RESUMO
The current study aimed to investigate the relationship between polymorphisms in detoxifying (GSTM1, GSTT1, and GSTP1) genes and their association with colorectal cancer (CRC) in tobacco addicts of Pashtun ethnicity. Polymorphisms in the selected genes were genotyped in a case-control study consisting of 100 histologically confirmed male CRC patients and 100 birth-year and gender-matched healthy controls using the PCR−RFLP method. The GSTM1 null, and GSTT1 null genotypes were significantly contributed to the risk of CRC in the cases (OR= 3.131, 95% CI: 1.451−6.758, P = 0.004, and OR= 3.541, 95% CI: 1.716−7.306, P = 0.001, respectively), whereas the association observed for GSTP1 Val/Val (1.139, 95% CI: 0.356−3.644, P = 0.826) did not show statistical significance. The combined GSTM1 null and GSTT1 null showed a 41-fold increased risk (95% CI: 4.945−351.950, P = 0.001), while, the combined GSTM1 null and GSTP1 Ile/Val or Val/Val variant genotypes exhibited about 3-fold (95% CI: 1.196−7.414, P = 0.019) increased risk to CRC. Similarly, the combined GSTT1 null and GSTP1 Ile/Val or Val/Val variant genotypes showed about a 3-fold (95% CI: 1.285−8.101, P = 0.013) increased risk of CRC. In the combination of three GST genotypes, the GSTM1 null, GSTT1 null, and GSTP1 Ile/Val or Val/Val variant genotypes demonstrated a more than a 22-fold (95% CI: 2.441−212.106, P = 0.006) increased risk of CRC. Our findings suggest that GSTM1 and GSTT1 polymorphism and its combination with GSTP1 may be associated with CRC susceptibility in the Naswar addicted Pashtun population of Khyber Pakhtunkhwa, Pakistan.
O presente estudo teve como objetivo investigar a relação entre polimorfismos em genes desintoxicantes (GSTM1, GSTT1 e GSTP1) e sua associação com câncer colorretal (CCR) em tabagistas da etnia pashtun. Os polimorfismos nos genes selecionados foram genotipados em um estudo de caso-controle composto por 100 pacientes do sexo masculino com CCR, confirmados histologicamente, e 100 controles saudáveis, ââpareados por ano de nascimento e sexo usando o método PCR-RFLP. Os genótipos GSTM1 nulo e GSTT1 nulo contribuíram significativamente para o risco de CCR nos casos (OR = 3,131, IC 95%: 1,451-6,758, P = 0,004; OR = 3,541, IC 95%: 1,716-7,306, P = 0,001, respectivamente), enquanto a associação observada para GSTP1 Val/Val (1,139, IC 95%: 0,356-3,644, P = 0,826) não apresentou significância estatística. O GSTM1 nulo e o GSTT1 nulo combinados mostraram um risco 41 vezes maior (IC 95%: 4,945-351,950, P = 0,001) para CCR, enquanto os genótipos GSTM1 nulo e GSTP1 Ile/Val ou Val/Val combinados apresentaram risco cerca de 3 vezes maior (IC 95%: 1,196-7,414, P = 0,019) para CCR. Da mesma forma, os genótipos combinados GSTT1 nulo e GSTP1 Ile/Val ou Val/Val tiveram um risco para CRC cerca de 3 vezes maior (95% CI: 1,285-8,101, P = 0,013). Na combinação de três genótipos GST, os genótipos GSTM1 nulo, GSTT1 nulo e GSTP1 Ile/Val ou Val/Val apresentaram um risco 22 vezes maior (IC 95%: 2,441-212,106, P = 0,006) para CRC. Nossos achados sugerem que o polimorfismo GSTM1 e GSTT1 e sua combinação com GSTP1 podem estar associados à suscetibilidade ao CRC da população pashtun de Khyber Pakhtunkhwa, Paquistão, viciada em Naswar.
Assuntos
Humanos , Polimorfismo Genético , Nicotiana , Neoplasias Colorretais , GlutationaRESUMO
BACKGROUND AND AIM: Different studies have shown pharmacogenetic variants related to drug toxicity in acute myeloid leukemia (AML) patients. Our aim was to identify the association between ABCB1, CDA, DCK, GSTT1, and GSTM1 variants with clinical outcomes and toxicity in pediatric patients with AML. METHODS: Fifty-one confirmed de novo AML pediatric patients were included. A SNaPshot™ assay and conventional PCR were used to evaluate ABCB1, CDA, DCK, GSTT1, and GSTM1 variants. Clinical outcomes and toxicity associations were evaluated using odds ratios and Chi-square analysis. RESULTS: Patients carrying ABCB1 (1236C > T, rs1128503) GG genotype in had a 6.8 OR (CI 95% 1.08-42.73, p = .044) for cardiotoxicity as compared to patients carrying either AA or GA genotypes 0.14 OR (CI 95% 0.023-0.92, p = .044). For ABCB1 (1236G > A rs1128503/2677C > A/T rs2032582/3435G > A rs1045642) AA/AA/AA combined genotypes had a strong association with death after HSTC OR 13.73 (CI 95% 1.94-97.17, p = .009). Combined genotypes GG/CC/GG with CDA (79A > C, rs2072671) CA genotype or CDA (-451G > A, rs532545) CT genotype, had a 4.11 OR (CI 95% 2.32-725, p = .007) and 3.8 OR (CI 95% 2.23-6.47, p = .027) with MRD >0.1% after first chemotherapy cycle, respectively. CONCLUSION: Our results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, and might be useful as a future tool for patient stratification for treatment.
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Leucemia Mieloide Aguda , Farmacogenética , Humanos , Criança , Colômbia/epidemiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Genótipo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/uso terapêuticoRESUMO
In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4-13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the GSTT1 and GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of GSTM1 and GSTT1, respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54-186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.
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Arilamina N-Acetiltransferase , Doença Hepática Induzida por Substâncias e Drogas , Glutationa Transferase/genética , Tuberculose , Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Estudos Transversais , Citocromo P-450 CYP2E1/genética , Predisposição Genética para Doença , Genótipo , Humanos , Isoniazida , Peru/epidemiologia , Polimorfismo Genético , Tuberculose/tratamento farmacológico , Tuberculose/genéticaRESUMO
Glutathione S-transferase Mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) enzymes are glutathione-S-transferases with broad significance for susceptibility or resistance to multifactorial human diseases, as well as detoxification of environmental chemicals and drugs. Moreover, some individuals may have a complete deletion of GSTM1 and GSTT1 genes, which can contribute to patient-to-patient variability in drug safety and efficacy. GSTM1 and GSTT1 gene deletion frequencies can vary according to ethnicity and continental origin of the studied population with implications for achieving the goal of precision/personalized medicine in clinical practice. We report here a worldwide systematic review of the null genotypes in these two clinically important genes by continents, ethnicities, and therapeutic areas (TAs). Searches were performed in the PubMed database covering the period from 1992 to 2020. Out of the 1925 articles included, most studies analyzed European individuals, corroborating the literature failure for not adequately considering the non-European ethnicities. The frequency of GSTM1 and GSTT1 null genotypes was higher in patients than in healthy volunteers. Conversely, in East Asians, higher frequencies of the null genotypes were observed in healthy volunteers than patients. Oncology was the most intensively studied TA (57% of the articles) in relation to GSTM1 and GSTT1. In all, these results demonstrate that there is an important gap in the literature in terms of failure to consider a broader range of populations, as well as diseases wherein GSTM1 and GSTT1 variations have clinical and biological implications. To achieve precision/personalized medicine on a global/worldwide scale, with equity and inclusiveness, this knowledge/research gap ought to be remedied in studies of GSTM1 and GSTT1 null genotypes. To the best of our knowledge, this is the largest systematic review conducted to date addressing the GSTM1 and GSTT1 null genotypes worldwide. The analyses from the 1925 articles highlighted the current knowledge gaps in different TAs, ethnicities, and populations. Filling these gaps is of importance, given the role these genes play in relation to the metabolism of substances to which we have frequent contact with, the associations observed between their deletion and diseases such as cancer, in addition to the interethnic differences observed for the deletion frequencies of these genes.
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Etnicidade , Polimorfismo Genético , Humanos , Etnicidade/genética , Glutationa Transferase/genética , Genótipo , Glutationa/genética , Predisposição Genética para Doença , Fatores de Risco , Estudos de Casos e ControlesRESUMO
BACKGROUND: Important risk factors for the most common sexually transmitted infection (STI) in the world, human papillomavirus (HPV), include early sexual activity, use of contraceptives, tobacco smoking, and immunological and genetic factors. This study aimed to investigate the relationship between GSTM1 and GSTT1 polymorphisms and HPV infection and associated risk factors in a group of women assisted in the public health system of southwestern Paraná, Brazil. METHODS AND RESULTS: A case-control study was designed with 21 women with HPV matched by age in the case group and 84 women without the virus in the control group. Viral detection was conducted via polymerase chain reaction (PCR) and GSTM1 and GSTT1 genotyping by Multiplex PCR. The results showed that the GSTT1 null allele was a protective factor against infection (ORadj 0.219; 95% CI 0.078-0.618; p = 0.004). No relationship was observed for the GSTM1 gene. Smoking was defined as a risk factor (ORadj 3.678; 95% CI 1.111-12.171; p = 0.033), increasing the chances of HPV by up to 3.6 times. CONCLUSION: This study showed, for the first time, the relationship between GSTM1 and GSTT1 genetic polymorphisms and HPV. We found that this relationship protected women from southern Brazil from viral infection, but not from susceptibility.
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Glutationa Transferase/genética , Infecções por Papillomavirus , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/genética , Polimorfismo Genético/genética , Fatores de RiscoRESUMO
The GSTM1 and GSTT1 genes encode homonymous enzymes, which are responsible for the detoxification of several substances potentially harmful to the human body, such as air pollution, drugs, pesticides, and tobacco. However, some individuals may present a complete deletion of these genes and, consequently, an enzyme deficiency leading to an inadequate metabolism and, therefore, a higher susceptibility to some clinical conditions. Interethnic variations have also been described for both genes, making necessary the study of the deletion frequencies of GSTM1 and GSTT1 in different populations around the world. So, the aim of this study was to enable the synthesis and discussion of the main population differences of GSTM1 and GSTT1 polymorphisms in healthy volunteers. Searches were performed in the PubMed database, including 533 articles and 178,566 individuals in the analyses. We found an overrepresentation of European individuals and studies, and an underrepresentation of non-European ethnicities. Moreover, there are significant frequency differences among distinct ethnic groups: East Asians present the highest frequencies worldwide for GSTM1 and GSTT1 deletions, which could suggest higher disorders risk for this population; in contrast, Sub-Saharan Africans presented the lowest frequency of GSTM1 worldwide, corroborating evolution inferences performed previously for other genes codifying metabolism enzymes. Also, admixture is a relevant component when analyzing frequency values for both genes, but further studies focusing on this subject are warranted.
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Predisposição Genética para Doença , Glutationa Transferase , Genótipo , Glutationa Transferase/genética , Voluntários Saudáveis , Humanos , Polimorfismo GenéticoRESUMO
The study was conducted to evaluate the frequency of polymorphisms in GSTM1 and GSTT1 genes in patients with breast cancer compared with individuals without history of cancer, and the association of these polymorphisms with clinical/epidemiological parameters.There were evaluated 752 women (219 patients and 533 controls). Molecular analysis was performed by the Polymerase Chain Reaction (PCR). Statistical analysis was used multiple logistic regression and descriptive statistics.Age ≥ 50 years (OR = 3.22, 95% CI = 2.30-4.51, p < 0.001) and alcohol consumption (OR = 1.60, 95% CI = 1.13-2.27, p = 0.008) were associated to the development of breast cancer, while smoking and null genotypes GSTM1 and GSTT1 presented no association. GSTM1 and GSTT1 polymorphisms presented no relationship with the clinical and histopathological parameters or molecular subtypes of breast cancer. Ninety-two percent of tumours were invasive ductal, 66% were grade II, 65% were larger than 2 cm, the stages II (35.3%) and III (31.2%) were the most prevalent, and 47.7% were molecular subtype luminal B.Individuals aged ≥ 50 years and alcohol consumers have more chance to developing breast cancer. GSTM1 and GSTT1 polymorphisms are not associated to the risk of breast cancer.
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Neoplasias da Mama , Glutationa Transferase , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Genótipo , Glutationa Transferase/genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
The objective of this study was to identify and evaluate the impact of exposure to mixtures of organochloride pesticides (OCPs) in agricultural workers by detecting their effects on the activity of the enzyme glutathione S-transferase (GST) and the presence of polymorphisms of the GSTT1 and GSTM1 genes. The presence of OCPs was identified and quantified by gas chromatography, while spectrophotometry was used to measure enzymatic GST activity. The frequencies of the GSTM1 genotypes were analyzed by multiplex PCR. A total of 18 metabolites of OCPs were identified in the workers' blood, most of which are either prohibited (DDT and its metabolites p, p'DDD and p, p'DDE, dieldrin, endrin, aldrin) and/or restricted (δ hexachlorocyclohexane, cis chlordane, methoxychlor, and endosulfan). The results obtained indicate lower levels of GST activity at higher OCPs concentrations detected in blood from exposed workers, together with an increase in OCP levels in individuals who presented the GSTT1*0 and GSTM1*0 genotypes. These conditions place the detoxification process in agricultural workers with null polymorphisms in the GST genes and high concentrations of OCPs in the blood (especially DDT and its metabolites, DDD and DDE) at risk, and increase their susceptibility to develop serious diseases.
Assuntos
Hidrocarbonetos Clorados , Praguicidas , Genótipo , Glutationa Transferase/genética , Humanos , Hidrocarbonetos Clorados/análise , México , Praguicidas/análise , Polimorfismo GenéticoRESUMO
Toxicity refers to the potential of a substance such as a pesticide to cause damage to the structure or functions of an exposed organism. Pesticides can lead to harmful biological effects in exposed animals and their offspring over the medium and long term. They can affect the immunological, nervous, endocrine, and reproductive systems. DNA damage has also been linked to exposure to pesticides, and this damage can cause abortions, degenerative diseases, and cancer. The aim of this work was to establish whether women who are indirectly exposed to pesticides exhibit a compromised health status, including genotoxic effect. Women exposed indirectly to pesticides in Chimchanga and Colaisaca in the south of Ecuador underwent hematological and biochemical tests and micronucleus assay in buccal cells. The subjects were also genotyped for GSTM1, GSTT1, GSTP1, and PON1 polymorphisms, which can modify an individual's capacity to metabolize pesticides and relation with damage of DNA. The study revealed hepatic toxicity in Colaisaca women (AST and ALT) and an increase in the rate of micronucleus (MN) in Colaisaca individuals. In addition, genetic polymorphisms in PON1 and GSTP1 showed effects of modulating the frequency of karyolytic cells, karyorrhectic cells, and condensed chromatin cells.
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Dano ao DNA/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Praguicidas/toxicidade , Adolescente , Adulto , Idoso , Arildialquilfosfatase/genética , Equador , Feminino , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Humanos , Testes para Micronúcleos , Pessoa de Meia-Idade , Mucosa Bucal , Polimorfismo GenéticoRESUMO
PURPOSE: During recent decades, several reports have suggested a decrease in semen quality and DNA damage due in part to environmental toxicants and industrial chemicals. Among these xenobiotics, polycyclic aromatic hydrocarbons (PAHs) are of particular concern because of their remarkable mutagenic and carcinogenic properties and because several experimental and epidemiological studies have reported adverse effects of PAHs on male reproductive health and DNA structure. The aim of the study was to evaluate the association between 1-hydroxypyrene (1-OHP) urinary levels and sperm quality, DNA damage and the frequency of CYP1A1, GSTT1, and GSTM1 polymorphisms. METHODS: Semen, urine and blood samples were taken for sperm-quality assessment, 1-OHP urinary level measurement, DNA damage evaluation and polymorphism frequency analysis of three genes implicated in PAH metabolism in a total of 70 Mexican subjects exposed and nonexposed to PAHs. RESULTS: A significant decrease in sperm quality and increased DNA damage were registered in occupationally exposed volunteers. Polymorphisms modified the 1-OHP urinary levels; however, no associations were found between them. Inverse associations were registered between the sperm concentration/mL and 1-OHP levels and between tail lengths and the GSMT1 null genotype. CONCLUSIONS: Our data showed an inverse association between 1-OHP urinary levels and both sperm quality and the DNA integrity. Additionally, the heterozygote variants of CYP1A1-m1 and CYP1A1-m2 significantly increased the urinary excretion of 1-OHP, and the GSTM1 null variant was inversely associated with the comet parameters evaluated.
Assuntos
Citocromo P-450 CYP1A1/genética , Exposição Ocupacional/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Pirenos/urina , Espermatozoides/fisiologia , Adolescente , Adulto , Ensaio Cometa , Citocromo P-450 CYP1A1/urina , Dano ao DNA , Glutationa Transferase/sangue , Glutationa Transferase/genética , Humanos , Entrevistas como Assunto , Modelos Lineares , Masculino , México , Pessoa de Meia-Idade , Hidrocarbonetos Policíclicos Aromáticos/sangue , Hidrocarbonetos Policíclicos Aromáticos/urina , Polimorfismo Genético , Análise do Sêmen , Adulto JovemRESUMO
Glutathione S-transferases (GSTs) comprise a number of genes that codify for a group of isoenzymes that participate in phase II xenobiotic detoxification by means of conjugation with glutathione, producing hydrosoluble compounds. It has been demonstrated that some pesticides are substrates for GST isoenzymes. Floriculture is one of the main economic activities in the municipalities of Villa Guerrero and Atlacomulco; pesticides, applied as mixtures, are intensively used in this activity. In this study, total GST enzymatic activity and glutathione S-transferases theta 1 (GSTT1) enzymatic activity were calculated for a group of floriculture workers exposed to pesticides and for an unexposed group. The former comprised 169 floriculture workers, while the latter, 96 students. The value of the median GST enzymatic activity in the exposed group was 0.560 and 0.169 µmol/min/mL in the unexposed individuals. GSTT1 activity was 1.234 µmol/min/mL in the exposed group and 0.221 µmol/min/mL in the unexposed group. Mann-Whitney U test showed a significant difference between these groups, for both total GST and GSTT1, p < 0.001. Our results show that exposure to pesticides increases the activities of total GST and GSTT1 enzymes.
Assuntos
Fazendeiros , Glutationa Transferase/metabolismo , Exposição Ocupacional , Praguicidas/efeitos adversos , Humanos , Isoenzimas/metabolismo , MéxicoRESUMO
Breast cancer (BC) is the main worldwide neoplasia in women. The metabolic balance between xenobiotic absorption and elimination rates plays an important role in preventing DNA damage and, consequently, tumor development. The glutathione S-transferases (GSTs), such as GSTM1 and GSTT1, and the NAD(P)H quinone oxidoreductase are important enzymes involved in phase II detoxification reactions. Deletions in GSTM1 and GSTT1, and single-nucleotide polymorphism (SNP) in NQO1 (rs1800655) have been investigated in cancer context, revealing conflicting results. The present study analyzed these genetic polymorphisms in 121 BC patients and 151 BC-free controls in order to verify if they could act as susceptibility modifiers and/or prognostic factors. Binary logistic regressions adjusted by age were performed to assess associations between allelic variants and interactions in polymorphisms combination with BC susceptibility, but no significant association was found. Genotypes distribution was also compared between BC subtypes, but no significant difference was observed (p > 0.05). GSTM1 deletion was significantly associated with histopathological grade, with a greater proportion of patients presenting grade III tumors (p = 0.007). Univariate analysis identified tumor size as the only clinicopathological parameter potentially associated with recurrence risk in patients that received adjuvant chemotherapy (p < 0.1). Thus, logistic regression analysis adjusted by tumor size revealed a positive association between GSTT1 deletion and recurrence risk in general BC (OR 4.25; p = 0.04), while GSTM1 was negatively associated with recurrence risk in ER/PR+HER2- samples (OR 0.07; p = 0.03). In conclusion, the present study indicated that GSTT1 deletion was associated with increased recurrence risk, while GSTM1 correlated with worst prognosis parameters at diagnosis, but was negatively associated with recurrence risk in luminal subtype samples.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Glutationa Transferase/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Prognóstico , Resultado do TratamentoRESUMO
Abstract The GSTT1 and GSTM1 genes are key molecules in cellular detoxification. Null variants in these genes are associated with increase susceptibility to developing different types of cancers. The aim of this study was to determine the prevalence of GSTT1 and GSTM1 null genotypes in Mestizo and Amerindian individuals from the Northwestern region of Mexico, and to compare them with those reported worldwide. GSTT1 and GSTM1 null variants were genotyped by multiplex PCR in 211 Mestizos and 211 Amerindian individuals. Studies reporting on frequency of GSTT1 and GSTM1 null variants worldwide were identified by a PubMed search and their geographic distribution were analyzed. We found no significant differences in the frequency of the null genotype for GSTT1 and GSM1 genes between Mestizo and Amerindian individuals. Worldwide frequencies of the GSTT1 and GSTM1 null genotypes ranges from 0.10 to 0.51, and from 0.11 to 0.67, respectively. Interestingly, in most countries the frequency of the GSTT1 null genotype is common or frequent (76%), whereas the frequency of the GSMT1 null genotype is very frequent or extremely frequent (86%). Thus, ethnic-dependent differences in the prevalence of GSTT1 and GSTM1 null variants may influence the effect of environmental carcinogens in cancer risk.
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AIM: To analyze the association between oncohematological diseases and GSTT1/GSTM1/CYP1A1 polymorphisms, dietary habits and smoking, in an argentine hospital-based case-control study. METHODS: This hospital-based case-control study involved 125 patients with oncohematological diseases and 310 control subjects. A questionnaire was used to obtain sociodemographic data and information about habits. Blood samples were collected, and DNA was extracted using salting out methods. Deletions in GSTT1 and GSTM1 (null genotypes) were addressed by PCR. CYP1A1 MspI polymorphism was detected by PCR-RFLP. Odds ratio (OR) and 95%CI were calculated to estimate the association between each variable studied and oncohematological disease. RESULTS: Women showed lower risk of disease compared to men (OR 0.52, 95%CI: 0.34-0.82, P = 0.003). Higher levels of education (> 12 years) were significantly associated with an increased risk, compared to complete primary school or less (OR 3.68, 95%CI: 1.82-7.40, P < 0.001 adjusted for age and sex). With respect to tobacco, none of the smoking categories showed association with oncohematological diseases. Regarding dietary habits, consumption of grilled/barbecued meat 3 or more times per month showed significant association with an increased risk of disease (OR 1.72, 95%CI: 1.08-2.75, P = 0.02). Daily consumption of coffee also was associated with an increased risk (OR 1.77, 95%CI: 1.03-3.03, P = 0.03). Results for GSTT1, GSTM1 and CYP1A1 polymorphisms showed no significant association with oncohematological diseases. When analyzing the interaction between polymorphisms and tobacco smoking or dietary habits, no statistically significant associations that modify disease risk were found. CONCLUSION: We reported an increased risk of oncohematological diseases associated with meat and coffee intake. We did not find significant associations between genetic polymorphisms and blood cancer.
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This study aimed to evaluate whether GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G and NQO2 c.-102A>C polymorphisms, involved in xenobiotic detoxification pathways, alter outcomes of epithelial ovarian cancer (EOC) patients. DNA from 84 EOC patients diagnosed at the University of Campinas Academic Hospital from January 1995 and July 2007 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival and overall survival (OS) of EOC patients was examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox proportional hazard ratio (HR) regression analyses. The significant results of Cox analyses were validated using a bootstrap resampling study (1000 replications). At 60 months of follow-up, lower OS was seen in patients with GSTT1 null genotype (50.0 vs. 76.7 %, P = 0.02) compared with the other genotype (Kaplan-Meier estimate). This outcome remained the same in univariate Cox analysis (HR 2.22, P = 0.02). After multivariate Cox analysis, patients with GSTT1 null (HR 2.11, P = 0.04, P bootstrap = 0.04) and NQO2 AA (HR 2.13, P = 0.03, P bootstrap = 0.04) genotypes were under greater risks of progressing to death when compared with those with others genotypes. Our data suggest, for the first time, that inherited abnormalities in xenobiotic detoxification pathway related to GSTT1 and NQO2 c.-102A>C polymorphisms act as independent prognostic factors for OS of EOC patients.
Assuntos
Glutationa Transferase/genética , Neoplasias Epiteliais e Glandulares/enzimologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Quinona Redutases/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Glutationa S-Transferase pi , Humanos , Inativação Metabólica/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Xenobióticos/farmacocinética , Adulto JovemRESUMO
Disease manifestations or susceptibilities often differ among individuals exposed to the same concentrations of arsenic (As). These differences have been associated with several factors including As metabolism, sex, age, genetic variants, nutritional status, smoking, and others. This study evaluated the associations between four As metabolism-related gene polymorphisms/null genotypes with urinary As methylation profiles in girls and boys chronically exposed to As. In a total of 332 children aged 6-12 years, the frequency of AS3MT, GSTO1, GSTT1, and GSTM1 polymorphisms/null genotypes and As urinary metabolites were measured. The results revealed that total As and monomethyl metabolites of As (MMA) levels were higher in boys than in girls. No differences in the frequency of the evaluated polymorphisms were found between girls and boys. In AS3MT-Met287Thr carriers, %MMA levels were higher and second methylation levels (defined as dimethylarsinic acid divided by MMA) were lower. In children with the GSTM1 null genotype, second methylation levels were higher. In boys, a positive association between the AS3MT-Met287Thr polymorphism with %MMA and between the GSTO1-Glu155del and As(v) was found; whereas, a negative relationship was identified between AS3MT-Met287Thr and second methylation profiles. In girls, a positive association was found between the GSTO1-Ala140Asp polymorphism with second methylation levels. In conclusion, our data indicate that gender, high As exposure levels, and polymorphisms in the evaluated genes negatively influenced As metabolism. Environ. Mol. Mutagen. 57:516-525, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Arsênio/urina , Glutationa Transferase/genética , Metiltransferases/genética , Polimorfismo Genético , Poluentes Químicos da Água/urina , Arsênio/metabolismo , Criança , Exposição Ambiental/análise , Genótipo , Humanos , Metilação , Análise Multivariada , Fatores Sexuais , Fatores de Tempo , População Urbana , Poluentes Químicos da Água/metabolismoRESUMO
INTRODUCTION: Several studies have reported increased oxidation of lipids, proteins and DNA in the brains of patients with Alzheimer disease (AD). Moreover, these patients display differences in the activity and polymorphisms of the genes encoding the enzymes GST (T1, M1) and MnSOD. For these reasons, we designed a study of the variability in GSTT1, GSTM1, and MnSOD genes in healthy and AD groups from a Venezuelan population. METHODS: We included 179 unrelated Venezuelan subjects classified as either AD patients (n=79) or healthy individuals (n=100). Presence or absence of the GSTT1/GSTM1 genes was determined using PCR-SSP, and polymorphisms of MnSOD and APOE genes were identified with PCR-RFLP. RESULTS: The genotype GSTT1+/GSTM1- seems to favour development of AD (OR=2.06, P=.01). The risk level is higher when it is combined with the É4 allele of the APOE gene: GSTT1+/GSTM1-/É3É4 (OR=3.07, P=.05), GSTT1+/GSTM1-/É4É4 (OR=5.52, P=.02). The Ala-9Val polymorphism does not appear to be related to AD. However, the presence of the Ala/Ala genotype increases the risk provided by the É4 allele of the APOE gene: AlaAla/É3É4 (OR=3.47, P=.03), AlaAla/É4É4 (OR=6.3, P=.01). CONCLUSIONS: The results support the hypothesis that impaired mitochondrial function and increased oxidative damage are involved in the pathogenesis of AD. It is important to study other genes related to oxidative stress and antioxidant pathways which could be involved in susceptibility to AD.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Glutationa Transferase/genética , Superóxido Dismutase/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Polimorfismo Genético/genética , Venezuela/epidemiologiaRESUMO
The contemporary Venezuelan population is the product of major admixture process across various historical events, which has provided it a particular genetic background. The aim of this study concerns the analysis of glutathione S-transferase (GST) GSTM1, GSTP1 and GSTT1 genetic variants and five polymorphisms at the TP53 gene, which are related to cancer susceptibility, in an urban/admixed population and five Amerindian tribes (Bari, Panare, Pemon, Warao and Wayuu) from Venezuela. Genotyping was carried out in 120 individuals from an urban sample and 188 Amerindians. The analysis performed on TP53 haplotype and GST allele distribution showed a close correlation for Pemon and Warao populations, while Bari group appears isolated from the other populations. GSTT1 null variant frequency in our admixed (11%) and native samples (0.0-11.4%) was lower when compared with Caucasians, Africans and Asians. Frequency of the GSTP1*Val cancer-associated allele found in Bari (88.6%) and Panare (63.0%) is of the highest so far reported. Fourteen TP53 haplotypes were observed in the admixed populations, whereas only 3 to 5 in Amerindians. To our knowledge this is the first report of GST polymorphisms and TP53 haplotype distribution in Venezuelans. The distribution of most of analyzed polymorphisms in the urban sample is consistent with the admixed origin of the present-day population of Venezuela. While, the inter-ethnic variations in genetic polymorphisms found in Native American tribes seem to be the result of the influence of demographic factors. These results provide additional data for undertaking ethnographic and disease association studies in Venezuela.
Assuntos
Variação Genética , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Proteína Supressora de Tumor p53/genética , Alelos , Frequência do Gene , Genótipo , Humanos , Mutação , Neoplasias/genética , Venezuela/etnologiaRESUMO
Deletions in GSTM1 and GSTT1 genes are considered to be a risk factor for cancer development but the exact location of these deletions in the genome was unknown. Three main objectives of the current study were to: (a) identify the boundaries of these deletions in the human genome, (b) screen homozygous (-/-) and heterozygous (+/-) deleted, as well as homozygous present (+/+) individuals using PCR assays, (c) detect associations of pharyngeal (PC) and laryngeal cancer (LC) with the respective genotypes. In total, 102 PC and 92 LC patients were screened and compared with 150 controls. PCR mapping and sequencing revealed a 6 kbp deletion for GSTM1 and a 9 kbp deletion for the GSTT1 gene. The mean age of PC cases was 48.1 (±16.7) years; for LC cases it was 48.5 (±17.4) years and for controls 46 (±17.7) years. The OR (odds ratio) for the GSTM1 null genotype in PC and LC cases was 10.2 and 1.0 (95% CI 5.04-20.7 and 1.1-1.7) respectively. Similarly, for GSTT1 the OR was 4.02 with a 95% CI of 2.3-7.1 in PC cases. For LC cases the OR was 0.8 with 95% CI of 0.4-1.7. A non-significant number of LC and PC patients had heterozygous deletions of GSTM1 compared to controls (OD 0.5, 95% CI 0.2- 1.6 and OR 0.5, 95% CI 0.2- 1.5 respectively). The GSTT1 gene also showed a non-significant association in PC (OD 0.9, 95% CI 0.4-1.9), as well as in LC patients (OD 0.7, 95% CI 0.3-1.7). The homozygous genotype was significantly associated with PC and LC, whereas the heterozygous was not so. The GSTM1 (-/-) and GSTT1 (-/-) genotypes are a risk factor for LC and PC, whereas the (+/-) genotypes are not.
RESUMO
Genetic polymorphisms in genes related to the metabolism of xenobiotics, such as genes of the glutathione S-transferases (GSTM1, GSTT1, and GSTP1) superfamily have been associated with an increased risk for breast cancer (BC). Considering the high incidence of BC in the city of Porto Alegre in southern Brazil, the purpose of this study was to characterize genotypic and allelic frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1, and correlate these molecular findings with established risk factors for breast cancer including mammographic density, in a sample of 750 asymptomatic women undergoing mammographic screening. Molecular tests were performed using the multiplex polymerase chain reaction (PCR) for GSTM1 and GSTT1, and quantitative PCR for GSTP1 polymorphisms. Overall, the frequencies of GSTM1 and GSTT1 null genotypes were 45% and 21%, respectively. For GSTP1 polymorphism, genotypic frequencies were 44% for the Ile/Ile genotype, 44% for the Ile/Val genotype, and 12% for Val/Val genotype, with an allelic frequency of 66% for the wild type allele in this population, similar to results of previous international publications. There was a statistically significant association between the combined GSTM1 and GSTT1 null genotypes (M-/T-) and mammographic density in post menopausal women (p = 0.031). When the GSTT1 null (T-) genotype was analyzed isolated, the association with mammographic density in post menopausal women and in the overall sample was also statistically significant (p = 0.023 and p = 0.027, respectively). These findings suggest an association of GSTM1 and GSTT1 null genotypes with mammographic density.
Polimorfismos genéticos em genes relacionados com o metabolismo de xenobióticos, como os genes da superfamília das glutationa S-transferases (GSTM1, GSTT1 e GSTP1) têm sido associados com o aumento do risco para câncer de mama (CM). Considerando a alta incidência de CM na cidade de Porto Alegre, região Sul do Brasil, a proposta deste estudo foi caracterizar genótipos e frequências alélicas dos polimorfismos GSTM1, GSTT1 e GSTP1, e correlacionar esses achados moleculares com fatores de risco já estabelecidos para câncer de mama, incluindo densidade mamográfica, em uma amostra de 750 mulheres assintomáticas durante o rastreamento mamográfico. Para os testes moleculares foi utilizado multiplex da reação em cadeia de polimerase (PCR) para GSTM1 e GSTT1, e PCR quantitativo para o polimorfismo GSTP1. As frequências dos genótipos GSTM1 e GSTT1 nulos foram 45% e 21%, respectivamente. Para o polimorfismo GSTP1, as frequências genotipicas foram: 44% para o genótipo Ile/Ile, 44% para o genótipo Ile/Val e 12% para o genótipo Val/Val. A frequência do alelo lle nesta população foi 66%, semelhante a outros estudos. Houve uma associação significativa entre a combinação dos genótipos (T-/M-) nulos e densidade mamográfica nas mulheres pós-menopáusicas (p = 0,031). Quando analisamos isoladamente o genótipo GSTT1 nulo (T-) também encontramos uma associação significativa com a densidade mamográfica nas mulheres pós-menopáusicas (p = 0,027) e na amostra total. Estes achados sugerem uma associação dos genótipos (T-/M-) nulos com densidade mamográfica.