Human glutathione S-transferase polymorphisms associated with prostate cancer in the Brazilian population.

OBJECTIVE: To evaluate the influence of polymorphisms in GSTA1, GSTM1, GSTT1, and GSTP1 in the risk of developing Prostate Cancer (PCa) in a population of Rio de Janeiro and compare the distribution of allele and genotype frequencies of the polymorphisms analyzed in the present study population with other regions in the country and different ethnic groups. MATERIALS AND METHODS: We analyzed a sample of the Brazilian population, comprising 196 patients with PCa treated by the urology services of the Brazilian National Cancer Institute (INCA) and Mario Kroeff Hospital (HMK), and 208 male blood donors from the Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro (UFRJ). The polymorphisms were determined in DNA, extracted from peripheral blood leucocytes using the Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS: Our results showed that the distribution of polymorphisms can vary significantly according to the Brazilian region and ethnic groups. The distribution of allele and genotype frequencies of the polymorphism GSTA1 was statistically different between cases and controls. Genotypes (A / B + B / B) were associated with protection (OR = 0.61, 95% CI = 0.40-0.92) for PCa in comparison to genotype A / A. CONCLUSION: The distribution of genotype frequencies of the polymorphism GSTA1 was statistically different between the case and control groups (p = 0.023), and the presence of genotypes A / B and B / B suggests a protective role against the risk of PCa compared to genotype A / A. This is the first study that reports the genotypic frequency of this polymorphism and its association with PCa in a Brazilian population sample.

Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: a HuGE-GSEC review.

The association of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers was assessed through a meta-analysis of published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens database (http://www.upci.upmc.edu/research/ccps/ccontrol/index.html ). Thirty publications used in the meta-analysis included a total of 7783 subjects (3177 cases and 4606 controls); 21 datasets, 9397 subjects (3130 cases and 6267 controls) were included in the pooled analysis. The GSTM1 deletion was 2-fold more likely to occur in African American and African cases than controls (odds ratio: 1.7, 95% confidence interval: 0.9-3.3), although this was not observed among whites (odds ratio: 1.0, 95% confidence interval: 0.9-1.1). The meta-analysis and pooled analysis showed a significant association between oral and pharyngeal cancer and the CYP1A1 MspI homozygous variant (meta-ORm2/m2: 1.9, 95% confidence interval: 1.4-2.7; Pooled ORm2m2: 2.0, 95% confidence interval: 1.3-3.1; ORm1m2 or [infi]m2m2: 1.3, 95% confidence interval: 1.1-1.6). The association was present for the CYP1A1 (exon 7) polymorphism (ORVal/Val: 2.2, 95% confidence interval: 1.1-4.5) in ever smokers. A joint effect was observed for GSTM1 homozygous deletion and the CYP1A1 m1m2 variant on cancer risk. Our findings suggest that tobacco use and genetic factors play a significant role in oral and pharyngeal cancer.

Glutathione S-transferase polymorphisms and oral cancer: a case-control study in Rio de Janeiro, Brazil.

This study evaluates the influence of genetic polymorphisms at GSTM1, GSTT1 and GSTP1 gene loci on oral cancer susceptibility among Brazilians from Rio de Janeiro. DNA extracted from white blood cells of 231 oral cancer patients and 212 hospital controls was analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. GSTM1 polymorphism distribution was different between cases and controls (P=0.006), with an overrepresentation of GSTM1 A/B genotype in controls. GSTM1 A/B individuals were at decreased oral cancer risk (OR=0.08; 95% CI=0.05-0.62). No statistically significant association was observed for GSTT1 and GSTP1 polymorphisms. Differences in the GSTM1 and GSTT1 null genotype frequencies were observed between individuals of European origin and African origin, but these genotypes do not seem to influence the risk of oral cancer. Therefore, these results do not support the hypothesis of increased risk of GSTP1 G/G, GSTM1 or GSTT1 null genotypes for developing cancer in oral cavity, but the GSTM1 A/B genotype emerged as a protective factor.

The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population.

The polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with leukemogenesis. In order to investigate the influence of two polymorphisms in the MTHFR gene, 677C>T and 1298A>C, on the risk of acute lymphoblastic leukemia (ALL) we performed a case-control study in children from different Brazilians' regions. Genotyping of 176 ALL and 199 unselected healthy subjects was performed using PCR-RFLP assay. There was no association between the 677C>T or 1298A>C and risk of ALL in total case-control sample. However, 677T allele was linked to a decrease risk of ALL [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.22-0.86], whereas the 1298A>C polymorphism presents an elevated risk factor [OR, 2.01; 95% CI, 1.01-3.99] in non-White children. Our investigation provides interesting data concerning the opposite effect of A1298C polymorphisms, particularly in the light of relatively scarce data regarding the MTHFR role in leukemia susceptibility in different populations.

Association between the MTHFR A1298C polymorphism and increased risk of acute myeloid leukemia in Brazilian children.

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the metabolism of folate. The presence of polymorphisms that reduce the activity of MTHFR has been linked to the multifactor process of development of acute leukemia. A case control study was conducted on Brazilian children in different regions of the country with the aim of investigating the role of MTHFR C677T and A1298C polymorphisms as risk factors in the development of acute myeloid leukemia (AML). We used the polymerase chain reaction restriction fragment length polymorphism method to genotyping 182 AML and 315 healthy individuals. The genotype 677 CT was associated with decreased risk [odds ratio (OR), 0.37; confidence interval (CI) 95%, 0.14 - 0.92], whereas 1298 AC genotype was linked with an increased risk [OR, 2.90; CI 95%, 1.26 - 6.71] of developing AML in non-white children. Further epidemiological study is needed to unravel the complex multiple gene-environment interactions in the role of the AML leukemogenesis.

Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: results from a case-control study in Rio de Janeiro.

Xenobiotic metabolizing enzymes are involved in the detoxification of many carcinogens and may be important in modulating cancer susceptibility. CYP1A1, CYP2E1, GSTM3, and NAT2 polymorphisms were determined in peripheral blood DNA of 231 oral cancer patients and 212 hospital controls in Rio de Janeiro, Brazil, using the PCR-RFLP technique. NAT2 polymorphism distribution was different between cases and controls (P=0.035), with an overrepresentation of NAT2( *)11 mutant allele in controls. Risk analysis showed that NAT2 4/4 individuals (OR=1.95, 95% CI=1.05-3.60) and combined GSTM3 and NAT2 heterozygotes (OR=1.94, 95% CI=1.04-3.66) were at increased oral cancer risk. No statistically significant association was observed for CYP1A1 and CYP2E1 polymorphisms. Our results suggest that NAT2 polymorphism, alone or combined with GSTM3, may modulate susceptibility to oral cancer in Rio de Janeiro.

Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility.

Epidemiological studies have estimated that approximately 80% of all cancers are related to environmental factors. Individual cancer susceptibility can be the result of several host factors, including differences in metabolism, DNA repair, altered expression of tumor suppressor genes and proto-oncogenes, and nutritional status. Xenobiotic metabolism is the principal mechanism for maintaining homeostasis during the body's exposure to xenobiotics. The balance of xenobiotic absorption and elimination rates in metabolism can be important in the prevention of DNA damage by chemical carcinogens. Thus the ability to metabolize and eliminate xenobiotics can be considered one of the body's first protective mechanisms. Variability in individual metabolism has been related to the enzymatic polymorphisms involved in activation and detoxification of chemical carcinogens. This paper is a contemporary literature review on genetic polymorphisms involved in the metabolism of endocrine disruptors potentially related to cancer development.

Superoxide dismutase, catalase, glutathione peroxidase and gluthatione S-transferases M1 and T1 gene polymorphisms in three Brazilian population groups.

Antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX1) reduce the oxidation rates in the organism. Gluthatione S-transferases (GSTs) play a vital role in phase 2 of biotransformation of many substances. Variation in the expression of these enzymes suggests individual differences for the degree of antioxidant protection and geographical differences in the distribution of these variants. We described the distribution frequency of CAT (21A/T), SOD2 (Ala9Val), GPX1 (Pro198Leu), GSTM1 and GSTT1 polymorphisms in three Brazilian population groups: Kayabi Amerindians (n = 60), Kalunga Afro-descendants (n = 72), and an urban mixed population from Federal District (n = 162). Frequencies of the variants observed in Kalunga (18% to 58%) and Federal District (33% to 63%) were similar to those observed in Euro and Afro-descendants, while in Kayabi (3% to 68%), depending on the marker, frequencies were similar to the ones found in different ethnic groups. Except for SOD2 in all population groups studied here, and for GPX1 in Kalunga, the genotypic distributions were in accordance with Hardy-Weinberg Equilibrium. These data can clarify the contribution of different ethnicities in the formation of mixed populations, such as that of Brazil. Moreover, outcomes will be valuable resources for future functional studies and for genetic studies in specific populations. If these studies are designed to comprehensively explore the role of these genetic polymorphisms in the etiology of human diseases they may help to prevent inconsistent genotype-phenotype associations in pharmacogenetic studies.

[NRAMP1 gene polymorphisms in individuals with leprosy reactions attended at two reference centers in Recife, northeastern Brazil]. / Polimorfismos do gene NRAMP1 em indivíduos com reações hansênicas, atendidos em dois Centros de Referência no Recife, nordeste do Brasil.

INTRODUCTION: To investigate susceptibility to leprosy reactions, three polymorphisms of the natural resistance-associated macrophage protein (NRAMP1) gene were determined in 201 individuals who were attended at two reference centers in Recife, between 2007 and 2008. Of these, 100 were paucibacillary and 101 were multibacillary. METHODS: The 274C/T, D543N and 1729+55del4 polymorphisms of the NRAMP1 gene were determined using the technique of restriction fragment polymorphism on DNA extracted from peripheral blood. Allelic and genotypic frequencies were estimated by direct counting. RESULTS: The predominant genotypes were: CC (51.8%) for 274C/T; GG (86.6%) for D543N; and +-TGTG (59.9%) for 1729+55del4. The mutant genotype 274 TT predominated in negativity of the reverse reaction (p = 0.03) and in positivity of erythema nodosum leprosum (p = 0.04). CONCLUSIONS: Our results suggest that 274 C/T polymorphism of the NRAMP1 gene may aid in determining the susceptibility to type II reactions among leprosy patients.

Human glutathione S-transferase polymorphisms associated with prostate cancer in the Brazilian population

Objective To evaluate the influence of polymorphisms in GSTA1, GSTM1, GSTT1, and GSTP1 in the risk of developing Prostate Cancer (PCa) in a population of Rio de Janeiro and compare the distribution of allele and genotype frequencies of the polymorphisms analyzed in the present study population with other regions in the country and different ethnic groups. Materials and Methods We analyzed a sample of the Brazilian population, comprising 196 patients with PCa treated by the urology services of the Brazilian National Cancer Institute (INCA) and Mario Kroeff Hospital (HMK), and 208 male blood donors from the Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro (UFRJ). The polymorphisms were determined in DNA, extracted from peripheral blood leucocytes using the Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP). Results Our results showed that the distribution of polymorphisms can vary significantly according to the Brazilian region and ethnic groups. The distribution of allele and genotype frequencies of the polymorphism GSTA1 was statistically different between cases and controls. Genotypes (A / B + B / B) were associated with protection (OR = 0.61, 95 % CI = 0.40-0.92) for PCa in comparison to genotype A / A. Conclusion The distribution of genotype frequencies of the polymorphism GSTA1 was statistically different between the case and control groups (p = 0.023), and the presence of genotypes A / B and B / B suggests a protective role against the risk of PCa compared to genotype A / A. This is the first study that reports the genotypic frequency of this polymorphism and its association with PCa in a Brazilian population sample. .

Glutathione S-transferase M1 and T1 polymorphisms in Brazilian African descendants.

The glutathione S-transferase gene family has an important role in the biotransformation and detoxification of different xenobiotics and endogenous compounds. Two polymorphic genes of this family, GSTM1 and GSTT1, present null alleles that consequently do not produce the respective enzyme when the genotype is homozygous. These polymorphisms are also interesting for population dynamics studies because they have great frequency variations among different ethnic groups and have been reported worldwide. The distribution of these alleles in urban and Amerindian populations in Brazil has been described, but none of those studies reported on African-descended rural populations. The aim of this study was to analyze the genotype frequency distribution of the GSTM1 and GSTT1 null alleles in an urban sample from the Federal District (n = 91) and in four semi-isolated African-descended populations: Mocambo (n = 55), Rio das Rãs (n = 117), Riacho de Sacutiaba (n = 34), and Kalunga (n = 68). The GSTM1 and GSTT1 null genotype frequencies in these populations range from 17% to 35% for GSTM1 and from 22% to 44% for GSTT1. These values are similar to those described in other African and African-descended populations. Despite this range, there is no distribution difference among the analyzed populations. Combined GSTM1 and GSTT1 null genotype frequencies range from 6% to 13% and are similar to European-derived populations, suggesting admixture with this ethnic group. This can be interpreted as a European contribution to these African-descended populations. Regarding the urban population in the Federal District, our results suggest an important African and European contribution.

Superoxide dismutase, catalase, glutathione peroxidase and gluthatione S-transferases M1 and T1 gene polymorphisms in three Brazilian population groups

Antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX1) reduce the oxidation rates in the organism. Gluthatione S-transferases (GSTs) play a vital role in phase 2 of biotransformation of many substances. Variation in the expression of these enzymes suggests individual differences for the degree of antioxidant protection and geographical differences in the distribution of these variants. We described the distribution frequency of CAT (21A/T), SOD2 (Ala9Val), GPX1 (Pro198Leu), GSTM1 and GSTT1 polymorphisms in three Brazilian population groups: Kayabi Amerindians (n = 60), Kalunga Afro-descendants (n = 72), and an urban mixed population from Federal District (n = 162). Frequencies of the variants observed in Kalunga (18 percent to 58 percent) and Federal District (33 percent to 63 percent) were similar to those observed in Euro and Afro-descendants, while in Kayabi (3 percent to 68 percent), depending on the marker, frequencies were similar to the ones found in different ethnic groups. Except for SOD2 in all population groups studied here, and for GPX1 in Kalunga, the genotypic distributions were in accordance with Hardy-Weinberg Equilibrium. These data can clarify the contribution of different ethnicities in the formation of mixed populations, such as that of Brazil. Moreover, outcomes will be valuable resources for future functional studies and for genetic studies in specific populations. If these studies are designed to comprehensively explore the role of these genetic polymorphisms in the etiology of human diseases they may help to prevent inconsistent genotype-phenotype associations in pharmacogenetic studies.

Polimorfismos do gene NRAMP1 em indivíduos com reações hansênicas, atendidos em dois Centros de Referência no Recife, nordeste do Brasil / NRAMP1 gene polymorphisms in individuals with leprosy reactions attended at two reference centers in Recife, northeastern Brazil

INTRODUÇÃO: Para investigar susceptibilidade às reações hansênicas, três polimorfismos do gene natural resistance-associated macrophage protein (NRAMP1), foram determinados em 201 indivíduos, atendidos em dois centros de referência no Recife, entre 2007 e 2008, sendo 100 paucibacilares e 101 multibacilares. MÉTODOS: A determinação dos polimorfismos 274C/T, D543N e 1729+55del4 do gene NRAMP1 foi realizada utilizando a técnica do polimorfismo de fragmento de restrição em DNA extraído de sangue periférico e as estimativas das freqüências alélicas e genotípicas foram feitas por contagem direta. RESULTADOS: Os genótipos predominantes foram: CC (51,8 por cento) para 274C/T, GG (86,6 por cento) para D543N e +-TGTG (59,9 por cento) para 1729+55del4. O genótipo mutante 274 TT predominou na negatividade da reação reversa (p=0,03) e na positividade do eritema nodoso (p=0,04). CONCLUSÕES: Nossos resultados sugerem que o polimorfismo 274 C/T do gene NRAMP1 pode auxiliar na determinação da susceptibilidade à reação tipo II em indivíduos com hanseníase.

INTRODUCTION: To investigate susceptibility to leprosy reactions, three polymorphisms of the natural resistance-associated macrophage protein (NRAMP1) gene were determined in 201 individuals who were attended at two reference centers in Recife, between 2007 and 2008. Of these, 100 were paucibacillary and 101 were multibacillary. METHODS: The 274C/T, D543N and 1729+55del4 polymorphisms of the NRAMP1 gene were determined using the technique of restriction fragment polymorphism on DNA extracted from peripheral blood. Allelic and genotypic frequencies were estimated by direct counting. RESULTS: The predominant genotypes were: CC (51.8 percent) for 274C/T; GG (86.6 percent) for D543N; and +-TGTG (59.9 percent) for 1729+55del4. The mutant genotype 274 TT predominated in negativity of the reverse reaction (p = 0.03) and in positivity of erythema nodosum leprosum (p = 0.04). CONCLUSIONS: Our results suggest that 274 C/T polymorphism of the NRAMP1 gene may aid in determining the susceptibility to type II reactions among leprosy patients.

Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms in a Brazilian mixed population.

The GSTM1 and GSTT1 null genotype frequencies were significantly different between 658 nonblack and black healthy blood donors from a Brazilian mixed population (Rio de Janeiro). The GSTM1 phenotype distribution was not in Hardy-Weinberg equilibrium in either group, mainly because of an excess of the GSTM1*A/*B genotype.

CYP1A1 and CYP2E1 polymorphism frequencies in a large Brazilian population

The enzymes encoded by the polymorphic genes CYP1A1 and CYP2E1 play an important role in the activation and inactivation of xenobiotics. These enzymes have been associated with xenobiotic-induced diseases, such as cancer, therapeutic failure and adverse effects of drugs. The aim of the present study was to determine the allelic and genotypic frequencies of these polymorphisms in a large, ethnically mixed Brazilian population sample from Rio de Janeiro. Polymorphisms CYP1A1 and CYP2E1 were determined in 870 unrelated individuals by PCR-RFLP analysis in peripheral blood DNA. The observed allelic frequencies were 0.90 for CYP1A1*1A and 0.95 for CYP2E1*1A, in the total sample. The allelic frequency of CYP1A1*2C in "pardos" (0.13) and Brazilian whites (0.11) was higher than in Caucasians (0.05), which may be a result of the Amerindian genetic component, that presents the highest frequency of this allele observed up to now. The genotype distributions for both polymorphisms were in Hardy-Weinberg equilibrium and were statistically different between males and females, and among ethnic groups.

Distribution of glutathione S-transferase GSTM1 and GSTT1 null phenotypes in Brazilian Amerindians

The distribution of glutathione S-transferase (GST) GSTM1 and GSTT1 null phenotype frequencies in two Brazilian Amerindian tribes, the Munduruku tribe from Missão Cururu village (79 individuals) and the Kayabi tribe (41 individuals), was analyzed by polymerase chain reaction (PCR) amplification. The GST null phenotype frequencies for the Munduruku sample were 0 percent for GSTM1 and 27 percent for GSTT1 while for the Kayabi sample the null phenotype frequencies were 27 percent for GSTM1 and 29 percent for GSTT1. This is the first report of the absence of the GSTM1 null phenotype in any ethnic group.

No evidence of linkage between Mitsuda reaction and the NRAMP1 locus

Thirty sib-pairs were ascertained through unrelated lepromatous probands. They consisted of 22 healthy individuals and 8 leprosy patients. The Mitsuda reactions of all sibs were evaluated both macroscopically and histologically, and high molecular weight genomic DNA was extracted from the white blood cells of all sib-pairs. Three DNA polymorphisms identified by polymerase chain reaction (274C/T, D543N, 1729 + 55del4) were used as chromosome markers at the NRAMP1 locus. Sib-pair comparisons did not disclose any sign of close linkage between the Mitsuda reaction and the genetic markers.

Glutathione S-transferase M1 (GSTM1) polymorphism in two Brazilian populations

A distribuiçäo das freqüências fenotípicas do gene GSTM1 de duas amostras brasileiras, compostas de doadores sanguíneos de ambos os sexos com idade entre 18 e 61 anos, foi estudada. A primeira amostra é composta de 658 indivíduos provenientes do Rio de Janeiro e a segunda de 179 indivíduos de Brasília. Os fenótipos da GSTM1 foram determinados utilizando-se a técnica da reaçäo em cadeia da polimerase e subsequente digestäo com a enzima de restriçäo HaeII. As freqüências observadas para o fenótipo GSTM1 nulo foram de 46,4 por cento e 48,6 por cento para as amostras do Rio de Janeiro e Brasília, respectivamente. Os resultados também mostram que a distribuiçäo fenotípica da GSTM1 näo está em equilíbrio de Hardy-Weinberg para ambas as amostras: X²1 = 11,49 (P < 0,001) para o Rio de Janeiro e X²1 = 6,77 (P < 0,01) para Brasília. Este desequilíbrio pode ser atribuído a fatores como seleçäo, erros na determinaçäo fenotípica ou panmixia ainda incompleta da populaçäo brasileira, cujos componentes raciais säo caucasóides, africanos e índios.

Exposição a substâncias químicas e câncer: aspectos epidemiológicos, genéticos e moleculares / Exposition to chemical substances and cancer: epidemiological, genetic and molecular aspects

Este trabalho realizou uma revisão sistemática da literatura no período 1999-2007, analisando a associação entre a exposição a substâncias químicas e o desenvolvimento de câncer. A contribuição da exposição a pesticidas nesta associação é abordada como estudo de caso na literatura internacional, e no Brasil em particular. O papel da exposição a substâncias químicas no processo de carcinogênese é revisto a partir dos conhecimentos contemporâneos sobre as interações genético-ambientais e a contribuição dos polimorfismos genéticos envolvidos na metabolização de substâncias xenobióticas. Estas relações são abordadas tanto na perspectiva da Biologia Molecular como da Epidemiologia, através de exemplos de associações observadas na população geral resultantes de exposições ocupacionais e ambientais.

A systematic literature review between 1999-2007 on the association between chemical exposure and cancer was carried out, and it was highlighted the case study of worldwide and Brazilian experiences of pesticides exposure. Current knowledge on the carcinogenesis process and the role of single genetic polymorphisms were addressed, both from a molecular and an epidemiological approach. Some examples of such association were discussed on the occupational and the environmental. (affecting the general population) perspectives.