolled as hearing loss group; after the adjustment for sex, type of work, age (difference≤5 years) , and working years of noise exposure (difference≤2 years) , according to the criteria of binaural average high-frequency hearing threshold <35 dB, and the speech frequency hearing threshold of any ear at any frequency band ≤25 dB, a total of 584 workers were enrolled as control group. The single nucleotide polymorphisms (SNPs) of rs1695 and rs6591256 in GSTP1 were genotyped by high throughput SNP genotyping assay. Hardy-Weinberg equilibrium of control group was checked. The association between the SNPs at the two loci and susceptibility to NIHL was analyzed. Results: The L(Aeq, 8 h) range of workers exposed to noise was 80.2-98.8 dB (A) . The risk of NIHL in individuals with allele G of rs1695 was 1.291 times of those with allele A (95%CI: 1.042-1.598, P<0.05) . The risk of NIHL in individuals with allele G of rs6591256 was 1.390 times of those with allele A (95%CI: 1.119-1.728, P<0.05) . The risk of NIHL in individuals with AG and GG genotypes of rs6591256 was 1.437 times of those with AA genotype (95%CI: 1.057-1.952, P<0.05) . With the increase of noise exposure duration, individuals with AG and GG genotypes of rs6591256 had a higher risk of NIHL than those with AA genotype (HR=1.273, 95%CI: 1.002-1.616, P<0.05) . Conclusion: The allele G of rs1695 and rs6591256 may be risk factors of NIHL.

274P - Identification of GSTP1 transferred by extracellular vesicles responsible for adriamycin-resistance in breast cancer cells

BackgroundAnthracycline/taxane-based chemotherapy is frequently used to treat breast cancer. However, not all patients respond to chemotherapy due to naturalor acquired chemo-resistance. Glutathione S-transferase P1(GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. MethodsWe identified GSTP1 as a drug-resistance-related factor by microarray. Then, we used cell apoptosis and immunofluorescence staining to confirm the ability of GSTP1-containing exosomes in conferring drug resistance. And the knockdown of GSTP1 gene was performed to found the influence of drug-resistance. Furthermore, the role of GSTP1 and its relationship with exosomes was proved by analysed 40 pairs of breast cancer tissues by IHC. Then, the levels of GSTP1 in serum exosomes were detected in 28 patients treated with neoadjuvant chemotherapy(NAC). ResultsBy microarray data, we found that GSTP1, which located in extracellular exosome, is higher in Adriamycin(ADR)-resistant cell line compared with its parental cell line. Then, we also confirmed a higher expression of GSTP1 protein in ADR-resistant cells by immunofluorescence staining and western blot. Moreover, the addition of GSTP1-containing exosomes can increase the resistance to ADR in sensitive cells. Also, we found that a higher expression GSTP1 in the PD/SD group than in the PR/CR group in 40 paired samples collected before and after chemotherapy. Similar results were obtained for the exosomal marker tumor susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. We further explored the levels of GSTP1 in serum exosomes of 28 patients treated with anthracycline/taxane-based NAC, and discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were higher than those in the PR/CR group. ConclusionsGSTP1-containing exosomes appeared to be essential in conferring resistance to anti-cancer drugs. We explored the predictive role of GSTP1 in circulating exosomes as a biomarker for chemo-sensitivity in patients treated with anthracycline/taxane-based chemotherapy. Legal entity responsible for the studyJinhai Tang. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Multidrug resistance affects the prognosis of primary epithelial ovarian cancer.

Multidrug-resistant tumor cells can tolerate different structures, functions and antidrug action mechanisms, therefore, allowing these cells to respond to various structurally unrelated mechanisms of different chemotherapy drugs and to exhibit cross-resistance. The present study aimed to investigate the role of Multi-drug resistance gene (MDR1), Placental glutathione S-transferase-P1 (GSTP1), Lung resistance protein (LRP) and Ras association domain family member 1 (RASSF1A) in primary epithelial ovarian cancer (PEOC). The mRNA (protein) expression levels of MDR1, product P glycoprotein, LRP and GSTP1 were evaluated with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis in all tissue samples, ovarian cancer cell line A2780 and A2780/DDP. Methylation-specific PCR (MSP) was used to detect RASSF1A gene methylation in all tissue samples. The resistance genes/proteins were either poorly or not expressed in A2780, however were highly expressed in A2780/DDP cell line. The expression of resistance genes/proteins decreased following different concentrations of zebularine-stimulated A2780/DDP. Hypermethylation and low expression of RASSF1A gene were detected in PEOC and A2780/DDP. Subsequent to being exposed to different concentrations of zebularine-stimulated A2780/DDP, the RASSF1A methylation level was decreased, while the unmethylation level was increased. The expression of RASSF1A gene/protein was gradually restored, and the gene/protein expression was enhanced with the increase in drug concentration. Multivariate logistic regression indicated that the expression level of gene LRP and GSTP1 was a risk factor for PEOC prognosis. Furthermore, the expression of LRP and GSTP1 in the negative-group survival curves was higher compared with the positive group. High expression of resistance genes may serve an important role in cancer primary resistance. Low expression caused by hyper-methylation of RASSF1A gene may serve an important role in cancer-acquired resistance in PEOC. The present study suggested that resistant gene expression may be a potential prognostic biomarker.

Association of glutathione-S-transferase p1 gene promoter methylation and the incidence of prostate cancer: a systematic review and meta-analysis.

Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer. The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots. Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60-35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer. Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.

Glutathione S-transferase T1, M1 and P1 gene polymorphisms and susceptibility to colorectal cancer, a Syrian population study

Colorectal cancer (CRC) is considered to be the third most common cancer worldwide, and it is the fourth most common cause of cancer deaths. CRC is described as multifactorial disease. Among others, Glutathione S-transferases are known to act pro-carcinogenic in CRCs, however, they are needed for the conjugation between chemotherapeutics and a wide spectrum of xenobiotics. In this study, 70 patients with CRC and 85 healthy volunteers without any cancer history were genotyped. Polymorphism genotypes for the genes GSTP1, GSTT1 and GSTM1 were studied by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and/or multiplex polymerase chain reaction. Our finding showed a significant risk for CRC associated with GSTP1 heterozygous Ile/Val (OR = 1.8; 95% CI: 0.93–3.44; p = 0.009), while GSTP1 Val/Val homozygous was observed only in the CRC patients. Significant differences in the frequency of GSTM1- and GSTT1-null genotypes were found. The GSTT1-null genotype was higher in CRC group (34.3%) than in control group (12.9%) (OR = 3.5; 95% CI: 1.57–7.83; p = 0.001). The GSTM1-null was higher in CRC cases (42.8%) compared with control group (21.1%) (OR = 2.79; 95% CI: 1.38–5.64; p = 0.003).Individuals carrying combined, both GSTM1/GSTT1-null genotype, were associated with an estimated 7.56-fold higher risk to form CRC than those having GSTM1/GSTT1-present genotype. Individuals carrying combined three genotypes of GSTM1-null/GSTT1-null/ heterozygous Ile/Val genotype for GSTP1 were associated with an estimated 21.63-fold higher risk to be CRC than those carrying GSTM1-present/GSTT1-present/ Ile/Ile genotype of the GSTP1 (OR = 21.63; 95% CI: 2.39–195.82; p = 0.001). Also, individuals with combined three genotypes of GSTM1-null/GSTT1-present/ heterozygous Ile/Val genotype for GSTP1 were associated with an estimated 13.9-fold higher risk to be CRC than those carrying GSTM1-present/GSTT1-present/ Ile/Ile genotype of the GSTP1 (OR = 13.9; 95% CI: 2.60–74.35; p = 0.0007). Overall, the results of this pilot study in 70 patients revealed that the GSTM1-null genotype, alone or in combination with GSTT1-null genotype, GSTP1-heterozygous is associated with enhanced risk for CRC in Syrian population.

Are genetic polymorphisms of glutathione S-Transferase P1 gene associated with urothelial carcinoma of the urinary bladder?

Background: Polymorphisms in genes encoding glutathione S-transferase (GST) may affect susceptibility to develop urothelial carcinomas (UCs). One of the extensively studied genes in this group is GST P1 (GSTP1), but studies of the relationship of polymorphisms of GSTP1 and UC of the bladder have been equivocal. Hence, we assessed the association between genetic polymorphism of GSTP1 gene and the development of UC of the urinary bladder. Materials and Methods: This prospective, case–control study was conducted in the departments of urology and clinical genetics at a tertiary care teaching hospital in South India, which included 52 patients with histopathologically confirmed UC bladder and matched with 46 controls from August 2012 to July 2013. The study participants provided a single venous blood sample for extraction of genomic DNA. Laboratory personnel was blinded to sample groups. The primary outcome of the study was to detect association of genetic polymorphism of GSTP1 gene with UC of the bladder. The secondary outcome was to assess if the risk of urothelial bladder cancer is increased in smokers with polymorphism of GSTP1 gene. Statistical Analysis Used: We used the Chi-square or Fisher's (F) exact test to compare discrete variables. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Results: Although the heterozygous polymorphic genotype ile/val (AG) was seen more frequently in cancer group (34.6% vs. 23.9%), the difference was not statistically significant (P = 0.202). None of the smokers had homozygous polymorphic valine allele and GSTP1 did not add to the susceptibility of UC bladder even among smokers. Conclusions: A lack of association between GSTP1 313 G/G polymorphism and urothelial cancer of bladder was observed.

GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly

Biomarkers of clinical and therapeutic outcome in acromegaly are needed. Polymorphisms or epigenetic changes of detoxification genes, such as those coding for the aryl hydrocarbon receptor (AHR) and the glutathione-S-transferase-P1 (GSTP1), could have a role in GH secreting pituitary tumors' pathophysiology and clinical expression. In this study, we assessed the contribution of GSTP1 gene promoter methylation status, per se or in combination with the occurrence of the AHR gene rs2066853 variant, on clinical features and response to somatostatin analogs (SSA) treatment in acromegaly patients. This is an observational, retrospective study, carried out in the Endocrine Unit of an Italian University Hospital. We enrolled 77 wild-type AIP gene acromegaly patients, who have been screened for germline AHR rs2066853 variant and GSTP1 gene promoter methylation. Clinical and biochemical parameters were compared after patients' stratification according to GSTP1 methylation status and the presence of AHR rs2066853. We also evaluated the response to SSA treatment in 71 cases. 17 patients carried the AHR rs2066853 variant and 26 had methylated GSTP1 (GSTP1-methyl) gene promoter. GSTP1-methyl patients showed a higher prevalence of diabetes mellitus (p = 0.01), colonic polyps (p = 0.05), and were more resistant to SSA (p = 0.02) as compared to GSTP1 unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHR wild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHR rs2066853 variant were all resistant to SSA (p = 0.01). In acromegaly, GSTP1 gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHR rs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.

Glutathione s-transferase m1, t1, and p1 gene polymorphism in exudative age-related macular degeneration: a preliminary report.

To elucidate whether the gene polymorphisms of glutathione S-transferase (GST) M1, T1, and P1 are associated with the development of exudative age-related macular degeneration. The authors genotyped 35 white patients with exudative age-related macular degeneration and 159 healthy controls. Genomic DNA from peripheral blood was examined using polymerase chain reaction and defined for the genetic polymorphisms of GST. No association was observed between GSTM1, GSTT1, and GSTP1 polymorphisms and age-related macular degeneration risk (p>0.05). The frequencies of the combination of the GSTM1 (null) and GSTP1 (mutant), GSTM1 (null), and GSTT1 (null) genotype polymorphisms in patients with exudative age-related macular degeneration differed greatly from those of the control group (p=0.001 OR [95% CI]: 7.70 [2.28-25.98] and p=0.007 OR [95% CI]: 3.88 [1.51-10.02], respectively). The present study suggests that the GSTM1 (null) and GSTT1 (null), GSTM1 (null), and GSTP1 (mutant) combinations may be a genetic risk factor for the development of exudative age-related macular degeneration. However, the potential role of GST polymorphisms as a marker of susceptibility to age-related macular degeneration needs further studies in a larger number of patients. (Eur J Ophthalmol 2006; 16: 105-10).

An updated meta-analysis for association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer.

The conclusions on the association between glutathione S-transferase P1 (GSTP1) gene polymorphism and lung cancer risk are still debated. This meta-analysis was performed to update 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. Fifty reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and lung cancer susceptibility. The association between GSTPI G allele/GG genotype and lung cancer risk was found in this meta-analysis (G allele: odds ratio [OR] = 1.08, 95% confidence interval [CI]: 1.02-1.14, P = 0.006; GG genotype: OR = 1.09, 95% CI: 1.00-1.18, P = 0.04). However, the AA genotype was not associated with the susceptibility of lung cancer. GSTP1 G allele/GG genotype is associated with the lung cancer susceptibility.

Glutathione S-transferase P1 gene polymorphisms and susceptibility to coronary artery disease in a subgroup of north Indian population.

The present study aimed to investigate the association of g.313A>G and g.341C>T polymorphisms of GSTP1 with coronary artery disease (CAD) in a subgroup of north Indian population. In the present case-control study, CAD patients (n = 200) and age-matched, sex-matched and ethnicity-matched healthy controls (n = 200) were genotyped for polymorphisms in GSTP1 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotype distribution of g.313A>Gand g.341C>T polymorphisms of GSTP1 gene was significantly different between cases and controls (P = 0.005 and 0.024, respectively). Binary logistic regression analysis showed significant association of A/G (odds ratio (OR): 1.6, 95% CI: 1.08-2.49, P = 0.020) and G/G (OR: 3.1, 95% CI: 1.41-6.71, P = 0.005) genotypes of GSTP1 g.313A>G, and C/T (OR: 5.8, 95% CI: 1.26-26.34, P = 0.024) genotype of GSTP1 g.341C>T with CAD. The A/G and G/G genotypes of g.313A>G and C/T genotype of g.341C>T conferred 6.5-fold increased risk for CAD (OR: 6.5, 95% CI: 1.37-31.27, P = 0.018).Moreover, the recessive model of GSTP1 g.313A>G is the best fit inheritance model to predict the susceptible gene effect (OR: 2.3, 95% CI: 1.11-4.92, P = 0.020). In conclusion, statistically significant associations of GSTP1 g.313A>G (A/G, G/G) and g.341C>T (C/T) genotypes with CAD were observed.

Single nucleotide polymorphisms and microsatellites in the canine glutathione S-transferase pi 1 (GSTP1) gene promoter

BackgroundGenetic polymorphisms within the glutathione S-transferase P1 (GSTP1) gene affect the elimination of toxic xenobiotics by the GSTP1 enzyme. In dogs, exposure to environmental chemicals that may be GSTP1 substrates is associated with cancer. The objectives of this study were to investigate the genetic variability in the GSTP1 promoter in a diverse population of 278 purebred dogs, compare the incidence of any variants found between breeds, and predict their effects on gene expression. To provide information on ancestral alleles, a number of wolves, coyotes, and foxes were also sequenced.ResultsFifteen single nucleotide polymorphisms (SNPs) and two microsatellites were discovered. Three of these loci were only polymorphic in dogs while three other SNPs were unique to wolves and coyotes. The major allele at c.-46 is T in dogs but is C in the wild canids. The c.-185 delT variant was unique to dogs. The microsatellite located in the 5′ untranslated region (5′UTR) was a highly polymorphic GCC tandem repeat, consisting of simple and compound alleles that varied in size from 10 to 22-repeat units. The most common alleles consisted of 11, 16, and 17-repeats. The 11-repeat allele was found in 10% of dogs but not in the other canids. Unequal recombination and replication slippage between similar and distinct alleles may be the mechanism for the multiple microsatellites observed. Twenty-eight haplotypes were constructed in the dog, and an additional 8 were observed in wolves and coyotes. While the most common haplotype acrossbreeds was the wild-type *1A(17), other prevalent haplotypes included *3A(11) in Greyhounds, *6A(16) in Labrador Retrievers, *9A(16) in Golden Retrievers, and *8A(19) in Standard Poodles. Boxers and Siberian Huskies exhibited minimal haplotypic diversity. Compared to the simple 16*1 allele, the compound 16*2 allele (found in 12% of dogs) may interfere with transcription factor binding and/or the stability of the GSTP1 transcript.ConclusionsDogs and other canids exhibit extensive variation in the GSTP1 promoter. Genetic polymorphisms within distinct haplotypes prevalent in certain breeds can affect GSTP1 expression and carcinogen detoxification, and thus may be useful as genetic markers for cancer in dogs.

P 140 - GSTP expression influences the metabolism and redox of cellular glutathione

Recently we described the role of glutathione-S-transferase P-1 (GSTP) expression in regulating Nrf2 transcriptional activity by protein-protein interaction. A functional interplay between Nrf2 and GSTP to control glutathione (GSH) biosynthesis, detoxification function and signal transduction through protein Cys glutathionylation can be hypothesized. To explore such interplay the effect of GSTP gene manipulation on the cellular levels and redox of main thiols in murine embryonic fibroblasts (MEFs) was investigated. GSTP knockout MEFs showed increased levels of all the identified forms of thiols that included GSH, GSSG, GSSP, Cys, Cyss, CyssP, HCys, HCyss, HCyssP, γ-GluCys and CysGly. The exposure to the Se-organic thiol-peroxidase compound Ebselen, further and massively up-regulated GSH, Cys and HCys and their corresponding disulfides in GSTP-KO, but not in wild-type (WT) cells. GSSP (protein glutathionylation), and to a lower extent HCyssP, increased after treatment with Se-organic compounds only in WT cells (confirmed by both HPLC and immunoblot analysis). These findings confirms the role of GSTP as a feedback component of Nrf2 pathway (control of GSH levels) and identify with an unbiased approach the role of this gene in mediating protein glutathionylation signalling during the exposure to Se-organic thiol-peroxidases.