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Genetic selection? A study of individual variation in the enzymes of folate metabolism
Barbara A Jennings, Gavin A Willis, Jane Skinner, Caroline L Relton
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-18
Abstract: We have looked at the prevalence of genetic variants of the enzymes MTHFR and TYMS in 2,898 DNA samples derived from five cohorts collected in the United Kingdom. The simultaneous analysis of genetic variants of the MTHFR and TYMS loci was carried out to investigate a putative gene-gene interaction that was first observed in an elderly male population from Norfolk.We have made a consistent observation in five population cohorts; the proportion of individuals who are homozygous for the 2R allele of the 5'UTR TYMS polymorphism is less in individuals who are homozygous for the T allele of MTHFR 677 than in individuals homozygous for the C allele of MTHFR 677 (p = 0.02).These data may suggest a gene-gene interaction and could be evidence of genetic selection, with some pregnancies more or less viable as a consequence of genetic variation. If these genetic phenomena affect the way folate is handled at the cellular level in utero it is possible that maternal folic acid intake may over-ride such genetic selection.Folate-dependent one-carbon metabolism is essential for nucleotide synthesis, methionine synthesis and for DNA methylation and depends on a number of enzymes that are functionally polymorphic. SNPs and other polymorphisms of the genes MTHFR, MTRR and TYMS have been associated with cardiovascular disease, neural tube defects, Down syndrome and leukaemia [1-4]. Adequate dietary folate, and its efficient metabolism have well-established roles in disease prevention; deficiency is associated with increased risk of neural tube defects, vascular disease, cancer and anaemia [5].Proposals for the mandatory fortification of flour with folate in the United Kingdom are driven by the importance of this B vitamin to the development of the early embryo [6]. Embryo development and viability has been the subject of many epidemiological studies of genetic variants, including, and possibly predominantly, in those genes involved in folate metabolism [2-4,7]. B-vitamin status and fola
Lack of Association between Genetic Polymorphisms in Enzymes Associated with Folate Metabolism and Unexplained Reduced Sperm Counts  [PDF]
Celia Ravel, Sandra Chantot-Bastaraud, Clementine Chalmey, Luis Barreiro, Isabelle Aknin-Seifer, Jerome Pfeffer, Isabelle Berthaut, E. Emmanuelle Mathieu, Jacqueline Mandelbaum, Jean-Pierre Siffroi, Ken McElreavey, Anu Bashamboo
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006540
Abstract: Background The metabolic pathway of folate is thought to influence DNA stability either by inducing single/double stranded breaks or by producing low levels of S-adenosyl-methionine leading to abnormal gene expression and chromosome segregation. Polymorphisms in the genes encoding enzymes in the folate metabolism pathway show distinct geographic and/or ethnic variations and in some cases have been linked to disease. Notably, the gene Methylenetetrahydrofolate reductase (MTHFR) in which the homozygous (TT) state of the polymorphism c.665C>T (p.A222V) is associated with reduced specific activity and increased thermolability of the enzyme causing mild hyperhomocysteinemia. Recently several studies have suggested that men carrying this polymorphism may be at increased risk to develop infertility. Methodology/Principal Findings We have tested this hypothesis in a case/control study of ethnic French individuals. We examined the incidence of polymorphisms in the genes MTHFR (R68Q, A222V and E429A), Methionine synthase reductase MTRR; (I22M and S175L) and Cystathionine beta-synthase (CBS; G307S). The case population consisted of DNA samples from men with unexplained azoospermia (n = 70) or oligozoospermia (n = 182) and the control population consisted of normospermic and fertile men (n = 114). We found no evidence of an association between the incidence of any of these variants and reduced sperm counts. In addition haplotype analysis did not reveal differences between the case and control populations. Conclusions/Significance We could find no evidence for an association between reduced sperm counts and polymorphisms in enzymes involved in folate metabolism in the French population.
Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women
Enbo Ma, Motoki Iwasaki, Ishihara Junko, Gerson Hamada, Ines Nishimoto, Solange Carvalho, Juvenal Motola, Fábio Laginha, Shoichiro Tsugane
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-122
Abstract: A case-control study was conducted in S?o Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B6, and vitamin B12 were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed for MTHFR A1298C and C677T, and MTR A2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).Neither dietary intake of folate, vitamin B6, or vitamin B12 nor MTHFR polymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83; Ptrend = 0.010). The MTR 2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92; Ptrend = 0.801), and statistically significant interactions with regard to risk were observed between the MTHFR A1298C polymorphism and folate (P = 0.024) or vitamin B6 (P = 0.043), and between the MTHFR C677T polymorphism and folate (P = 0.043) or vitamin B12 (P = 0.022).MTHFR polymorphisms and dietary intake of folate, vitamin B6, and vitamin B12 had no overall association with breast cancer risk. However, increased risk was observed in total women with the MTR 2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions between MTHFR polymorphisms and B vitamins, warrant further investigation.Folate and other methyl-related B vitamins are essential nutrients which play important roles in DNA synthesis (genetics), repair, and methylation (epigenetics). These roles in turn indicate a potential association for these vitamins with the development of several types of cancer [1-3]. For example, in one folate metabolism pathway, the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) irreversibly cat
No Evidence for Strong Recent Positive Selection Favoring the 7 Repeat Allele of VNTR in the DRD4 Gene  [PDF]
Izumi Naka, Nao Nishida, Jun Ohashi
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024410
Abstract: The human dopamine receptor D4 (DRD4) gene contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor. The DRD4 7R allele, which seems to have a single origin, is commonly observed in various human populations and the nucleotide diversity of the DRD4 7R haplotype at the DRD4 locus is reduced compared to the most common DRD4 4R haplotype. Based on these observations, previous studies have hypothesized that positive selection has acted on the DRD4 7R allele. However, the degrees of linkage disequilibrium (LD) of the DRD4 7R allele with single nucleotide polymorphisms (SNPs) outside the DRD4 locus have not been evaluated. In this study, to re-examine the possibility of recent positive selection favoring the DRD4 7R allele, we genotyped HapMap subjects for DRD4 VNTR, and conducted several neutrality tests including long range haplotype test and iHS test based on the extended haplotype homozygosity. Our results indicated that LD of the DRD4 7R allele was not extended compared to SNP alleles with the similar frequency. Thus, we conclude that the DRD4 7R allele has not been subjected to strong recent positive selection.
Association between GSTM1 and GSTT1 polymorphisms and susceptibility to methamphetamine dependence
Mohammad Rashid Khalighinasab, Khyber Saify, Mostafa Saadat
Molecular Biology Research Communications , 2015,
Abstract: Glutathione S-transferases (GSTs; EC: are ubiquitous multifunctional enzymes, which play a key role in cellular detoxification. Functional genetic polymorphisms in genes encoding GSTM1 (a member of GST class mu; OMIM: 138350), and GSTT1 (a member of GST class theta; OMIM: 600436) have been well defined. The functional null alleles of GSTM1 and GSTT1 represent deletions of GSTM1 and GSTT1 genes, respectively. The aim of the present study is to investigate the association between GSTM1 and GSTT1 polymorphisms and methamphetamine dependence. The present population-based case-control study was performed in Shiraz (southern Iran). In total, 52 methamphetamine dependence (11 females, 41 males) and 635 healthy controls (110 females, 525 males) were included in this study. The genotypes of GSTM1 and GSTT1 polymorphisms were determined by PCR. Neither GSTM1 (OR=0.92, 95% CI: 0.52-1.61, P=0.771) nor GSTT1 (OR=0.71, 95% CI: 0.33-1.54, P=0.381) null genotypes were significantly associated with risk of methamphetamine dependence. It should be noted that although there was no association between the GSTM1 null genotype and risk of methamphetamine dependence, in both genders, there was significant interaction between gender and GSTM1 polymorphism (P=0.029). The combination genotypes of the GSTM1 and GSTT1 polymorphisms revealed that the genotypes of these two polymorphisms had no additive effect in relation to the susceptibility to methamphetamine dependence. The present study revealed that genetic polymorphisms of GSTT1 and GSTM1 are not risk factors for methamphetamine dependence.
Association between GSTM1 and GSTT1 Allelic Variants and Head and Neck Squamous Cell Cancinoma  [PDF]
Yang Zhang, Yuanyuan Ni, Hao Zhang, Yongchu Pan, Junqing Ma, Lin Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047579
Abstract: Backgrounds GSTM1 and GSTT1 are involved in the detoxification of carcinogens such as smoking by-products, and polymorphisms in these two genes with a result of loss of enzyme activity may increase risk of carcinogenesis. Although many epidemiological studies have investigated the association between GSTM1 or GSTT1 null genotype and head and neck squamous cell carcinoma (HNSCC), the results remain conflicting. To elucidate the overall association of GSTM1, GSTT1 and HNSCC, we included all available studies and performed this meta-analysis. Methodology/Principal Findings A dataset including 42 articles for GSTM1, 32 articles for GSTT1, and 15 articles for GSTM1 and GSTT1 in combination were identified by a search in PubMed. Associations beween HNSCC and polymorphisms of GSTM1 and GSTT1 alone and in combination were analysed by software RevMan 5.1. Stratification analysis on ethnicity and smoking status, sensitivity analysis, heterogeneity among studies and their publication bias were also tested. Association was found in overall analysis between HNSCC and GSTM1 and GSTT1 null genotype. Stratified by ethnicity, we found increased risks of HNSCC in carriers with GSTM1 null genotype in Asian, GSTT1 null genotype in South American, and dual null genotype in European and Asian. When stratified by smoking, a more significant association of GSTM1 null genotype with HNSCC risk was observed in smokers. Conclusions/Significance This meta-analysis presented additional evidence of the association between GSTM1 and GSTT1 polymorphisms and HNSCC risk.
Polymorphisms in the CYP2E1 and GSTM1 Genes as Possible Protection Factors for Leprosy Patients  [PDF]
Pablo Pinto, Claudio Guedes Salgado, Ney Santos, Dayse O. Alencar, Sidney Santos, Mara H. Hutz, ?ndrea Ribeiro-dos-Santos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047498
Abstract: Background The CYP2E1 and GSTM1 genes encode metabolic enzymes that have key functions in drug modification and elimination. Methodology/Principal Findings We investigated the possible effects of CYP2E1 and GSTM1 polymorphisms in 71 leprosy patients and in 110 individuals from the general population. The GSTM1*0 null allele and INDEL CYP2E1*1D mutant genotypes were analyzed by conventional PCR, while CYP2E1 SNPs (1053C>T, 1293G>C and 7632T>A) were determined by RT-PCR. In leprosy patients, the GSTM1*0 and CYP2E1*5 alleles and the combined alleles GSTM1*0/CYP2E1*6 and GSTM1*0/CYP2E1*5 were significantly related to a baciloscopic index (BI) (BI<3), while the CYP2E1*6 allele was related to a better clinical evolution in the leprosy spectrum. Conclusions/Significance Therefore, GSTM1*0, CYP2E1*5 and CYP2E1*6 may be possible protection factors for leprosy patients.
Relationship of Polymorphisms of Glutathione S-Transferase GSTT1 and GSTM1 With the Response to Chemotherapy In Mexican Women with Advanced Breast Cancer  [PDF]
Odeth Soto-Quintana, Paula Cabrera-Galeana, Gabriel Téllez-Trevilla, José Luis Barrera-Franco, Alejandro Juárez-Ramiro, Julieta Castillo-Cadena
Journal of Cancer Therapy (JCT) , 2011, DOI: 10.4236/jct.2011.23048
Abstract: Introduction: Breast cancer is a common disease diagnosed in Mexican women and the first leading cause of death [1]. Heterogeneity in patients’ response to treatment is consistently observed across populations. Glutathione S-transferases (GSTs) are involved in the metabolism of environmental carcinogens, reactive oxygen species and chemotherapeutic agents by catalyzing the glutathione with electrophilic compounds. The deletion of GSTT1 and GSTM1 genes result in loss of enzyme activity. A few studies evaluated the response to treatment and the polymorphisms of GSTT1 and GSTM1. The aim of this work is to make the association of the null polymorphisms of GSTT1 and GSTM1 with the response to chemotherapy basically doxorubicin and cyclophosphamide. Methods: The genotyping of thirty patients with breast cancer was made with the Polymerase chain reaction, to identify the polymorphisms of GSTT1 and GSTM1. We determine the status of Her-2 neu, estrogen and progesterone receptors, then the response to treatment was made with an ultrasound and pathological data. We made the association with the χi2 statistics using a p≤0.05. Results: Using the Sigma Stat 3.5 program and the chi-squared analysis, we do not observe a significant association with the GSTT1+/GSTM1+, GSTT1-/GSTM1+ and GSTT1-/GSTM1-polymorphisms and the better or worse response to cyclophosphamide and doxorubicin. With the Her-2 neu, estrogen and progesterone receptors status, we neither found an association with the response to the therapy. Conclusion: This study suggests that GSTT1 and GSTM1 polymorphisms have no statistical significance between the genotype of women with advanced breast cancer and the response to neoadjuvant chemotherapy, but we can see a clear tendency toward better response with the null genotype.
"Frequency of Glutathione S-transferase M1 (GSTM1) and GSTT1 Null Genotypes in Fars Population (South of Iran)"
M Saadat,DD Farhud,I Saadat
Iranian Journal of Public Health , 2001,
Abstract: The genes glutathione S-transferase M1 (GSTM1) and GSTT1 code for cytosolic enzymes GSTμ and GSTθ, respectively, which are involved in phase II metabolism. In human, both genes may be deleted. In the present study, the genetic polymorphisms of GSTM1 and GSTT1 were detected by PCR method in 236 healthy individuals from Shiraz population, Fars province, south of Iran. The frequency of GSTM1 and GSTT1-null genotypes were 37.7 and 31.8 percent, respectively. The studied population was then compared with reported frequencies for neighboring populations, as well as, with those for European and African populations.
No association between GSTM1 and GSTT1 genetic polymorphisms and susceptibility to opium sap dependence
Khyber Saify, Mohammad Rashid Khalighinasab, Mostafa Saadat
Molecular Biology Research Communications , 2016,
Abstract: Glutathione S-transferases (GSTs; EC: are a ubiquitous family of eukaryotic and prokaryotic phase II metabolic isozymes. Genes encoding GSTM1 (OMIM: 138350), and GSTT1 (OMIM: 600436) are members of class mu and theta, respectively. The most common polymorphism in the GSTM1 is a deletion of the whole GSTM1 gene with a lack of enzyme activity. A homozygous deletion in the GSTT1 has also been reported (null genotypes of GSTT1). The aim of the present study was to investigate the association between GSTM1 and GSTT1 polymorphisms and risk of dependency to opium sap. The present study was performed in Shiraz (southern Iran). In total, 71 males dependent to opium sap and 590 healthy males (as a control group) were included in this study. The genotypes of GSTM1 and GSTT1 polymorphisms were determined by PCR. Our data indicate that neither GSTM1 (OR=0.78, 95% CI: 0.47-1.27, P=0.325) nor GSTT1 (OR=1.25, 95% CI: 0.70-2.21, P=0.442) null genotypes significantly associated with the risk of opium sap dependence. There is no additive effect of the null genotypes of GSTT1 and GSTM1 in relation to the risk of dependency to opium sap. The present study indicated that the null genotypes of GSTT1 and GSTM1 are not risk factor for opium sap dependence.
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