GSTP1 Ile105Val Research Articles

Ile105Val polymorphism in the GSTP1 gene is associated with susceptibility to acute myeloid leukemia: an updated systematic review and meta-analysis

Background and Objective Several genetic variations are associated with acute myeloid leukemia (AML) susceptibility, including the GSTP1 Ile105Val polymorphism. Even with the existing meta-analysis conducted on the topic, no consensus has been reached since none of the studies available performed in-depth data analysis. Hence, we performed an updated systematic review and meta-analysis in this paper to obtain more precise estimates. Materials and Methods We searched various databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine whether the GSTP1 Ile105Val polymorphism is associated with AML susceptibility. Further statistical analysis was also done to obtain more accurate and reliable findings. Results A total of 15 studies are included in the systematic review, but only 9 were included in the meta-analysis due to the studies deviating from the Hardy-Weinberg equilibrium. The analysis showed significantly increased susceptibility to AML in the allelic, co-dominant, and recessive models. Furthermore, subgroup analysis noted increased AML susceptibility in the non-Asian population. Comparing the proportions of the genotypes and alleles showed a significantly higher proportion of the Val/Val genotype and Val allele in the non-Asian cohort. Conclusion The GSTP1 Ile105Val polymorphism is significantly associated with AML susceptibility, especially among non-Asians. Further investigation should be performed to strengthen the current results.

Glutathione S-transferase M1, T1, and P1 polymorphisms and periodontitis in a Caucasian population: a case-control study

BackgroundGlutathione S-transferases (GSTs) play important roles in protecting cells against oxidative stress and toxic chemicals. This study aimed to investigate the distribution of GSTM1, GSTT1, and GSTP1 variants and their roles in periodontitis susceptibility in a Caucasian population.MethodsWe analyzed 406 participants, including 204 healthy controls and 203 periodontitis patients. A multiplex polymerase chain reaction (PCR) approach was used to analyze GSTM1 and GSTT1 loci. GSTP1 variants were detected by PCR-haplotyping method in a subgroup of participants (N = 350). Chi-square or Fisher´s exact tests were used to compare genotypic and allelic differences. The Bonferroni method was applied to correct for multiple comparisons (pcorr).ResultsThe GSTM1 genotype distribution did not differ significantly between controls and periodontitis patients (p = 0.44). Additionally, the wild/null genotypes of GSTT1, Ile105Val and Ala114Val frequencies of GSTP1 were not significantly different between the two groups after correction for multiple comparisons (p = 0.05, p = 0.55, p = 0.02, pcorr>0.05, respectively). The GSTM1 and GSTP1 Ile105Val gene variants were similarly distributed between non-smokers and smokers in both groups (p = 0.38, p = 0.20, and p = 0.14, p = 0.35, respectively). However, the wild genotype of the GSTT1 and Ala114Ala variant of the GSTP1 genes were present more frequently in non-smoking periodontitis patients than in non-smoking controls (p = 0.03, pcorr>0.05, and p = 0.009, pcorr>0.05, respectively) although their frequencies did not differ between smoking periodontitis patients and smoking controls (p = 0.23, p = 0.68, respectively).ConclusionsThis study in a Czech Caucasian population did not confirm a highly significant association between GST gene variants and susceptibility to periodontitis, as previously reported by Arshad and colleagues in Pakistanis. However, a weak relationship between GSTT1 and GSTP1 rs1138272 polymorphisms and periodontitis in non-smokers was observed.

Interactive associations of eczema with glutathione S-transferase genes in relation to autism spectrum disorder and its severity in Jamaican children

BackgroundComorbidity of eczema withith autism spectrum disorder (ASD) is increasing. We investigated the associations of eczema and its possible interaction with polymorphisms in glutathione S-transferase (GST) genes in relation to ASD and ASD severity. MethodUsing data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of eczema with GST genes in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domain-specific comparison scores (CSs) by fitting general linear models. ResultsAfter adjusting for child’s age and history of breastfeeding, eczema had no additive association with ASD [Matched Odds ratio (MOR) and 95 % Confidence Intervals (CI): 1.04 (0.76, 1.41), P = 0.82] or ASD severity (all P > 0.20). Using a recessive genetic model, eczema was significantly associated with ASD only among children with the Val/Val genotype for the GSTP1 Ile105Val polymorphism [MOR (95 % CI) = 2.04 (1.02, 4.08), P = 0.04, P for interaction = 0.03]. In addition, among ASD cases with the GSTM1 DD genotype, those with eczema had a marginally significant higher mean ADOS-2 Social Affect CS than those without eczema (7.3 vs. 6.8, P = 0.08, P for interaction = 0.09). ConclusionOur findings suggest children with certain genotypes for GST genes may be more susceptible for comorbidity of eczema and ASD, which is consistent with the role of GST genes in both conditions.

Are there sex differences in interactive associations of environmental exposure to Lead (Pb), Mercury (Hg), and Manganese (Mn) with GST Genes (GSTP1, GSTT1, and GSTM1) in relation to ASD in Jamaican children?

BackgroundMale preponderance is well-established in children with autism spectrum disorder (ASD). Glutathione S-transferase (GST) genes play a crucial role in suppressing oxidative stress triggered by environmental stressors. ObjectiveTo determine whether the association between metals and ASD differs by sex and by GST genes. MethodsUsing data from 344 pairs of sex-and age-matched cases and controls, we assessed the association of each metal with ASD or ASD severity, by applying conditional logistic regression (CLR) or general linear models (GLM). Sex was assessed as an effect modifier in separate GST genetic models. ResultsFor Pb exposure, using a recessive model for the GSTP1 Ile105Val polymorphism, CLR revealed significant overall interaction between sex and GSTP1 (P = 0.04). However, sex-specific matched odds ratios revealed marginally lower odds of the Val/Val genotype among ASD cases than controls in females (MORfemales= 0.23 (95 % CI): 0.05–1.11, P = 0.06), but not among males (MORmales= 1.18 (95 % CI): 0.66–2.16, P = 0.57) in the adjusted model. GLMs for Hg exposure detected significant overall interactions in GSTP1 co-dominant and recessive genetic models. For example, the mean difference in ASD severity among children with Val/Val genotype compared to those with Ile/Ile or Ile/Val were MORfemales= −0.26 and MORmales= 1.30, respectively, in the adjusted model. ConclusionThe association of Pb and Hg with ASD significantly differed by sex under the GSTP1 co-dominant and recessive genetic models. Such findings reflect potential sex differences in metal detoxification mechanisms. Replication is warranted due to the limited sample size of female participants.

Prediction of uncontrolled course of bronchial asthma in children based on polymorphisms of genes of signaling molecules of the immune system and detoxification genes

Aim. To study the possibility of predicting the asthma control at various stages of the development of the disease, possibly on the basis of taking into account the genetic polymorphisms of Toll-like receptors, cytokines and detoxification system genes using the statistical method of learning neural networks.Materials and methods. We ex­amined 167 children with bronchial asthma. The degree of asthma control was determined, the following mutations were detected: TLR2-Arg753Glu, TLR4-Asp299Gly, TLR4-Ghr399Ile, TLR9-T1237C, TLR9-A2848G; IL4-C589T, IL6- C174G, IL10-G1082A, IL10-C592A, IL10-C819T, IL12B-A1188C, TNFa-G308A; GSTM, GSTT, GSTM/GSTT, GSTP1 Ile105Val, GSTP1 Ala114Val, by PCR. The STATISTICA Automated Neural Networks package was used to model neural networks.Results. The model is based on the MLP (15-9-3) multilayer perceptron architecture with a layer of 15 input neurons (by the number of analyzed variables), a hidden intermediate layer of 9 neurons and an output layer of 3 neurons by the number of values of the classified variable (control). The training algorithm was chosen by BFGS as the most adequate to the classification task. The error function is traditionally chosen as the sum of squared deviations. The activation function of output neurons is Softmax. The activation function of the intermediate layer is hyperbolic. The volume of the training sample was 88 sets. The volume of samples for testing and quality control of the model was 36 sets. The resulting model was able to predict 79.01% of the correct values of the target variable (the degree of asthma control).Conclusion. The application of the developed program makes it possible to predict the possibility of uncontrolled or partially controlled asthma at any stage of the disease, including preclinical and pre-nosological for groups with a high risk of asthma. This allows you to individually adjust the measures of secondary and even primary prevention of asthma within the personal­ization of therapeutic approaches.

Contribution of Glutathione-S-Transferases Polymorphism and Risk of Coronary Artery Diseases: A Meta-Analysis.

Oxidative stress is one of the risk components in the development of coronary artery diseases (CAD). Genetic polymorphism in major antioxidant genes like Glutathione- S-Transferases (GST) has been associated with increased CAD susceptibility and severity. To get a precise evaluation and to update the association, a meta-analysis on GST (GSTM1, GSTT1, and GSTP1) polymorphism with CAD was performed. Moreover, the combined effect of GSTM1/GSTT1 null genotypes on CAD risk has not yet been studied, but it has the highest risk of developing diseases. PubMed, Embase, and Web of Science were systematically searched for eligible studies. Case-control studies in the English language and with genotypic frequency were selected in order to provide data and calculate the odds ratio (OR). OR with 95% CI was calculated, and a random effect model was used. NOS scale was used to assess the quality of the included studies. Meta-analysis indicated that the GSTM1 null genotype and GSTP1 (Ile105Val) polymorphism is significantly associated with CAD risk with a pooled OR-1.38, p=0.01 for GSTM1 and OR-1.19, p=0.04 for GSTP1. The dual null genotype of GSTM1-GSTT1 has the highest risk for CAD development (OR-1.59, p=0.003), and there is no significant association between GSTT1 null genotype with CAD. In the subgroup analysis, GSTM1 showed an increased risk for Asians (OR- 1.68, p=<0.01) and smokers (OR-1.98, p=<0.01). Publication bias was not observed. The findings suggest that the GSTM1 and GSTP1 polymorphism can be a predictive factor for CAD risk, and a larger sample size is required further to confirm the association.

Interactions between Environmental Factors and Glutathione S-Transferase (GST) Genes with Respect to Detectable Blood Aluminum Concentrations in Jamaican Children.

Aluminum (Al) is a metallic toxicant at high concentrations following natural or unnatural exposures. Dietary intake is considered as the main source of aluminum exposure in children. We used data from 366 typically developing (TD) children (ages 2–8 years) who participated as controls in an age- and sex-matched case–control study in Jamaica. We investigated additive and interactive associations among environmental factors and children’s genotypes for glutathione S-transferase (GST) genes (GSTT1, GSTM1, GSTP1), in relation to having a detectable blood aluminum concentration (BAlC) of >5.0 μg/L, using multivariable logistic regression models. Findings from interactive models revealed that the odds of having a detectable BAlC was significantly higher among children who ate string beans (p ≤ 0.01), whereas about 40% lower odds of having a detectable BAlC was observed in children with higher parental education level, (p = 0.02). A significant interaction between consumption of saltwater fish and GSTP1 in relation to having a detectable BAlC using either co-dominant or dominant genetic models (overall interaction p = 0.02 for both models) indicated that consumption of saltwater fish was associated with higher odds of having a detectable BAlC only among children with the GSTP1 Ile105Val Ile/Ile genotype using either co-dominant or dominant models [OR (95% CI) = 2.73 (1.07, 6.96), p = 0.04; and OR (95% CI) = 2.74 (1.08, 6.99), p = 0.03]. Since this is the first study from Jamaica that reports such findings, replication in other populations is warranted.

Влияние генетического полиморфизма генов GSTM1, GSTT1 и GSTP1 на содержание металлов в крови у плавильщиков производства сплавов цветных металлов

Heavy metal ions are known to induce generation of a large number of reactive oxygen species (ROS). Glutathione S-transferases (GSTs) play an important role in adaptation and response to oxidative stress. GSTM1, GSTT1, and GSTP1 genes have numerous described polymorphisms, the most significant being GSTM1, GSTT1, and GSTP1 Ile105Val deletion ones. Our objective was to study the relationship between the genetic polymorphism of GSTM1, GSTT1, GSTP1 genes and blood levels of metals in smelter operators engaged in crude lead refining. We examined 55 male lead-refining furnace operators working at a non-ferrous metal alloy plant. Blood metal concentrations were measured by inductively coupled plasma mass spectrometry. GSTM1 and GSTT1 deletion polymorphisms were determined using real-time SYBR Green qPCR and that of GSTP1 Ile105Val – using a commercial SNP Screening Kit. Statistical data processing was carried out using the Mann – Whitney U-test. Blood levels of industry-specific metals were not statistically different between the workers with GSTT1 and GSTP1 genotypes. We established, however, that men with the null genotype of GSTM1 had significantly higher blood arsenic levels. Our findings indicate that a high blood arsenic level associated with occupational exposure may be attributed to the GSTM1 null genotype. This observation can be used to identify the most vulnerable groups of individuals at risk of overexposure to arsenic.

Effects of genetic polymorphisms of GSTM1, GSTT1, and GSTP1 genes on blood metal levels in non-ferrous metal alloy smelter operators

Heavy metal ions are known to induce generation of a large number of reactive oxygen species (ROS). Glutathione S-transferases (GSTs) play an important role in adaptation and response to oxidative stress. GSTM1, GSTT1, and GSTP1 genes have numerous described polymorphisms, the most significant being GSTM1, GSTT1, and GSTP1 Ile105Val deletion ones. Our objective was to study the relationship between the genetic polymorphism of GSTM1, GSTT1, GSTP1 genes and blood levels of metals in smelter operators engaged in crude lead refining. We examined 55 male lead-refining furnace operators working at a non-ferrous metal alloy plant. Blood metal concentrations were measured by inductively coupled plasma mass spectrometry. GSTM1 and GSTT1 deletion polymorphisms were determined using real-time SYBR Green qPCR and that of GSTP1 Ile105Val – using a commercial SNP Screening Kit. Statistical data processing was carried out using the Mann – Whitney U-test. Blood levels of industry-specific metals were not statistically different between the workers with GSTT1 and GSTP1 genotypes. We established, however, that men with the null genotype of GSTM1 had significantly higher blood arsenic levels. Our findings indicate that a high blood arsenic level associated with occupational exposure may be attributed to the GSTM1 null genotype. This observation can be used to identify the most vulnerable groups of individuals at risk of overexposure to arsenic.

Association of GSTT1, GSTM1 and GSTP1 (Ile105Val) mRNA Expression with Cardiometabolic Risk Parameters in Women with Breast Cancer and Comorbidities

Breast cancer (BC) and cardiometabolic diseases share a multifactorial and modifiable etiology, modulated by complex molecular pathways. Glutathione S-transferase (GST) plays a critical role, providing protection against xenobiotics and regulating levels of enzymes and proteins in the cell. GST variants have a significant impact on susceptibility to diseases whose pathogenesis involves oxidative stress, as is the case in many inflammatory diseases such as BC and cardiometabolic pathologies. However, the expression of these polymorphic variants has not been studied in BC. This study aimed to evaluate the presence of GST mRNA isoforms and their association with clinical and cardiometabolic parameters in women with BC. This was a case-control study, and a total of 57 participants were recruited. Concentrations of glucose and lipids in blood were measured in all the participants. GST variants (GSTT1, GSTM1 and GSTP1 Ile105Val polymorphism) were evaluated in all the participants by real-time PCR analysis. There was a significant association (p &lt; 0.05) between the frequency of GSTP1 and LDL-c in the BC group. However, the control group showed significant associations between blood pressure with GSTT1 and GSTP1 variants with total cholesterol (TC), LDL-c, VLDL-c and triacylglycerols (TG). Therefore, GSTT1 and GSTP1 variants could be emerging biomarkers to discriminate between BC cases related or not to cardiometabolic disease factors.

Reflection of p53 phenotype in tumor tissue by genotypic variants in glutathione S-transferases: An association with DNA damage in lung adenocarcinoma

BackgroundGenetic deficiency of glutathione S-transferase (GST) results in the accumulation of tobacco carcinogens. Consequently, the elevated risk of lung carcinoma is due to increased DNA damage and p53 caretaker gene mutational frequency. ObjectiveWhether GSTM1, GSTT1 deletion, and GSTP1 Ile105Val variants genotypes are associated with the relative risk of developing p53 mutant expression and DNA damage in patients with lung adenocarcinoma. MethodsGenetic polymorphisms in GSTM1 (+/−), GSTT1 (+/−), and GSTP1 (Ile 105 Val) were identified using restriction fragment length PCR. Subsequently, the p53 phenotype was categorized as the mutant type (>50 % and ++/+++ intensity on immunohistochemistry). Lymphocytic DNA damage was assessed using a comet assay. ResultsSmoking pack-years [median (Q1-Q3); 3.5; 37.3–60.5] were associated with p53 mutant expression. Pack-years in the wild-type p53 expression group (38; 18.5–48.5, p = 0.01). The GSTM1 (−/−) null genotype was significantly associated with the risk of p53 mutant expression (RR: 1.81, p = 0.03). GSTP1 (Val/Val) also showed a significant relative risk for p53 mutant phenotype (RR: 2.23, p = 0.04). In contrast, GSTT1 was not associated with the p53 phenotype. GSTM1 (−/−)/GSTP1 (Val/Val) combined genotype showed a significant additive effect on p53 mutant phenotypic expression (RR: 4.0, p = 0.019). DNA damage was significantly associated with GSTM1 (−/−), GSTT1 (−/−) deletion genotypes, and smoking (p = 0.001, p = 0.002 and p < 0.0001, respectively). However, the p53 phenotype was not associated with DNA damage in lymphocytes. ConclusionGSTM1 (−/−) and GSTP1 (Val/Val) genotypes increased the relative risk of the p53 mutant phenotype by two-fold. GSTM1 (−/−)/GSTP1 (Val/Val) amplified the risk of the p53 mutant phenotype by four-fold. DNA damage was significantly associated with smoking, GSTM1, and GSTT1 deletions.

Detoxification Role of Metabolic Glutathione S-Transferase (GST) Genes in Blood Lead Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Glutathione S-transferases (GST) are involved in the detoxification of exogenous chemicals including lead (Pb). Using data from 344 pairs of autism spectrum disorder (ASD) cases and age- and sex-matched typically developing (TD) controls (2–8 years old) from Jamaica, we investigated the interaction between three GST genes and ASD status as determinants of blood Pb concentrations (BPbCs). We found that ASD cases had lower geometric mean BPbCs than TD children (1.74 vs. 2.27 µg/dL, p < 0.01). Using a co-dominant genetic model, ASD cases with the Ile/Val genotype for the GSTP1 Ile105Val polymorphism had lower GM BPbCs than TD controls, after adjusting for a known interaction between GSTP1 and GSTT1, child’s parish, socioeconomic status, consumption of lettuce, fried plantains, and canned fish (Ile/Val: 1.78 vs. 2.13 µg/dL, p = 0.03). Similarly, among carriers of the I/I or I/D (I*) genotype for GSTT1 and GSTM1, ASD cases had lower adjusted GM BPbCs than TD controls (GSTT1 I*: 1.61 vs. 1.91 µg/dL, p = 0.01; GSTM1 I*: 1.71 vs. 2.04 µg/dL, p = 0.01). Our findings suggest that genetic polymorphisms in GST genes may influence detoxification of Pb by the enzymes they encode in Jamaican children with and without ASD.

GSTP1 Ile105Val and GPX1 Pro198Leu Polymorphisms and Their Association with Response to Radiotherapy in Nasopharyngeal Carcinoma Patients

Objectives: Radio-resistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment. Due to individual variations in radio-sensitivity, biomarkers are needed to tailor radiation treatment. Within this frame, the identification of series of genetic signatures mainly SNPs for NPC patients treated with radiotherapy may help to predict treatment outcome and deliver personalized therapy. The aim of this study was to evaluate the possible association between the GSTP1 Ile105Val and GPX1 Pro198Leu polymorphisms and response to radiotherapy in NPC patients. Methods: From September 2016 to October 2018, a total of 101 patients with confirmed NPC, recruited at Mohammed IV Center for Treatment of Cancer of Casablanca, underwent radiotherapy. DNA was extracted from peripheral blood. Genotyping of the GPX1 Pro198Leu and GPX1 Val105Leu polymorphisms was carried out by PCR amplification and DNA sequencing. SPSS was used to analyse the association of GSTP1 and GPX1 genotypes with clinico-pathological features and response to radiotherapy. Results: The genotyping data revealed the presence of only two genotypes namely Pro/Pro (57.4%) and Pro/Leu (40.6%) for GPX1 gene. The allelic frequencies of C and T alleles were 78.7% and 21.3% respectively. For GSTP gene, the homozygous genotypes Val/Val and Leu/Leu were detected in 35.6% and 12.9% of patients respectively. The heterozygous genotype Val/Leu prevailed (51.5%). Allelic frequencies showed the presence of the two alleles A and G in 57.1% and 42.9% patients respectively. Statistical analysis failed to find any significant association between GSTP Val105Ile and GPX1 Pro198Leu genetic polymorphisms and socio-demographic and clinico-pathological features as well as response to radiotherapy (p>0.05). Conclusion: Further research is warranted on the potential role of SNPs within antioxidant defines genes in radiotherapy response and to identify reliable predictive and non-invasive biomarkers for radio-resistance among NPC patients for personalised therapies. Keywords: Nasopharygeal carcinoma, genetic polymorphisms, GSTP1, GPX1, radio-resistance, prognosis

Additive and Interactive Associations of Environmental and Sociodemographic Factors with the Genotypes of Three Glutathione S-Transferase Genes in Relation to the Blood Arsenic Concentrations of Children in Jamaica.

Arsenic (As) is a metalloid that has been classified as a xenobiotic with toxic effects on human beings, especially on children. Since the soil in Jamaica contains As, dietary intake is considered the main source of As exposure in Jamaicans. In addition, glutathione S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play an important role in the metabolism of xenobiotics including As in humans. Using data from 375 typically developing children (2–8 years) in Jamaica, we investigated the environmental and sociodemographic factors, as well as their possible interactions with the children’s genotype for GST genes in relation to having a detectable level of blood As concentration (i.e., >1.3 μg/L). Using multivariable logistic regression, we have identified environmental factors significantly associated with blood As concentrations that include a child’s age, parental education levels, and the consumption of saltwater fish, cabbage, broad beans, and avocado (all p < 0.01). Based on the multivariable analysis including gene x environment interactions, we found that among children with the Ile/Ile genotype for GSTP1 Ile105Val, children who consumed avocado had higher odds of having a detectable blood As concentration compared to children who did not eat avocado.

GSTP1 Ile105Val polymorphism among North Indian lung cancer patients treated using monotherapy and poly-pharmacy.

Genetic polymorphism within the P1 isoenzyme of the Glutathione-S-Transferase (GST) family is found to modulate and alter the enzyme activity of GSTP1 protein and thus may result in a change of sensitivity to platinum-based chemotherapy. We investigated the relationship between GSTP1 Ile105Val polymorphisms and overall survival, treatment response, and for both hematological and non-hematological toxicity of advanced North Indian lung cancer patients undergoing platinum-based double chemotherapy. The polymorphism of GSTP1 Ile105Val in North Indian lung cancer patients was assessed by polymerase chain reaction-restriction fragment length polymorphism. A total of 682 lung cancer patients were enrolled in the study, and it was observed that patients who were carrying both the mutant alleles (Val/Val) for the GSTP1 polymorphism showed a higher trend of median survival time (MST) as compared to the patients bearing the wild type of genotype (Ile/Ile) (MST = 8.30 vs. 7.47, p = 0.56). Based on toxicity profiling, we observed that lung cancer patients with the mutant genotype of GSTP1 (Val/Val) had an increased risk of leukopenia (OR = 2.41; 95% CI = 1.39-4.18, p = 0.001) as compared to subjects carrying both copies of the wild alleles (Ile/Ile). Our data suggested that patients with heterozygous genotype (Ile/Val) had a 2.14-fold increased risk of developing severe anemia (OR = 2.14, 95% CI = 0.97-4.62, p = 0.03). Our data also showed that in small cell lung carcinoma (SCLC) patients' polymorphism of GSTP1 was associated with thrombocytopenia (χ2 test = 7.32, p = 0.02). Our results suggest that GSTP1 Ile105Val polymorphism could be a predictive biomarker for hematological toxicity, like leukopenia and anemia, but not thrombocytopenia or neutropenia.

Allele and genotype frequencies of CYP3A4, CYP3A5, CYP3A7, and GSTP1 gene polymorphisms among mainland Tibetan, Mongolian, Uyghur, and Han Chinese populations.

Over 50% prescribed drugs are metabolised by cytochrome P450 3A (CYP3A) and glutathione S-transferase pi (GSTP1) adds a glutathione to the oxidative products by CYP3A, which increases the hydrophilic property of metabolites and facilitates the excretion. Single nucleotide polymorphisms (SNPs) of CYP3A and GSTP1show a diverse allele and genotype frequencies distribution among the world populations. The present study aimed to investigate the genotype and allele frequency distribution patterns of CYP3A4, CYP3A5, CYP3A7 and GSTP1 polymorphisms among healthy participants in mainland Tibetan, Mongolian, Uyghur, and Han Chinese populations. Blood samples were collected from 842 unrelated healthy subjects (323Tibetan, 134Mongolian, 162 Uyghur, and 223 Han) for genotyping analysis. Variant allele frequencies of CYP3A4 rs2242480, CYP3A5 rs776746, CYP3A7 rs2257401, and GSTP1 Ile105Val were observed in Han (0.253, 0.686, 0.312 and 0.188), Tibetan (0.186, 0.819, 0.192 and 0.173), Mongolian (0.198, 0.784, 0.228 and 0.235) and Uyghur (0.179, 0.858, 0.182 and 0.250) respectively. The allele frequency of CYP3A7*1C in Uyghur (0.019) was higher than that in Tibetan (0.002, p<0.01). There was a strong linkage disequilibrium between CYP3A4 rs2242480, CYP3A5 rs776746, and CYP3A7 rs2257401 among the four ethnic groups. The results might be useful for the precise medication in the Chinese populations.

Association of GSTP1 Ile105Val polymorphism with the risk of coronary heart disease: An updated meta-analysis.

BackgroundNumerous case-control studies have investigated the association between GSTP1 Ile105Val polymorphism and CHD risk, but the results from published studies were inconclusive. The present meta-analysis was performed to derive a more precise estimation.MethodsPubMed, EMBASE, and Web of Science database searches were conducted to retrieve relevant articles.ResultsUltimately, 5,451 CHD cases and 5,561 controls from 15 studies were included. Pooled analysis did not yield any statistically significant association between GSTP1 Ile105Val polymorphism and CHD risk for the overall population (Val vs. Ile: OR, 1.05; 95% CI, 0.93 to 1.18; Val/Val vs. Ile/Ile: OR, 1.09; 95% CI, 0.83 to 1.42; Val/Ile vs. Ile/Ile: OR, 1.09; 95% CI, 0.93 to 1.28; Val/Val vs. Val/Ile+Ile/Ile: OR, 1.04; 95% CI, 0.83 to 1.30; Val/Val+Val/Ile vs. Ile/Ile: OR, 1.14; 95% CI, 0.97 to 1.33). Subgroup analyses and sensitivity analyses indicated that GSTP1 Ile105Val polymorphism was still not associated with an increased risk of CHD. After excluding studies detected by Galbraith plots as major sources of heterogeneity, these relationships were still not significant.ConclusionsThe overall results did not reveal a major role of the GSTP1 Ile105Val polymorphism in modulating CHD risk. Well-designed studies with large sample sizes are needed to validate our findings and explore the possible gene-gene or gene-environment interactions.

Busulfan Pharmacogenetics and Drug Exposure in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Busulfan, a bifunctional alkylating agent widely used in conditioning regimens before hematopoietic stem cell transplantation (HSCT), is metabolized via glutathione-S-transferases (GSTs) and cytochrome P450 (CYP) enzymes. Busulfan demonstrates wide interpatient variability in pharmacokinetics (PK); high drug exposure is associated with increased risk of toxicities (e.g. veno-occlusive disease) and low drug exposure is associated with increased risk of relapse and graft failure. Drug exposure within a narrow therapeutic range yields optimal results. PK-guided dosing is used in many patients to achieve optimal drug exposure; however, better methods to select the initial dose would improve consistency of busulfan exposure and the likelihood of achieving the target area under the concentration-time curve (AUC). Previous pharmacogenomic (PGx) studies have identified GST polymorphisms as predictors of drug exposure, however, these were primarily performed in pediatric populations and/or Asians. We performed a PGx study in adult HSCT patients to identify polymorphisms in candidate genes associated with busulfan AUC and clearance.Methods: Buccal swabs were collected from HSCT patients scheduled to receive busulfan as part of their conditioning regimen on the day of admission (one day prior to initiating busulfan) between 04/28/14 and 06/06/2017. DNA was extracted using the GenElute™ Mammalian Genomic DNA Kit. A custom Ion AmpliSeq™ PGx Panel and various orthogonal methods were used to genotype the samples for polymorphisms in GSTA1 (135T>C), GSTM1 (null/present), GSTP1 (Ile105Val, Ala114Val), CYP2B6 (*2, *4, *5, *6, *18, *22), CYP2C8 (*2, *3), CYP2C9 (*2, *3, *8, *11), CYP2C19 (*2, *3, *17), and MTHFR (A1298C, C677T). Phenotypes were inferred according to established guidelines or literature. IV busulfan was administered once daily over 3 hours at 2.8 mg/kg (for autos) or 3.2 mg/kg (for allos) for a total of 4 doses. PK samples were obtained at 15 mins, 1 hr, 2 hrs, 3 hrs, and 5 hrs after the end of the first infusion. Non-compartmental analysis was performed to estimate PK parameters and doses 3 and 4 were adjusted to target an AUC of either 4500 or 5000 uM*min/L, depending on transplant type and conditioning regimen. The primary objective was to investigate the impact of polymorphisms on busulfan AUC, which was measured using univariate linear regression analysis adjusting for dose. Secondary objectives included a comparison of mean AUCs between phenotypes, which was measured using ANOVA, and to determine the association between SNPs and busulfan clearance using univariate linear regression adjusting for dose.Results: A total of 36 patients were evaluable for the primary endpoint. The median age was 47 (22-73) years, 56% were male, 75% received busulfan/cyclophosphamide/etoposide, 22% received busulfan/cyclophosphamide with post-transplant cyclophosphamide, and 3% received thiotepa/busulfan/cyclophosphamide. The genotype and inferred phenotype frequencies are summarized in Table 1. The mean AUC across all patients was 4255 µM*min/L (range 2834-5989). Results from the univariate linear regression analysis identified that CYP2B6 polymorphisms were significantly associated with busulfan AUC (intermediate [IM] vs. poor metabolizer [PM], p = 0.05; normal/rapid metabolizer [NM/RM] vs. PM, p = 0.02) (Table 2). The mean AUC in CYP2B6 PMs, IMs, NM/RMs was 5242, 4277, and 4134 µM*min/L, respectively (p = 0.03 by ANOVA test). There was no association of polymorphisms in GSTA1, GSTM1, GSTP1, CYP2C8, CYP2C9, CYP2C19 and MTHFR with AUC. CYP2B6 polymorphisms were also associated with busulfan clearance (IM vs. PM, p = 0.07; NM/RM vs. PM, p = 0.03).Conclusion: CYP2B6 polymorphisms were significantly associated with busulfan AUC and clearance; these appear to be an important determinant of drug exposure, however, GST polymorphisms did not replicate as significant, possibly due to differences in patient populations. PGx testing for CYP2B6 may provide an important tool to individualize up front dosing and improve the likelihood of achieving the target AUC earlier or to achieve target AUC in a higher proportion of the many patients who do not receive PK-guided dosing; however, our findings require further validation in larger cohorts of patients. We plan to enroll more patients and assess the relationship between PK, PGx and clinical outcomes, including toxicity and response. [Display omitted] DisclosuresTrivedi:Pharmacyclics: Consultancy, Honoraria. Grunwald:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; ARIAD: Consultancy; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Janssen: Research Funding. Ghosh:AbbVie: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jassen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding.

Polymorphism of GSTM1,GSTT1,GSTP1, and GSTA1 genes In Iraqi Population

One of the phase II enzymes that are responsible for detoxification of the body are Glutathione S-transferases (GSTs). Type and frequency of polymorphism of GSTs differ among the population. The current paper was designed to detect the polymorphisms in GSTM1, GSTT1, GSTP1 and GSTA1 genes among the Iraqi population, and the results were compared with other population. Data will be collected in the future to obtain a genetic map of the Iraqi population. To our knowledge, this study is the first done on the Iraqi population. In this study blood samples were collected from 110 healthy individuals (51 males and 59 females) aged between 15-50 years. The presence or absence of GSTM1 and GSTT1 genes was identified by multiplex-PCR. In addition, PCR-RFLP was used to detect polymorphism of GSTP1 (Ile105Val) and GSTA1 (A*/B*). The study revealed the frequencies of GSTM1 null, GSTT1 null, GSTP1 (Ile105Val), and GSTA1 A*/B* were 34.55%, 25.45%, 45.46%, and 41.82% respectively. The most frequently observed combinations were GSTM1 Present/GSTT1 Present/Ile/Val/A*/A* (18.18%). For the first time in Iraq by this study, four sequences were recorded in NCBI under the following accession numbers LC081235.1, LC090205.1, LC081236.1, and LC090206.1. These findings provide us the basic data for genotypes distribution and allele frequencies of GSTM1, GSTT1, GSTP1 and GSTA1 in the Iraqi population, and this is open a new prospect for further investigations by researchers in identifying differences between individuals in the genetic susceptibility of various diseases caused by environmental gene, rather than depending on results obtained from other populations.

Effects of GSTP1 Ile105Val polymorphism on both susceptibility and treatment response of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a multifactorial disease, which is caused by a complicated interaction between genetic and environmental agents. The Gluthation- S-transferase (GST) covers a family of multifunctional enzymes that involved in the detoxification of various toxic substances and anticancer drugs. Some polymorphisms in GSTs gene, could influence cancer susceptibility and drug resistance. The aim of the present study was to explore the influence of GSTP1 105 Ile/Val (rs1695) gene polymorphism on both CML susceptibility and response to Imatinib.DNA was extracted from blood samples by salting-out method; the Ile105Val polymorphism was genotyped in all participants (200 controls and 112 patients with chronic myeloid leukemia) by using PCR-RFLP method.The results of the present study revealed the absence of a significant association between GSTP1 105 Ile/Val gene polymorphism and CML risk, the variant allele Val was more frequent among controls (32%) than among patients (30)%). However, Hematologic response loss, cytogenetic resistance, side effects related to imatinib and none cytogenetic responders were more frequent among patients harboring val/val genotype compared with patients carrying Ile/ Ile and Ile/val genotypes.We have shown that this polymorphism is not associated with the risk of CML, but it influences the response of our patients treated by imatinib.