Academic literature on the topic 'Dhfr polymorphism'
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Journal articles on the topic "Dhfr polymorphism"
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DURAISINGH, M. T., L. VON SEIDLEIN, A. JEPSON, P. JONES, I. SAMBOU, M. PINDER, and D. C. WARHURST. "Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum." Parasitology 121, no. 1 (July 2000): 1–7. http://dx.doi.org/10.1017/s0031182099006022.
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Chloroquine-resistance in Plasmodium falciparum is associated with polymorphisms in a locus on or near the cg2 gene on chromosome 7, and in the pfmdr1 gene on chromosome 5. In this study we typed P. falciparum DNA from uncomplicated malaria cases in The Gambia in 1990, 1995 and 1996 for size polymorphism in the omega repeat of cg2, for sequence polymorphisms in pfmdr1 at codons 86 and 184, in dhfr at codon 108 and in the msp2 gene. Chloroquine sensitivity tests were conducted in vitro. A significant but incomplete association was found between the presence of the cg2 Dd2-like omega repeat size polymorphism and in vitro resistance, and between the tyr-86 allele of pfmdr1 and in vitro resistance. Furthermore there was strong linkage disequilibrium between the pfmdr1 asn-86 allele and the cg2 not Dd2-like omega repeat allele located on different chromosomes. In contrast, no linkage disequilibrium was found between these alleles and either the dhfr ser-108 allele or the msp2 IC sequence polymorphism. No significant linkage was measured between pfmdr1 asn-86 and phe-184 although these loci are separated only by 296 base pairs. Our results suggest that genetic elements linked to the cg2 and the pfmdr1 genes are important determinants of chloroquine resistance. It can be concluded that the observed linkage disequilibrium is maintained epistatically through selection by chloroquine.
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Mendes, Cristiani Cortez, Joice Matos Biselli, Bruna Lancia Zampieri, Eny Maria Goloni-Bertollo, Marcos Nogueira Eberlin, Renato Haddad, Maria Francesca Riccio, Hélio Vannucchi, Valdemir Melechco Carvalho, and Érika Cristina Pavarino-Bertelli. "19-base pair deletion polymorphism of the dihydrofolate reductase (DHFR) gene: maternal risk of Down syndrome and folate metabolism." Sao Paulo Medical Journal 128, no. 4 (July 2010): 215–18. http://dx.doi.org/10.1590/s1516-31802010000400008.
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CONTEXT AND OBJECTIVE: Polymorphisms in genes involved in folate metabolism may modulate the maternal risk of Down syndrome (DS). This study evaluated the influence of a 19-base pair (bp) deletion polymorphism in intron-1 of the dihydrofolate reductase (DHFR) gene on the maternal risk of DS, and investigated the association between this polymorphism and variations in the concentrations of serum folate and plasma homocysteine (Hcy) and plasma methylmalonic acid (MMA). DESIGN AND SETTING: Analytical cross-sectional study carried out at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: 105 mothers of individuals with free trisomy of chromosome 21, and 184 control mothers were evaluated. Molecular analysis on the polymorphism was performed using the polymerase chain reaction (PCR) through differences in the sizes of fragments. Folate was quantified by means of chemiluminescence, and Hcy and MMA by means of liquid chromatography and sequential mass spectrometry. RESULTS: There was no difference between the groups in relation to allele and genotype frequencies (P = 0.44; P = 0.69, respectively). The folate, Hcy and MMA concentrations did not differ significantly between the groups, in relation to genotypes (P > 0.05). CONCLUSIONS: The 19-bp deletion polymorphism of DHFR gene was not a maternal risk factor for DS and was not related to variations in the concentrations of serum folate and plasma Hcy and MMA in the study population.
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Mishra, Prasunkumar J., Giuseppe S. A. Longo, Lata G. Menon, Emine Abali, Debabrata Banerjee, and Joseph Bertino. "A 3′ UTR Single Nucleotide Polymorphism 829C→T in Dihydrofolate Reductase Gene Results in an Increase in DHFR Protein Level and MTX Resistance." Blood 104, no. 11 (November 16, 2004): 2084. http://dx.doi.org/10.1182/blood.v104.11.2084.2084.
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Abstract Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF) required for the synthesis of thymidylate and purines. Methotrexate (MTX) acts as a tight-binding inhibitor of DHFR and remains an important chemotherapeutic agent for treatment of leukemias and lymphomas. Increased DHFR confers resistance to antifolates in target cells. A previously reported single nucleotide polymorphism (SNP) 829C/C→829T/T (829C→T) found in the 3′- untranslated region of DHFR gene transcript (between the first and second polyadenylation site) was associated with higher expression of the DHFR transcript. The SNP was identified in 5.4% of the cases and 6.0% in the controls of Japanese patients with childhood leukemia/lymphomas (Goto et al. 2001, Clinical Cancer Research, Vol. 7, 1952-1956). The objective of the present study was to determine the role of the 3′ UTR SNP 829C→T in DHFR gene expression, DHFR protein level and resistance to MTX. The mutation 829C→T in the 3′ UTR of wild type DHFR was introduced by site directed mutagenesis and the mutant cDNA expressed in DHFR deficient CHO cells (DG-44), wild type DHFR and vector alone constructs were also transfected into DG44 as controls. After two weeks of selection in G418 containing media, several well-isolated surviving colonies were picked and expanded as cell lines in media containing G418. Real-time quantitative PCR was used to compare mRNA and genomic DNA level of the clones while Western blotting was used to compare the protein levels. MTX cytotoxicity assay was carried out in media lacking thymidine. Clones expressing the mutant 829C→T showed greater than two fold enhanced expression of DHFR transcripts as compared to wild type clones. Corresponding to the high mRNA levels, an increase in DHFR protein level was observed in the mutant clones without an increase in DHFR gene copy number. Cytotoxicity studies showed that cell lines with increased levels of DHFR were significantly more resistant to MTX than cells with wild type 3′ UTR. Of interest clonogenic efficiency of the mutants in medium lacking thymidine was greater than wild type and was directly proportional to the level of DHFR expressed in the clones. This study demonstrates that when SNP 829C→T is introduced in the 3′ UTR of wild type DHFR, the expression of the DHFR mRNA is enhanced with a corresponding increase in the protein level. The presence of a SNP 829C→T in patients with ALL may contribute to treatment failure, as MTX is a key drug in curative regimen for this disease. Future studies are directed toward determining the abundance of this SNP in other populations, and the correlation between this SNP and clinical methotrexate resistance and or decreased MTX toxicity.
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Detera-Wadleigh, S. D., D. Coffman, and T. Shimada. "A frequent DHFR polymorphism detected by an intron fragment." Nucleic Acids Research 17, no. 15 (1989): 6432. http://dx.doi.org/10.1093/nar/17.15.6432.
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Costa-Lima, Marcelo Aguiar, Hazel Nunes Barboza, Joissy Aprigio, Cláudia de Melo Moura, Thereza Fonseca Quirico-Santos, Márcia Gonçalves Ribeiro, and Márcia Rodrigues Amorim. "Dihydrofolate Reductase (DHFR) del19bp Polymorphism and Down Syndrome Offspring." Journal of Molecular Neuroscience 70, no. 9 (May 22, 2020): 1410–14. http://dx.doi.org/10.1007/s12031-020-01561-4.
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Tisato, Veronica, Paola Muggeo, Tracy Lupiano, Giovanna Longo, Maria Luisa Serino, Massimo Grassi, Ermanno Arcamone, et al. "Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS)." Genes 10, no. 9 (August 22, 2019): 634. http://dx.doi.org/10.3390/genes10090634.
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Childhood acute lymphoblastic leukemia (ALL) peaks around age 2–4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of DHFR 19bp ins/del (rs70991108; W/D), MTHFR C677T (rs1801133; C>T), and MTHFR A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DHFR DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; P = 0.002) as well as MTHFR 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; P = 0.006), and according to the strong linkage disequilibrium between MTHFR 677 T-allele and 1298C-allele, MTHFR TT-children showed early mean age of onset though not significant. Offspring of MTHFR 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; P = 0.017). DHFR/MTHFR 677 polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; P = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers (P = 0.00052). Correction for multiple comparisons maintained statistical significance for DHFR ins/del and MTHFR A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1–8.6; P = 0.03). The opposite effect DHFR promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency.
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Flower, Michael, Vilija Lomeikaite, Marc Ciosi, Sarah Cumming, Fernando Morales, Kitty Lo, Davina Hensman Moss, et al. "MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1." Brain 142, no. 7 (June 19, 2019): 1876–86. http://dx.doi.org/10.1093/brain/awz115.
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Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.
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Imwong, Mallika, Sasithon Pukrittakayamee, Sornchai Looareesuwan, Geoffrey Pasvol, Jean Poirreiz, Nicholas J. White, and Georges Snounou. "Association of Genetic Mutations inPlasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates." Antimicrobial Agents and Chemotherapy 45, no. 11 (November 1, 2001): 3122–27. http://dx.doi.org/10.1128/aac.45.11.3122-3127.2001.
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ABSTRACT Mutations in the Plasmodium falciparum gene (dhfr) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfrgene of P. vivax (pvdhfr) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (n = 100), India (n = 16), and Madagascar and the Comoros Islands (n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr(pvdhfr), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure.
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Wu, Yuanyuan, A. David Smith, Nasser E. Bastani, Helga Refsum, and Timothy Kwok. "The dihydrofolate reductase 19-bp deletion modifies the beneficial effect of B-vitamin therapy in mild cognitive impairment: pooled study of two randomized placebo-controlled trials." Human Molecular Genetics 31, no. 7 (November 12, 2021): 1151–58. http://dx.doi.org/10.1093/hmg/ddab246.
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Abstract Background: Higher serum homocysteine is associated with cognitive decline in older people. But homocysteine-lowering trials including folic acid (FA) show inconsistent results on cognitive decline. The reduction of FA to dihydrofolate by dihydrofolate reductase (DHFR) is slow in humans. Objective: We examined the effects of the DHFR 19-bp deletion/insertion (del/ins) polymorphism on FA-containing treatment on cognitive decline and brain atrophy in older people with mild cognitive impairment (MCI). Methods: This study used pooled data from two randomized B-vitamin trials on 545 MCI subjects who received either FA-containing B vitamins or placebo for 24 months. Subjects were typed for the DHFR genotype. Primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). Secondary outcomes were CDR-sum of boxes score (CDR-SOB), memory and executive Z-scores and whole brain atrophy rate by serial MRI. Results: The proportions of subjects with del/del, del/ins and ins/ins genotype were 29.5, 44.3 and 26.1%, respectively. DHFR genotypes modified the effects of B vitamins on CDR-global, CDR-SOB and executive function Z-score (Pinteraction = 0.017, 0.014 and 0.052, respectively), with significant benefits being observed only in those with ins/ins genotype (Beta = −1.367, −0.614 and 0.315, P = 0.004, 0.014 and 0.012, respectively). The interaction was not significant for memory Z-score and whole brain atrophy rate. Notably, the supplements only slowed brain atrophy in members of the ‘ins/ins’ group who were not using aspirin. Conclusions: Our data indicate that the beneficial effects of B vitamins including FA on cognitive function are only apparent in those with ins/ins genotype, i.e. relatively better preserved DHFR activity.
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Park, Jeong A., Hyoung Jin Kang, Ho Joon Im, Hee Young Shin, and Hyo Seop Ahn. "Association of genetic polymorphisms in the folate pathway with efficacy and toxicity of methotrexate in pediatric osteosarcoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10051. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10051.
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10051 Background: Osteosarcoma is the most common childhood malignant bone tumor. Methotrexate (MTX), one of the main drugs used for osteosarcoma, is a representative folic acid antagonist. Genetic polymorphisms in folate pathway genes are expected to influence the response and toxicity of high-dose MTX therapy. However, there are scarce data available regarding associations between genetic polymorphisms and pediatric osteosarcoma. This study evaluated the effect of common genetic polymorphisms in the folate metabolic pathway on overall survival, event-free survival and histological response to neoadjuvant chemotherapy including high-dose MTX. In addition, whether these genetic polymorphisms affect the concentrations of MTX and toxicity after high-dose MTX therapy for osteosarcoma was investigated. Methods: Blood and tissue samples from 48 osteosarcoma patients who had completed chemotherapy were obtained, and the following polymorphisms were analyzed; RFC1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, AMPD1 34C>T, ATIC 347C>G, and ITPA 94C>A. Associations between candidate polymorphisms and survival, histological response (tumor necrosis rate) and MTX level and toxicity after high-dose MTX therapy were analyzed. Results: Event-free survival significantly decreased in DHFR 829 CC homozygote (P=0.045). Variant carriers of MTHFR 677C>T had tendency towards poor histological response (P=0.078). MTX concentration was significantly associated with RFC1 80G>A polymorphism (P=0.027). Liver toxicity after high-dose MTX was associated with ATIC 347C>G (P=0.043) and tended to increase in carriers of MTHFR 677C>T (P=0.069). Severe stomatitis was associated with RFC1 80G>A (P=0.012). Conclusions: This study has demonstrated that several genetic polymorphisms in folate pathway can significantly influence therapeutic response, clinical outcome and MTX level and toxicity after high-dose MTX therapy in osteosarcoma patients. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of patients with osteosarcoma, aiding the development of tailored therapeutic approaches.
Dissertations / Theses on the topic "Dhfr polymorphism"
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LOTTO, VALENTINA. "Nutrient-gene interactions within one-carbon metabolism and effects on epigenetic regulation through dna methylation in peripheral blood mononuclear cells." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/18016.
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Epigenetics is a field of molecular biology that copes with the study of gene function regulation without variations in DNA structure or nucleotide sequences.
Among the main epigenetic phenomema in eukaryotic cells there are DNA methylation and post-traslational mechanisms among which the major are histone methylation and acetylation.
Epigenetic changes are potentially reversible phenomena that are controlled also by nutritional factors as the methyl-donors involved in the folate cycle.
Plasma levels of B vitamins, among which “in primis” plasma folate concentrations, are implicated in epigenetic modulation so that it can be hypothesized that they may affect the modulation of gene expression through epigenetic mechanisms.
Epigenetic modifications represent one of the earliest events in the genesis of some complex pathologies, therefore the study of the interaction between epigenetics and nutritional status is of great interest either to define the physiopathological mechanisms of development of some illnesses, and for possible personalized strategies of prevention.
The present work has been articulated, at first, on the analysis of gene-nutritional interaction mechanisms within the folate cycle through the study of polymorphisms of enzymes involved in the metabolism of methyl-group donors; the aim was to study their possible role on the modulation of genomic DNA methylation in relationship to different plasma levels of idrosoluble B vitamins. In this regard, the most important functional polymorfisms known on the genes of one-carbon metabolism and their relationship with methylation status of polymorphonuclear cells DNA have been analyzed from a cohort of around 800 subjects within a clinical study, underlining the role of the key folate-related enzymes in the modulation of DNA methylation.
Besides the function of genomic DNA methylation, the methylation status at specific sites has been also approached with the specific intent of considering a possible interrelationship between the role of promoter methylation and the co-presence of functional polymorphisms in the same genic site for a gene for which a precise functional effect is well-known. To address this issue the promoter region of coagulation factor VII gene was evaluated for both genetic and epigenetic modifications as a possible model of genetic-epigenetic interaction in the modulation of gene product regulation. The results showed the key importance of genetic-epigenetic interactions, so far unknowm, in modulating gene-expression at promoter gene sites.
The role of other vitamins involved in one-carbon metabolism in major chronic diseases, and specifically the emerging role of B6 vitamin, have been also studied.
Furthermore, a clinical study is now in progress to evaluate the function of gene-specific methylation in liver tissue where most of the folate cycle functions take place. The aim of this project is the evaluation of both genome-wide and gene-specific methylation status in the liver in comparison to that observed in peripheral blood mononuclear cells DNA to define whether methylation status of peripheral blood DNA may be regarded as a good systemic biomarker for this epigenetic feature of DNA in relation to B vitamins nutritional status in cancer disease. Results from this study may help to define possible functional markers of gene-nutrients interactions with effects on epigenetic modulation for future preventive or therapeutic strategies. With that purpose, a novel high-throughput array-based technique for the detection of gene-specific methylation at promoter sites has been optimized in our laboratory.
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ORIOLI, Elisa. "GENETIC POLYMORPHISMS OF THE FOLATE METABOLIC PATHWAY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. A MOLECULAR STUDY AND A PROPOSAL FOR AN INTERPRETATIVE MODEL." Doctoral thesis, Università degli studi di Ferrara, 2014. http://hdl.handle.net/11392/2389047.
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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer accounting for 80% of childhood leukemia. The uncontrolled proliferation of lymphoid progenitors in the bone marrow and the accumulation of malignant lymphoblasts in peripheral blood characterize the disease. The molecular analysis of common genetic alterations in lymphoblastic cells has strongly contributed to the comprehension of ALL pathogenesis. Different gene polymorphisms (most of them SNPs) play an important role in the susceptibility to childhood ALL which probably derives from a combination and relation of genetic and environmental factors. Folic acid and the pool of folate of the one carbon-metabolic-pathway are key elements involved in several processes including DNA synthesis and methylation. Polymorphisms in genes coding for enzymes of the folate metabolic pathway can alter the intracellular folate status or distribution and sub-optimal/anomalous folate levels/distribution increase the risk of developing several neoplasias. The two main enzymes involved in cyclization of folate isoforms are DHFR and MTHFR. The first one is responsible for the conversion of dihydrofolate to tetrahydrofolate whilst the second one catalyzes the reduction of 5,10-methylene-THF to 5-methyl-THF. Studies have demonstrated that subjects with the homozygous DD-genotype have higher DHFR mRNA levels that may be responsible for storage of THF and other isoforms within the cell; reduced enzyme activity instead, has been associated to MTHFR 677TT homozygotes. This condition is responsible for an underutilization of methylene-THF in the cell with storage of folate reduced isoforms. Several studies have demonstrated that DHFR and MTHFR polymorphisms may be protective against hematological cancers such as ALL. It is to note that current treatment regimens achieve levels about 80% in overall survival (OS). Unfortunately, the side effects derived from the chemotherapeutic agents used can be severe, especially for high-risk patients. Therefore, the identification of additional markers which can improve risk stratification and individual tailored therapy regimens would be a great goal, in order to avoid over-treatment which can increase long-term adverse side effects.
The aim of the present study was, therefore, to investigate whether common polymorphisms (i.e. MTHFR C677T and A1298C in addition to DHFR 19 bp INS/DEL and Bcl-2 -938 C>A) might influence the risk of childhood ALL. After a single analysis we can ascribe to MTHFR C677T gene polymorphism a protective significant role against childhood ALL (P=0.046), whilst Bcl-2 -938 C>A gene polymorphism seems to be a risk factor for the susceptibility to the disease (P=0.049). Then, considering parameters such as disease onset and therapy duration we can observe a significant higher mean age onset disease for homozygotes MTHFR 1298-CC (P=0.05). From the analysis of the therapy duration we found a significant association for MTHFR A1298C and Bcl-2 -938 C>A polymorphisms: MTHFR 1298CC homozygotes showed a slight higher mean therapy duration (P=0.05), as well as Bcl-2 -938AA homozygotes (P=0.03). Finally, in an exploratory way, to validate the proposed model we evaluated among healthy PBL cells harvested from subjects with opposite genotype condition considering DFHR and MTHFR genes (respectively, WW/CC and DD/TT), possible differences in base-line cellular viability and under MTX treatment. The pharmacological induced restriction in folate availability (MTX) yields to results in favor of WW/CC, whilst the base-line cell viability yields comparable results among genotypes. This is in line with the hypothesis that a higher MTX level could be present in DD/TT cells, prone to storage either natural folate isoforms (useful for the cell viability) or synthetic toxic analogue (MTX). This observation argues us into hypothesizing that also MTX being itself a synthetic folate analogue follows the same handling process. Now, inside the cell it should result in an elevated toxicity level, being responsible for an elevated death.
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Al-Shakfa, Fidaa. "Pharmacogénétique du DHFR chez les enfants leucémiques." Thèse, 2009. http://hdl.handle.net/1866/3692.
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Le dihydrofolate réductase (DHFR) est la principale cible du méthotrexate, un important composant du traitement de la leucémie lymphoblastique aiguë (LLA). Une association des polymorphismes du promoteur de DHFR avec l’issue de la LLA a été mise en évidence au laboratoire. Une survie sans événement (EFS) réduite corrélait avec les allèles A -317 et C -1610, et l’haplotype *1, défini par ces allèles. L’haplotype *1 était aussi associé à une expression élevée du DHFR. Dans cette étude, nous étendons l’analyse à la région régulatrice adjacente, d’environ 400 pb, correspondant au transcrit mineur non-codant du DHFR, qui joue un rôle essentiel dans la régulation de la transcription au niveau du promoteur majeur. Six polymorphismes ont été identifiés, parmi lesquels 5 étaient des SNPs et un polymorphisme de longueur composé d’un nombre variable d’éléments de 9 pb et d’une insertion/délétion de 9 pb. L’analyse d’haplotype, incluant tous les polymorphismes promoteurs, a révélé une diversification de l’haploytpe *1 en 5 sous-types (*1a à *1e). Les variations du promoteur majeur et les sous-types de l’haplotype *1 ont été par la suite analysés pour l’association avec l’issue de LLA. Un EFS réduit corrélait avec l’allèle A du polymorphisme G308A (p=0,02) et avec l’haplotype *1 (p=0,01). Des niveaux élevées d’ARNm étaient trouvés chez les porteurs de l’haplotype *1b (p=0,005) et pas pour les autres sous-types de l’haplotype *1. Alors, la mauvaise issue de LLA associée avec l'haplotype *1 est en effet déterminée par le sous-type *1b. Cette étude donne un nouvel aperçu des polymorphismes régulateurs du DHFR définissant plus précisément les variations du DHFR prédisposant un événement.Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. We recently reported an association of DHFR promoter polymorphisms with ALL outcome. Lower event free survival (EFS) correlated with the alleles A -317 and C -1610, and with haplotype *1, defined by these alleles. Haplotype*1 was also associated higher DHFR expression. Here we extended the analysis to adjacent 400bp regulatory region corresponding to non-coding minor DHFR transcript which plays an essential role in the regulation of transcription from the major promoter. Six polymorphisms were identified, of which 5 were SNPs and one length polymorphism composed of variable number of 9bp elements and 9bp insertion/deletion. Haplotype analysis including all promoter polymorphisms revealed diversification of haplotype *1 into 5 subtypes (*1a to *1e). Major promoter variations and haplotype *1 subtypes were subsequently analyzed for the association with ALL outcome. Lower EFS correlated with an A allele of G308A polymorphism (p=0.02) and with *1b haplotype (p=0.01). Higher mRNA levels were found in the carriers of *1b haplotype (p=0.005) and not for remaining haplotype *1 subtypes. So, the worse ALL outcome associated with haplotype *1 is actually determined by the subtype *1b. The study provides a new insight into DHFR regulatory polymorphisms defining more precisely event–predisposing DHFR variations.
Conference papers on the topic "Dhfr polymorphism"
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Castro, Margarida, Joana Ferreira, Diogo Sarmento, Carla Carvalho, Andreia Matos, and Manuel Bicho. "19 bp del DHFR POLYMORPHISM IN BRONCHIAL ASTHMA." In ERS International Congress 2018 abstracts. European Respiratory Society, 2018. http://dx.doi.org/10.1183/13993003.congress-2018.pa4461.
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Husna, M. Z., I. Endom, S. Ibrahim, N. Amaramalar Selvi, H. Fakhrurazi, R. Ohnmar Htwe, Y. Kanehaswari, et al. "Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers." In THE 2013 UKM FST POSTGRADUATE COLLOQUIUM: Proceedings of the Universiti Kebangsaan Malaysia, Faculty of Science and Technology 2013 Postgraduate Colloquium. AIP Publishing LLC, 2013. http://dx.doi.org/10.1063/1.4858667.
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