Articles de revues : « Folate pathway polymorphism »

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Masud, Rizwan, et Haider Zaigham Baqai. « The communal relation ofMTHFR,MTR,ACEgene polymorphisms and hyperhomocysteinemia as conceivable risk of coronary artery disease ». Applied Physiology, Nutrition, and Metabolism 42, n^o 10 (octobre 2017) : 1009–14. http://dx.doi.org/10.1139/apnm-2017-0030.

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Homocysteine and its modulating genes have strongly emerged as novel biomarkers for coronary artery disease (CAD). In the present study, we investigated whether polymorphisms in homocysteine pathway genes and the plasma levels of homocysteine, folate, and vitamin B12, independently or in combination, are associated with CAD risk. A total of 504 participants were recruited (cases, n = 254; controls, n = 250, respectively). Tetra primer allele refractory mutation system polymerase chain reaction (PCR) was used for resolving the genotypes of 5′10′ methylenetetrahydrofolate reductase ‘MTHFR’ polymorphisms (rs1801133, rs1801131), 5′ methyl tetrahydrofolate homocysteine methyltransferase ‘MTR’ polymorphism (rs1805087), paroxanse1 ‘PON1’ polymorphism (rs662), and cystathionine beta synthase ‘CBS’ polymorphism (rs5742905). Conventional PCR amplification was carried out for resolving angiotensin converting enzyme ‘ACE’ insertion/deletion (I/D) polymorphism (rs4646994). ANOVA analysis, adjusted for the covariates, revealed that rs1801133, rs1805087 polymorphisms and homocysteine levels were associated with CAD. Logistic regression analysis (adjusted) revealed similar findings. Logistic regression analysis after applying factorial design to the studied single nucleotide polymorphisms (SNPs) revealed that homocysteine levels and heterozygous and mutant alleles at rs1801133, rs1805087, along with mutant alleles at rs1801131, rs4646994, conferred higher risk for CAD. Our results provide insight into the multifactorial nature of coronary artery disease. We highlight that SNPs in folate pathway genes and homocysteine have role in disease causation and can be used in disease prediction strategies.

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Mrozikiewicz, Aleksandra E., Anna Bogacz, Magdalena Barlik, Aleksandra Górska, Marlena Wolek et Małgorzata Kalak. « The role of folate receptor and reduced folate carrier polymorphisms in osteoporosis development ». Herba Polonica 65, n^o 2 (1 juin 2019) : 30–36. http://dx.doi.org/10.2478/hepo-2019-0011.

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Summary Introduction: Osteoporosis is a chronic metabolic disease with multifactorial etiology. One of possible osteoporosis causes may be impairment of osteoclasts function which leads to increased bone resorption. This may be a result of many metabolic changes. It is believed that changes of folate-methionine metabolism in osteoporosis play an essential role in the etiology of this disease. Objective: The aim of this study was to examine how polymorphisms of SLC19A1 and FOLR3 genes may play the key role in folate-methionine pathway and influence on the etiology of osteoporosis. Results: The statistically overrepresentation of mutated GG genotype of FOLR3 (rs11235449) was observed in the control group compared to the osteopenia (34.9% in osteopenia vs. 37.8% in controls, p=0.025, OR=0.61). As to the SLC19A1 (rs3788200) polymorphism we have noted the statistically significant over-representation of wild-type GG genotype (35.8% vs. 26.2%, p=0.046, OR=1.57) and overrepresentation of wild-type G allele (56.9% vs. 50.2%, p=0.061, OR=1.31) in osteopenia group if compared to the controls. Conclusions: In our study we shown the protective role of mutated GG genotype of FOLR3 (rs11235449) polymorphism to osteopenia progress and possible role of wild-type GG genotype and wild-type G allele of SLC19A1 (rs3788200) polymorphism in osteopenia development.

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Goricar, Katja, Viljem Kovac et Vita Dolzan. « Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma ». Radiology and Oncology 48, n^o 2 (1 juin 2014) : 163–72. http://dx.doi.org/10.2478/raon-2013-0086.

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Abstract Introduction. A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM. Methods. MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival. Results. Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03−0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10−8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05−0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03−0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15−52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64−19.66). Conclusions. MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.

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Erculj, Nina, Barbara Faganel Kotnik, Marusa Debeljak, Janez Jazbec et Vita Dolzan. « The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma ». Radiology and Oncology 48, n^o 3 (1 septembre 2014) : 289–92. http://dx.doi.org/10.2478/raon-2013-0076.

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Abstract Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTXrelated toxicity in children with NHL.

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Martinelli, Marcella, Luca Scapoli, Gabriella Mattei, Giampaolo Ugolini, Isacco Montroni, Davide Zattoni, Giancarlo Rosati et Rossella Solmi. « A candidate gene study of one-carbon metabolism pathway genes and colorectal cancer risk ». British Journal of Nutrition 109, n^o 6 (16 juillet 2012) : 984–89. http://dx.doi.org/10.1017/s0007114512002796.

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The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case–control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.

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Sener, Elif Funda, Didem Behice Oztop et Yusuf Ozkul. « MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders ». Genetics Research International 2014 (6 novembre 2014) : 1–5. http://dx.doi.org/10.1155/2014/698574.

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Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism.

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Vraneković, Jadranka, Goran Slivšek et Dijana Majstorović. « Methyltetrahydrofolate-homocysteine methyltransferase reductase gene and congenital heart defects in Down syndrome ». Genetics & ; Applications 4, n^o 1 (23 juin 2020) : 12. http://dx.doi.org/10.31383/ga.vol4iss1pp12-17.

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Congenital heart defects (CHD) are the most common abnormalities occurring in 40% -60% of Down syndrome (DS) patients. The 5-methyltetrahydrofolate homocysteine methyl transferase reductase (MTRR) is one of the key regulatory enzymes involved in folate pathway. Disrupted folate pathway due to MTRR polymorphism could be a risk factor for CHD in DS. The aim of the study was to determine the association between polymorphism MTRR 66A> G and CHD in DS. Additionally, the impact of maternal endogenous factors on CHD was analyzed, intake of folate through diet, periconceptional folic acid supplementation, smoking and alcohol drinking. A total of 155 children with DS and 148 their mothers have been enrolled in this study. Genotyping was performed by PCR-RFLP. The frequency of alleles and genotypes of MTRR 66A> G polymorphisms was not significantly different between a group with CHD compared to a group without CHD among DS subjects as well as in their mothers. The mothers with mutated homozygous genotypes who have taken folic acid preparations from the fourth week before pregnancy to eight weeks of pregnancy were more likely to have DS-CHD+ child. The study results suggested that maternal MTRR 66A> G polymorphisms associated with their lifestyle habits such as folic acid intake could altered individual risk for CHD in DS child.

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Kim, Hee Nam, Il-Kwon Lee, Yeo-Kyeoung Kim, Huong Thi Thanh Tran, Deok-Hwan Yang, Je-Jung Lee, Min–Ho Shin et al. « Association between folate-metabolizing pathway polymorphism and non-Hodgkin lymphoma ». British Journal of Haematology 140, n^o 3 (février 2008) : 287–94. http://dx.doi.org/10.1111/j.1365-2141.2007.06893.x.

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SUMMERS, CAROLYN M., ANDREW J. CUCCHIARA, ELENI NACKOS, ANDREA L. HAMMONS, ELISABETH MOHR, ALEXANDER S. WHITEHEAD et JOAN M. VON FELDT. « Functional Polymorphisms of Folate-Metabolizing Enzymes in Relation to Homocysteine Concentrations in Systemic Lupus Erythematosus ». Journal of Rheumatology 35, n^o 11 (novembre 2008) : 2179–86. http://dx.doi.org/10.3899/jrheum.080071.

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ObjectiveTo determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls.MethodsWe investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine β-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78.ResultsHomocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homocysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race.ConclusionPolymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

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Carinci, Francesco, Annalisa Palmieri, Luca Scapoli, Francesca Cura, Fabio Abenavoli, Aldo Bruno Giannì, Antonio Russillo, Raffaella Docimo et Marcella Martinelli. « Association between oral cleft and transcobalamin 2 polymorphism in a sample study from Nassiriya, Iraq ». International Journal of Immunopathology and Pharmacology 33 (janvier 2019) : 205873841985557. http://dx.doi.org/10.1177/2058738419855571.

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Orofacial clefts are common congenital defects whose prevalence differs between geographical regions and ethnic groups. The inheritance is complex, involving the contribution of both genetic and environmental factors. The involvement of genes belonging to the folate pathway is still matter of debate, with strong evidences of association and conflicting results. After demonstrating the contribution, for a sample from the Italian population, of common mutations mapping on three genes of the folate pathway, our group tried to unravel their contribution in independent sample studies with different ethnicity. In the present investigation a set of 34 triads with oral cleft from Nassiriya, Iraq, has been genotyped for rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS polymorphisms. Association analysis evidenced a decreased risk of cleft for children carrying the 667G allele at TCN2 gene ( P = 0.02). This evidence further supported the relationship between polymorphisms of folate related genes and oral clefts, and outlined the relevance of studying populations having different ethnicity.

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Park, Jeong A., Hyoung Jin Kang, Ho Joon Im, Hee Young Shin et 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, n^o 15_suppl (20 mai 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.

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Miyan, Jaleel, Charlotte Buttercase, Emma Beswick, Salma Miyan, Ghazaleh Moshkdanian et Naila Naz. « Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile ». Metabolites 12, n^o 6 (24 mai 2022) : 475. http://dx.doi.org/10.3390/metabo12060475.

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Metabolic disorders may be important potential causative pathways to Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by such changes in CSF, and genetic susceptibilities may exist in this pathway. In the current study, we aimed to identify whether any single nucleotide polymorphism (SNPs) affecting folate and the associated metabolic pathways were significantly associated with AD. We took a functional nutrigenomics approach to look for SNPs in genes for the linked folate, methylation, and biogenic amine neurotransmitter pathways. Changes in metabolism were found with the SNPs identified. An abnormal SNP in methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) was significantly predictive of AD and associated with an increase in tissue glutathione. Individuals without these SNPs had normal levels of glutathione but significantly raised MTHFD1. Both changes would serve to decrease potentially neurotoxic levels of homocysteine. Seven additional genes were associated with Alzheimer’s and five with normal ageing. MTHFD1 presents a strong prediction of susceptibility and disease among the SNPs associated with AD. Associated physiological changes present potential biomarkers for identifying at-risk individuals.

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Patel, Jenil, Emine Bircan, Xinyu Tang, Mohammed Orloff, Charlotte A. Hobbs, Marilyn L. Browne, Lorenzo D. Botto et al. « Paternal genetic variants and risk of obstructive heart defects : A parent-of-origin approach ». PLOS Genetics 17, n^o 3 (8 mars 2021) : e1009413. http://dx.doi.org/10.1371/journal.pgen.1009413.

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Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

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Kishi, Shinji, Cheng Cheng, Deborah French, Deqing Pei, Soma Das, Edwin H. Cook, Nobuko Hijiya et al. « Ancestry and pharmacogenetics of antileukemic drug toxicity ». Blood 109, n^o 10 (30 janvier 2007) : 4151–57. http://dx.doi.org/10.1182/blood-2006-10-054528.

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Abstract Treatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.

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Cortese, Claudio, et Corradino Motti. « MTHFR gene polymorphism, homocysteine and cardiovascular disease ». Public Health Nutrition 4, n^o 2b (avril 2001) : 493–97. http://dx.doi.org/10.1079/phn2001159.

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AbstractHomocysteine is an emerging new risk factor for cardiovascular disease. It is a thiol compound derived from methionine and involved in two main metabolic pathways: the cycle of activated methyl groups, requiring folate and vitamin B12 as cofactors, and the transsulfuration pathway to cystathionine and cysteine requiring vitamin B6 as cofactor. The homocysteine metabolism represents an interesting model of gene-environment interaction. Elevations in homocysteine may be caused by genetic defects in enzymes involved in its metabolism or by deficiencies in cofactor levels. A common polymorphism in the gene coding for the 5, 10-methylene tetrahydrofolate reductase (MTHFR) (C677T, Ala → Val) is associated with a decreased activity of the enzyme due to thermolability. In case of homozygosity for the Val allele, a relative deficiency in the remethylation process of homocysteine into methionine leads to a mild-to-moderate hyperhomocysteinemia, a condition recognized as an independent risk factor for atherosclerosis. The genetic influence of the MTHFR polymorphism on homocysteine levels is attenuated in females in premenopausal age and is not significant in subjects who exhibit serum levels of folate and/or vitamin B12 above the 50th percentile of distribution in the general population. The prevalence of the Val/Val genotype varies among different ethnic groups. It is very low in African populations, whereas in Europe and North America it ranges between 5% and 15%. In Italy an even higher prevalence has been reported in some regions. The question whether the MTHFR polymorphism might be per se an independent contributor to cardiovascular risk is debated. The interaction between this or other genetic factors and environmental/nutritional conditions (i.e. intake of vitamins such as folate) is a key determinant for homocysteine concentrations in healthy conditions as well as in some disease (i.e. in renal disorders). Another example of gene/environment interaction in the field of atherosclerosis is given by the apolipoprotein E polymorphism and its influence in response to diet. The presence of a high prevalence of risk-related allelic variants of such candidate genes within a certain population could serve to locally reinforce the recommendations concerning nutrient intake.

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T., Sunitha, Sowmya Gayatri C., Jharna P. et Satyanarayana U. « MATERNAL GENE POLYMORPHISMS OF VITAMIN B12 METABOLIC PATHWAY AND THEIR ASSOCIATION WITH CONGENITAL HEART DISEASES ». International Journal of Advanced Research 9, n^o 12 (31 décembre 2021) : 863–68. http://dx.doi.org/10.21474/ijar01/13986.

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Congenital heart disease (CHD) describes a huge set of structural and functional abnormalities that arises during cardio embryogenesis. Low levels of maternal vitamin B12 can disturb the homeostasis of the fetal folate metabolism pathway. The gene CUBN encodes for the intrinsic factorâ€“ cobalamin receptor (cubilin), which acts as a receptor for intrinsic factor to many compounds such as vitamin B12.Main aim of our study was to analyze association of CUBN G253A (rs1801222) variant with maternal serum folate, vitamin B12 and homocysteine (Hcy) levels and thereby its link with congenital heart defects. 110 pregnant women with vitamin B12 deficiency and carrying fetuses with CHD and equal number of age matched healthy women were selected as cases and control subjects respectively. Maternal serum folate, vitamin B12 and homocysteine levels as well as genetic polymorphism CUBN G253 â†’ A were assessed. In the present study, it was observed that cases with GA genotype, A allele under the dominant (p=<0.001) and allelic models (p<0.001) respectively and cases with AA genotype under the co-dominant (p<0.01) and recessive models (p<0.001) demonstrated an increased risk of an offspring with CHD. Furthermore, while cases with GA and AA genotypes of CUBN G253A variant showed significantly elevated Homocysteine, it was observed that all the CHD case mothers were vitamin B12 deficient irrespective of the CUBN genotype.

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Rai, Vandana. « Folate Pathway Gene MTHFR C677T Polymorphism and Risk of Lung Cancer in Asian Populations ». Asian Pacific Journal of Cancer Prevention 15, n^o 21 (28 novembre 2014) : 9259–64. http://dx.doi.org/10.7314/apjcp.2014.15.21.9259.

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Rai, Vandana. « Folate Pathway Gene Methylenetetrahydrofolate Reductase C677T Polymorphism and Alzheimer Disease Risk in Asian Population ». Indian Journal of Clinical Biochemistry 31, n^o 3 (23 juin 2015) : 245–52. http://dx.doi.org/10.1007/s12291-015-0512-2.

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Al-Gazali, L. I., R. Padmanabhan, S. Melnyk, P. Yi, I. P. Pogribny, M. Pogribna, M. Bakir et al. « Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect ». American Journal of Medical Genetics 103, n^o 2 (2001) : 128–32. http://dx.doi.org/10.1002/ajmg.1509.

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Chen, Qing, Nancy Fassinger, Ronald Thomas, Ana C. Xavier, Yubin Ge, Larry H. Matherly et Jeffrey W. Taub. « Altered Folate Metabolism Maybeo the Develop Linked tment of Acute Lymphoblastic Leukemia in African American Children. » Blood 114, n^o 22 (20 novembre 2009) : 4118. http://dx.doi.org/10.1182/blood.v114.22.4118.4118.

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Abstract Abstract 4118 Background Acute lymphoblastic leukaemia (ALL) is the most common form of childhood cancer in the United States. The incidence of ALL is approximately 2-3-fold higher in Caucasian compared to African American (AA) children, suggesting potential differences in genetic susceptibility and/or exogenous exposures. Multiple epidemiologic studies have examined both genetic and environmental factors linked to the development of childhood ALL, primarily in Caucasian populations. Hence, identifying factors associated with racial differences in incidence of leukemia may provide new insights into the role of endogenous versus exogenous factors in the development of leukemia. A number of studies have reported relationships between folate metabolism and the risk of developing ALL including: i)maternal folate supplementation during pregnancy (reduced risk of ALL in offspring); and ii)polymorphisms of genes encoding enzymes involved in folate metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR) (increased and decreased risks). To date, no studies have been performed specifically examining the role of folate metabolism in AA children. The objective of this study was to identify factors associated with folate metabolism which may be linked to the development of ALL in AA children compared to healthy controls. Patients and Methods AA children with B-precursor (BP) ALL were enrolled from the Hematology/Oncology Division of Children's Hospital of Michigan, while healthy AA children were enrolled as controls. Patients' racial backgrounds were based on parental reporting. The frequencies of polymorphisms in the MTHFR [677C>T, 1298A>C], thymidylate synthase [TS 2R3R], cystathionine-β-synthase [CBS 844ins(68)], and reduced folate carrier [RFC 80G>A] genes were determined by genotyping between AA childhood BP-ALL [n=26; 14 males] and healthy AA children [n=87; 47 males]. The distributions of genotypes between cases and controls were compared using Fisher's exact test. Results The genotype distributions of the polymorphisms of the folate pathway genes are summarized in Table 1. The frequencies of the MTHFR gene variants 677 CT/TT were 2-fold higher in the ALL cohort than that in the healthy control cohort. MTHFR 677 CT/TT was significantly associated with a risk of developing ALL in the AA patients. There were no significant differences in the distributions of the TS, CBS, or RFC polymorphisms between the groups. High birth weight has been associated with an increased risk of developing ALL, though we found no significant difference in birth weights between ALL and control groups. Conclusion Our study is the first to demonstrate that there is a higher frequency of the variant MTHFR C677T polymorphism (associated with reduced enzyme activity and altered distribution of folate forms) in AA children with ALL compared to healthy controls. Low MTHFR enzyme activity leads to imbalances in the thymidylate and de novo purine biosynthetic pathways, ultimately affecting DNA synthesis and repair and likely increasing the risk of leukemia. Thus, the role of altered folate metabolism may contribute to the development of ALL in AA children similar to Caucasian children, although additional studies are still required to identify factors linked to the higher incidence of ALL in Caucasian children and/or low incidence in AA children. Disclosures: No relevant conflicts of interest to declare.

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Dekou, Vanessa, Vilmundur Gudnason, Emma Hawe, George Miller, David Stansbie et Steve Humphries. « Gene-environment and Gene-gene Interaction in the Determination of Plasma Homocysteine Levels in Healthy Middle-aged Men ». Thrombosis and Haemostasis 85, n^o 01 (2001) : 67–74. http://dx.doi.org/10.1055/s-0037-1612906.

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SummaryHealthy middle-aged men (n = 1470) from eight general practices across Britain were examined for plasma total homocysteine levels and genotyped for the A222V polymorphism in the methylene-tetrahydrofolate (MTHFR) gene, the 68 bp insertion polymorphism in exon 8 of the cystathionine b synthase (CBS) gene and the D919G polymorphism in the methionine synthase (MS) gene. The median value for plasma homocysteine was 11.90 μmol/l (25–75% Interquartile range 10.10-14.20) for the whole sample. Smokers had significantly higher homocysteine levels than non-smokers (12.90 vs 11.70 μmol/l and p <0.00005) and levels significantly differed according to folate (p-value <0.00005), with men in the lowest quartile of folate having the highest median homocysteine levels. Genotype at all three loci was associated with differences in plasma homocysteine level. Individuals homozygous for the MTHFR V222 allele had 1.6 μmol/l higher median homocysteine levels when compared to the other two genotypes (p <0.00005), while for the CBS and MS genes, individuals carrying one or more of the rare alleles had lower median homocysteine than individuals homozygous for the common allele (0.80 μmol/l, p <0.03, and 0.70 μmol/l, p <0.04 respectively). The raising effect associated with homozygosity for the V222 allele was greater in men in the lowest quartile of folate (interaction between folate and genotype p = 0.02), but none of the genotype effects was significantly modulated by B12 levels. While the raising effects of V222 and MS D919 homozygosity on homocysteine level were essentially additive, the homocysteine lowering effect associated with the CBS 68bp allele was seen most strongly in men homozygous for the V222 allele (MTHFR-CBS genotype interaction p = 0.03) and the D919 allele (MS-CBS interaction p = 0.09). Age, folate, B12 and smoking explained 13.48% of the variance while the three genotypes combined and with interaction terms explained only an additional 2.63%. This interaction between CBS genotype and MTHFR and MS genotype points to a key role of the CBS transulphuration pathway in the metabolism of homocysteine that may be particularly important as a compensatory mechanism in subjects with low dietary folate.

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Laksono, Bremmy, Ani Melani Maskoen, Tri Indah Winarni, Syarief Taufik et Sultana MH Faradz. « Frequency of MTHFR GENE C677T Polymorphism for Non-Syndromic Autism Spectrum Disorder Patients ». Journal of Biomedicine and Translational Research 1, n^o 2 (31 décembre 2015) : 33. http://dx.doi.org/10.14710/jbtr.v1i2.61.

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Background: The folate metabolism is a pathway that may involve in the non-syndromic Autism Spectrum Disorder (ASD). Methylenetetrahydrofolate reductase enzyme has a key role in folate metabolism. The C677T polymorphism of MTHFR gene could reduce the effectiveness of the enzyme.Objectives: To evaluate the frequency of MTHFR geneC677T polymorphism for non-syndromic ASD patients.Method: Thirty-four DNA samples were taken from each group. PCR mixture was consisted of 1µL DNA, 2.5µL PCR buffer, 0.5µL dNTP, 1.5µL MgCL2, 0.125µLTaqenzyme, 0.5µLofforwardandreverseprimerandaquabidesttoreach a volume of 25 µL. The PCR profiles were initiation 95ºC for 5 min, denaturation 94ºC for 1min, annealing 55ºCfor 45 seconds, and elongation 72ºC for30 seconds. The cycles were done in 35 times an dfinal elongation was at 72ºC for 5min. The PCR product was 198bp, and then digested by the Hinfl enzyme for 16hours at 37°C, and visualized using2%agarosegeland then electrophoresed for 30 minutes at 100 volts.Result: Non-syndromic ASD samples showed none had homozygote mutant type (677TT), 3 (8.8%) samples had heterozygote (677CT)and 31 (91.2%) samples had wild type (677CC). Meanwhile, normal control showed only 1 (2.9%)sample had homozygote mutant type(677TT), 9 (26.5%) samples had heterozygote (677CT)and 24 (70.6%) samples had wild type (677CC).Conclusion: The frequency of MTHFR geneC677T polymorphism in patients with non-syndromic ASD and controls are not significantly different.

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Yi, Jian, Lan Xiao, Sheng-Qiang Zhou, Wen-Jiang Zhang et Bai-Yan Liu. « The C677T polymorphism of the methylenetetrahydrofolate reductase gene and susceptibility to late-onset Alzheimer’s disease ». Open Medicine 14, n^o 1 (4 janvier 2019) : 32–40. http://dx.doi.org/10.1515/med-2019-0006.

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AbstractFolate metabolism makes a crucial contribution towards late-onset Alzheimer’s disease (LOAD). Moreover, methylenetetrahydrofolate reductase (MTHFR) constitutes the primary enzyme of the folate pathway. We hypothesize that there is an association of C677T polymorphism in the MTHFR gene with the susceptibility to LOAD. Previous published research has investigated the link between the MTHFR C677T polymorphisms and LOAD susceptibility; nevertheless, the findings have continued to be not only controversial, but also indecisive. Accordingly, we carried out the present meta-analysis for the assessment of the potential link that exists between the MTHFR C677T polymorphism and the susceptibility to LOAD. Furthermore, we carried out a literature search of the PubMed, EMBASE, Cochrane Library, and WanFang database up to August 10, 2018. The odds ratios (ORs) with the respective 95% confidence interval (95%CI) were put to use for the evaluation of the robustness of the link of the MTHFR C677T polymorphism with the vulnerability to LOAD. All statistical analyses were carried out using STATA 15.0. An aggregate of 14 case-control research works was retrieved, involving 2,467 LOAD patients as well as 2,877 controls. We found that a substantial link exists between C677T polymorphism and LOAD risk in a codominant framework (TC vs. CC: OR=1.22, 95%CI=1.00-1.49, P=0.049). In addition to the stratified analysis based on ethnicity, which suggested that C677T polymorphism was likely linked only to an augmented threat of LOAD in Asians, it did not exist among Caucasians. Furthermore, in the subgroup analysis carried out using APOE ɛ4 status, a substantial increase in the susceptibility to LOAD was detected in APOE ɛ4 carriers as well as non-APOE ɛ4 carriers. In sum, the current meta-analysis revealed that MTHFR C677T polymorphism was associated with susceptibility to LOAD. Further extensive case-control studies are required.

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Bakhareva, Y. S., V. N. Maksimov, A. A. Ivanova, N. N. Chapaeva, S. V. Aidagulova et M. I. Voevoda. « Polymorphisms of candidate genes determining the clinical and hemostasiological characteristics of endocarditis of various etiology ». Bulletin of Siberian Medicine 21, n^o 1 (12 avril 2022) : 6–13. http://dx.doi.org/10.20538/1682-0363-2022-1-6-13.

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Aim. To investigate polymorphisms of 18 genes as possible molecular genetic markers of predisposition or resistance to development of non-infective (NE) or infective endocarditis (IE).Materials and methods. The study encompassed 81 patients with NE and 94 patients with IE. The control group included 225 conditionally healthy people. Polymorphisms of 18 genes were tested using polymerase chain reaction (PCR).Results. For the first time, a statistically significant relationship was identified between gene polymorphisms and valvular vegetations: for genes in the hemostatic system – rs6025 (1691 G > A) of the F5 gene (AG genotype), rs1126643 (807 C > T) of the ITGA2 gene (TT genotype); for folate pathway genes – rs1805087 (2756 A > G) of the MTR gene (AG genotype) and rs11697325 (–8202 A/G) of the MMP9 gene (AA genotype) and rs2476601 (C1858T) of the PTPN22 gene (TT genotype). The protective effect of gene polymorphisms was revealed: for the NOS3 gene (4b / 4b genotype) and G (–572) C of the IL6 gene (CC genotype). For two polymorphisms, an association with thromboembolic complications in NE was revealed: rs1126643 (807 C > T) of the ITGA2 gene and rs1799889 (–675 5G > 4G) of the PAI (SERPINE1) gene. In IE, such an association was detected for the polymorphism rs11697325 (–8202 A/G) of the MMP-9 gene.Conclusion. The polymorphisms of candidate genes were revealed, that are associated with the clinical and hemostasiological characteristics of IE and NE. In NE, for the first time, the association with thromboembolic complications was identified for two polymorphisms: rs1126643 (807 C > T) of the ITGA2 gene and rs1799889 (– 675 5G > 4G) of the PAI-1 (SERPINE1) gene. In IE, such a relationship was detected for one polymorphism – rs11697325 (8202 A/G) of the MMP-9 gene.

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Pradhan, Mandakini, Sanjay Behari, Samir K. Kalra, Priti Ojha, Sarita Agarwal et Vijendra K. Jain. « Association of methylenetetrahydrofolate reductase genetic polymorphisms with atlantoaxial dislocation ». Journal of Neurosurgery : Spine 7, n^o 6 (décembre 2007) : 623–30. http://dx.doi.org/10.3171/spi-07/12/623.

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Object Genetic mechanisms of atlantoaxial dislocation (AAD) have not previously been elucidated. The authors studied association of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes enzymes of the folate pathway (implicated in causation of neural tube defects [NTDs]), in patients with AAD. Methods Molecular analysis of MTHFR polymorphisms (677C→T, cytosine to thymine and, 1298A→C, adenine to cytosine, substitutions) was carried out using polymerase chain reaction and restriction enzyme digestion in 75 consecutive patients with AAD and in their reducible (nine patients, 12%) and irreducible (66 patients, 88%) subgroups. Controls were 60 age- and sex-matched patients of the same ethnicity. Comparisons of genotype and allele frequencies were performed using a chi-square test (with significance at p < 0.05). Results The CT genotype frequency of MTHFR 677C→T polymorphism was significantly increased in the full group of patients with AAD (odds ratio [OR] 3.00, 95% confidence interval [CI] 1.28–7.14, p = 0.005) as well as in the irreducible subgroup (OR 2.81, 95% CI 1.17–6.86, p = 0.01). The frequency of T alleles was also higher in the AAD group (25.3%) than in controls (15%). The comparison of the combined frequency of CT and TT genotypes with the frequency of the CC genotype again showed significant association in AAD (OR 2.63, 95% CI 1.98–5.90, p = 0.009) and the irreducible (OR 2.5, 95% CI 1.1–5.74, p = 0.016) subgroup. There was, however, no significant association of MTHFR 1298A→C polymorphism with AAD. Conclusions Both MTHFR 677C→T polymorphism and higher T allele frequency have significant associations with AAD, especially the irreducible variety. Perhaps adequate supplementation of periconceptional folic acid to circumvent effects of this missense mutation (as is done for prevention of NTDs) would reduce the incidence of AAD.

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Masud, Rizwan, et Irfan Zia Qureshi. « Tetra primer ARMS-PCR relates folate/homocysteine pathway genes and ACE gene polymorphism with coronary artery disease ». Molecular and Cellular Biochemistry 355, n^o 1-2 (13 mai 2011) : 289–97. http://dx.doi.org/10.1007/s11010-011-0866-6.

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Pinheiro Torres, R., F. Pimentel Dos Santos et J. Branco. « AB0014 METHOTREXATE - IMPLICATIONS OF PHARMACOGENETICS IN THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS ». Annals of the Rheumatic Diseases 80, Suppl 1 (19 mai 2021) : 1041.2–1042. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3749.

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Background:Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease modifying anti-rheumatic drug (DMARD), being widely used for the treatment of rheumatoid arthritis (RA) (1).Objectives:This review aims to describe the main genetic variants identified concerning proteins that play a role in methotrexate’s kinetics and efficiency profile.Methods:A literature review was conducted since January of 2000 until December 2020, by searching the PubMed and Embase bibliographic databases, employing the following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics and rheumatoid arthritis. The search was limited to articles in English language. Two independent reviewers screened the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. A total of 48 articles matched the research criteria and were analysed.Results:Genetic variants of four main proteins, with different functions, have been consistently described.Reduced folate carrier 1 (RFC1), a constitutively expressed folate transport protein that has high affinity for MTX is responsible, almost exclusively, for the transport of folate and MTX into the cell. The most commonly studied variant of the gene is the 80G > A variant (rs1051266), mapped within exon 2, on chromosome 21. It seems to improve RA responses to MTX, clinical efficacy with long disease remission (2).ABC transporters are involved in the eflux of MTX from cells. An increased expression and function of these transporters should decrease MTX concentrations in target cells, resulting in lack of therapeutic response. ABCB1 3435 C/T (rs1045642) is a high frequency polymorphism, significantly associated with RA good responses, symptom remission and reduced adverse events, due to MTX treatment (3).Thymidylate synthase (TYMS) is involved in thymidine synthesis. MTX decreases TYMS activity by inhibition and decreasing the access to tetrahydrofolate (THF) cofactors (1). The most common genetic variant of the TYMS gene consists of a 28 bp tandem repeat (rs34743033), with double and triple number of repeats (2R and 3R). The 3R allele genotype was associated with decreased efficacy and increased toxicity (4).The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is indirectly inhibited by MTX. The most common SNPs of the MTHFR gene are C677T (rs1801133) and A1298C (rs1801131). Both are associated with a decreased efficacy and an increased toxicity of MTX (5).Conclusion:MTX response is affected by many gene variants; the effect of each variant separately is likely to be small. Additionally, gene-gene interaction, enhancing the potential role of linkage disequilibrium. This shows the emerging need for a better gene characterization and to improve the knowledge about variants distribution according to ethnicity, to explain different responses to MTX at an individual level.References:[1]Song, G. et al. Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol33, 1715–1724 (2014).[2]Hayashi H. et al. A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet. 2013;28(2):164-8.[3]Zhu H. et al. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014 Mar;15(4):551-66.[4]Owen SA. et al. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharm J. 2013;13:227–34.[5]Hughes LB. et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2006;65:1213–8.Disclosure of Interests:None declared

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Colomina, Jose, Pere Cavallé-Busquets, Sílvia Fernàndez-Roig, Pol Solé-Navais, Joan Fernandez-Ballart, Mónica Ballesteros, Per Ueland, Klaus Meyer et Michelle Murphy. « Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy ». Nutrients 8, n^o 10 (9 octobre 2016) : 621. http://dx.doi.org/10.3390/nu8100621.

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Kempisty, Bartosz, Anna Bober, Marta Łuczak, Piotr Czerski, Aleksandra Szczepankiewicz, Joanna Hauser et Paweł P. Jagodziński. « Distribution of 1298A > ; C polymorphism of methylenetetrahydrofolate reductase gene in patients with bipolar disorder and schizophrenia ». European Psychiatry 22, n^o 1 (janvier 2007) : 39–43. http://dx.doi.org/10.1016/j.eurpsy.2006.11.003.

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AbstractWe investigated the genotype frequency of methylenetetrahydrofolate reductase (MTHFR) 1298A > C polymorphism in the group of patients with bipolar disorder type I (BDI) (n = 200) and schizophrenia (n = 200) and in the control group (n = 300). Odds ratio (OR) for patients with BD and schizophrenia in 1298CC homozygous state was 3.768 (95% CI = 1.752–8.104); P = 0.0003; (P = 0.0006 after Bonferroni correction) and 2.694; (95% CI = 1.207–6.013); P = 0.0123 (P = 0.0246 after Bonferroni correction), respectively. The stratification of patients based on gender revealed significant association of 1298CC genotype with female patients only with BDI (OR = 7.293; 95% CI = 2.017–26.363; P = 0.0005).Our results confirm association of BD and schizophrenia with the 1p36.3 MTHFR locus and with the methyl group transfer using folate-dependent one-carbon pathway.

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Liu, Shuguang, Chao Gao, Ruidong Zhang, Xiaoxi Zhao, Lei Cui, Weijing Li, Huyong Zheng et Zhigang Li. « Germline Genetic Variations in Methotrexate Candidate Genes Are Associated with Pharmacokinetics and Outcome in Pediatric Acute Lymphoblastic Leukemia in China ». Blood 128, n^o 22 (2 décembre 2016) : 1595. http://dx.doi.org/10.1182/blood.v128.22.1595.1595.

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Abstract BackgroundMethotrexate (MTX) is a key chemotherapeutic agent in the treatment of pediatric acute lymphoblastic leukemia (ALL). Nevertheless, MTX can cause severe adverse effects and toxicities. The aim of the present study was to identify genetic polymorphisms in candidate genes of the MTX pathway associated with MTX pharmacokinetics, toxicity, and outcome in ALL in China. MethodsThree hundred and twenty-two Chinese children with ALL in the standard-risk and medium-risk treatment branches from the Beijing Children's Hospital-2003 and Chinese Childhood Leukemia Group-2008 protocols were enrolled in this study. Sequenom MassARRAY was used to genotype 12 single nucleotide polymorphisms (SNPs) in 4 candidate genes of the MTX/folate pathway. A total of 1268 high-dose MTX (HD-MTX) courses were analyzed. The plasma MTX levels were evaluated at 48 h after the first dose of HD-MTX infusion. Oral mucositis during the consolidation therapy period was recorded. Results No polymorphism was associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. Long-term outcome was better in SLCO1B1 rs4149056 T and TC allele carriers than patients with C allele (5-year RFS 92.3±1.6% vs. 27.8±23.2%,P<0.0001), in ABCB1 rs1128503 T and TC allele carriers than patients with C allele (92.7±1.6% vs. 78.2±6.9%, P=0.020), and in SCL19A1 rs2838958 AG and G allele carries than patients with A allele (93.9±1.6% vs. 83.0±4.2%, P =0.010). Multiple Cox regression analyses revealed an association of MRD at day 33 (hazard ratio 3.356; P=0.018), MRD at day 78 (hazard ratio 2.843; P=0.034), and SLCO1B1 rs4149056 (hazard ratio 8.073; P=0.002) with RFS in the study population. As to MTX pharmacokinetics, ABCB1 rs1128503 showed a significant association with serum MTX levels (P=0.004). SNPs (rs3788200, rs1131596, rs1051266) of the SLC19A1 gene were also associated with the plasma levels of MTX (P=0.003, 0.004, and 0.003, respectively). No association was found between oral mucositis with any polymorphism. Conclusions Genetic variations substantially influence the kinetics and response to HD-MTX therapy in childhood ALL. Disclosures No relevant conflicts of interest to declare.

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Isidori, Alessandro, Annamaria Ruzzo, Federica Loscocco, Maria Teresa Voso, Francesco Graziano, Sara Barulli, Emanuele Canestrari et al. « The Mutational Status Of Genes Involved In DNA Repair and Folate Pathway Predicts Overall Survival Of Patients With Low-Risk, Untreated Myelodysplastic Syndrome ». Blood 122, n^o 21 (15 novembre 2013) : 2815. http://dx.doi.org/10.1182/blood.v122.21.2815.2815.

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Abstract Background Despite the prediction of a fairly benign clinical course, a subset of patients with low-risk myelodysplastic syndromes (MDS) have a more aggressive disease and shorter overall survival. The DNA repair and folate pathway genes play an important role in prognosis and progression in both solid and hematological cancers, and their expression has been known to be associated with polymorphism of genes. However, the impact of polymorphisms of these genes on MDS patients outcome has not yet been demonstrated. The aim of this study was to investigate the association between the polymorphisms of genes encoding main proteins of BER system (XRCC1, XRCC3 and APE1) and folate-metabolizing enzymes (TS, MTHFR) and survival in IPSS low-intermediate1 MDS patients. Methods the study was designed according to the Schoenfeld design for biomarkers, assuming the presence of an unfavorable pharmacogenetic profile (one or more adverse genotypes) in at least one-third of the study population. Accordingly, 10 events in 54 patients would allow the detection of an Hazard Ratio (HR) >6 associated with the group having unfavorable genotypes (80% power and 5% type I error for a two-tailed test). We thus prospectively genotyped 54 MDS patients (median age 75 years) with IPSS low (n=23) or intermediate-1 (n=31) treated with best supportive care only. Genomic DNA was isolated from 1ml of peripheral blood by means of commercially available kits. Polymorphisms were determined by PCR-HRM (High Resolution Melting) assay and restriction digests of PCR products. All samples were analyzed for the following polymorphisms: XRCC1 194 (rs1799782 C/T, Arg/Trp) and 399 (rs25487 G/A, Arg/Gln), XRCC3 241 (rs861539 C/T, Thr/Met), TS5'-UTR (2R/3R and rs183205964 G/C) and 3'-UTR Ins/Del (rs11280056 6bp+/6bp-), MTHFR 677 (rs1801133 C/T, Ala/Val) and 1298 (rs801131 A/C, Gln/Ala), APE1 148 (rs1130409 T/G, Asp/Glu). The characteristics and laboratory features of MDS patients with each polymorphisms were compared using Х2-test and Mann-Whitney test. The associations between polymorphisms status and survival were assessed using Kaplan-Meier method and Log-rank test. For the multivariate survival analysis, Cox proportional hazard models, was used to identify the genotypes fitted as indicator variables. Before performing clinical correlations, genotype frequencies were checked for agreement with those expected under the Hardy-Weinberg equilibrium. Results The frequencies of genotypes of studied gene polymorphisms in patients with low/Int-1 risk are listed in Table 1. At univariate analysis, a significantly shorter survival was associated with XRCC1 399 GG, TS3’-UTR -6/-6, TS5’-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR 677 TT variant alleles. In multivariate analysis, using a stepwise logistic regression model, patients with TS3’-UTR -6/-6, XRCC1-399 GG, TS5’-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR- 677 TT unfavorable genotypes presented with an Hazard Ratios of 4.65, 7.07, 11.44 and 67.12, respectively, if compared to the reference group of variant alleles (P=.058, P=.024, P=.026 and P=.000). Accordingly, we performed an exploratory analysis to investigate the effect on survival arising from the combination of the unfavorable genotypes to each other. As a fact, 3-years OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles, suggesting that patients with a higher number of variant alleles had a shorter survival. Conclusions The mutational status of BER, TS and MTHFR genes predicts the overall survival of patients with low-Int-1 IPSS MDS treated with best supportive care only. If confirmed on larger series, these polymorphisms could help to identify a subset of low-risk MDS patients with shorter survival, who might benefit from an early therapy with hypometilating agents. Acknowledgments The study was supported in part by AIL Pesaro Onlus. Disclosures: No relevant conflicts of interest to declare.

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Faganel Kotnik, Barbara, Iztok Grabnar, Petra Bohanec Grabar, Vita Dolžan et Janez Jazbec. « Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma ». European Journal of Clinical Pharmacology 67, n^o 10 (21 avril 2011) : 993–1006. http://dx.doi.org/10.1007/s00228-011-1046-z.

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Karas Kuželički, Nataša, Alenka Šmid, Maša Vidmar Golja, Tina Kek, Borut Geršak, Uroš Mazič, Irena Mlinarič-Raščan et Ksenija Geršak. « A Common Polymorphism in the MTHFD1 Gene Is a Modulator of Risk of Congenital Heart Disease ». Journal of Cardiovascular Development and Disease 9, n^o 6 (24 mai 2022) : 166. http://dx.doi.org/10.3390/jcdd9060166.

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Several environmental and genetic factors may influence the risk of congenital heart defects (CHDs), which can have a substantial impact on pediatric morbidity and mortality. We investigated the association of polymorphisms in the genes of the folate and methionine pathways with CHDs using different strategies: a case–control, mother–child pair design, and a family-based association study. The polymorphism rs2236225 in the MTHFD1 was confirmed as an important modulator of CHD risk in both, whereas polymorphisms in MTRR, FPGS, and SLC19A1 were identified as risk factors in only one of the models. A strong synergistic effect on the development of CHDs was detected for MTHFD1 polymorphism and a lack of maternal folate supplementation during early pregnancy. A common polymorphism in the MTHFD1 is a genetic risk factor for the development of CHD, especially in the absence of folate supplementation in early pregnancy.

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Shiao, S., James Grayson et Chong Yu. « Gene-Metabolite Interaction in the One Carbon Metabolism Pathway : Predictors of Colorectal Cancer in Multi-Ethnic Families ». Journal of Personalized Medicine 8, n^o 3 (6 août 2018) : 26. http://dx.doi.org/10.3390/jpm8030026.

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For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike’s Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer.

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Liu, Ching-Ti, David Karasik, Hanfei Xu, Yanhua Zhou, Kerry Broe, L. Adrienne Cupples, Lisette Cpgm de Groot et al. « Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density ». American Journal of Clinical Nutrition 114, n^o 2 (8 mai 2021) : 578–87. http://dx.doi.org/10.1093/ajcn/nqab093.

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ABSTRACT Background Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin–dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine β-synthase (CBS). Objectives We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin–related measures with bone mineral density (BMD) and strength. Methods We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5’-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. Results The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. Conclusions Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength. These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.

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Coppedè, Fabio, Andrea Stoccoro, Pierpaola Tannorella et Lucia Migliore. « Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels ». Metabolites 9, n^o 12 (7 décembre 2019) : 298. http://dx.doi.org/10.3390/metabo9120298.

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DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped for MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131), MTRR 66A > G (rs1801394), MTR 2756A > G (rs1805087), SLC19A1 (RFC1) 80G > A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp insertion/deletion (indel) (rs34489327), DNMT3A -448A > G (rs1550117), and DNMT3B -149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation.

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Matsuo, Keitaro, Ritsuro Suzuki, Nobuyuki Hamajima, Michinori Ogura, Yoshitoyo Kagami, Hirofumi Taji, Eisei Kondoh et al. « Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma ». Blood 97, n^o 10 (15 mai 2001) : 3205–9. http://dx.doi.org/10.1182/blood.v97.10.3205.

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Abstract Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C→T and MTHFR1298 A→C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A→G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospital-based case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. Further studies to confirm the association and detailed biologic mechanisms are now required.

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Kitami, Toshimori, Renee Rubio, William O'Brien, John Quackenbush et Joseph H. Nadeau. « Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice ». Physiological Genomics 35, n^o 2 (octobre 2008) : 182–90. http://dx.doi.org/10.1152/physiolgenomics.00294.2007.

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Dietary folate supplementation can dramatically reduce the severity and incidence of several common birth defects and adult diseases that are associated with anomalies in homocysteine and folate metabolism. The common polymorphisms that adversely affect these metabolic pathways do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test involvement of folate, homocysteine, and other pathways in disease pathogenesis and treatment response, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared with the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE-deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting that homeostasis among the homocysteine, folate and cholesterol metabolic pathways contributes to the beneficial effects of dietary folate supplementation.

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Santos-Rebouças, C. B., J. C. Corrêa, A. Bonomo, N. Fintelman-Rodrigues, K. C. V. Moura, C. S. C. Rodrigues, J. M. Santos et M. M. G. Pimentel. « The impact of Folate Pathway Polymorphisms Combined to Nutritional Deficiency As a Maternal Predisposition Factor for Down Syndrome ». Disease Markers 25, n^o 3 (2008) : 149–57. http://dx.doi.org/10.1155/2008/487023.

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Polymorphisms in genes encoding folate metabolizing enzymes have been linked to an increased risk of maternal chromosomal nondisjunction in several populations. With the purpose of evaluating this relationship, we compared the frequencies of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and 66A>G in the methionine synthase reductase gene (MTRR) between 103 young mothers of Down syndrome (DS) individuals and 108 control mothers, whose offspring was karyotypically normal, correlating it with an estimative of folate and – related micronutrients levels intake. Maternal and paternal transmission frequencies ofMTHFR677T allele were also examined to access potential parent-of-origin effects. PCR-RFLP for genomic DNA was accomplished and allele/genotype frequencies differences were determined using the x2test, whereas pattern of transmission of theMTHFR677 allele was analyzed by transmission disequilibrium test. None of the polymorphisms seemed to be more frequent in case mothers than in controls, either individually or combined. The estimative of nutritional intake revealed that folate consumption median was inadequate in both groups, whereas methionine and zinc consumption medians were significantly greater in control mothers. It suggests that such interaction between genetic profile and environment could predispose this sub group of women to have a DS child. Additional studies focusing the interaction between nutritional intakes, biochemical data and folate pathway polymorphisms are needed to confirm the present results. The possibility of neutralize the biochemical negative effects of folate-related polymorphisms through oral supplementation could provide new targets for DS prevention.

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Mithen. « Effect of Genotype on Micronutrient Absorption and Metabolism : a Review of Iron, Copper, Iodine and Selenium, and Folates ». International Journal for Vitamin and Nutrition Research 77, n^o 3 (1 mai 2007) : 205–16. http://dx.doi.org/10.1024/0300-9831.77.3.205.

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For the majority of micronutrients, there are very little data, or none at all, on the role of genetic polymorphisms on their absorption and metabolism. In many cases, the elucidation of biochemical pathways and regulators of homeostatic mechanisms have come from studies of individuals that have mutations in certain genes. Other polymorphisms in these genes that result in a less severe phenotype may be important in determining the natural range of variation in absorption and metabolism that is commonly observed. To illustrate some of these aspects, I briefly review the increased understanding of iron metabolism that has arisen from our knowledge of the effects of mutations in several genes, the role of genetic variation in mediating the nutritional effects of iodine and selenium, and finally, the interaction between a genetic polymorphism in folate metabolism and folic acid fortification.

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Yeoh, Allen Eng-Juh, Shirley Kow-Yin Kham, Yi Lu, Toon-Chai Foo, Hany Ariffin et Thuan-Chong Quah. « Genetic Polymorphisms in the Folate Pathway and Risk of Childhood Acute Lymphoblastic Leukemia (ALL) : MTHFR, MTHFD1, RFC1 and TS. » Blood 108, n^o 11 (1 novembre 2006) : 2274. http://dx.doi.org/10.1182/blood.v108.11.2274.2274.

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Abstract Folate is critical for DNA synthesis and methylation; dysfunction in methylating enzymes may result in genomic instability and DNA damage via the nucleotide synthesis pathways. We hypothesize that perturbation in the folate metabolism pathway may alter the risk of developing childhood leukaemia. We recently reported that methylenetetrahydrofolate reductase (MTHFR 677C>T) was associated with reduced risk in childhood ALL. We aim to explore the value of a pathway approach, in this case exploring the impact of polymorphisms in multiple enzymes involved in the folate pathway, to determine its role in development of childhood ALL. As childhood ALL is highly heterogeneous and that some like TEL-AML1 and hyperdiploid subgroups have in utero origin, we postulated that the impact of folate metabolism may be greatest for in utero onset ALL. We analyzed the methylenetetrahydrofolate dehydrogenase (MTHFD1), reduced folate carrier (RFC1) and thymidylate synthase (TSER 5′-UTR 28bp repeat, TSER 3′-UTR 6bp deletion) in 360 children with ALL and 433 controls of Chinese and Malay origin (Ch=221, Mal=212). Genotyping was performed by RFLP-PCR, TEL-AML1 by RT-PCR, and hyperdiploidy either DNA index (≥1.16) or karyotyping. The latter was only available in some patients, especially in the Chinese. Using logistic regression model analysis, MTHFR 677C>T and MTHFD1 1958G>A showed significant influence on leukemia susceptibility in the Chinese (n=235, p=0.005) and Malays (n=125, p=0.032) respectively. In the Chinese cohort, MTHFR 677 CT and TT genotypes significantly decreased risk of childhood ALL as compared to CC wild type (p=0.004, OR=0.57, 95%CI=0.39–0.83), as well as in the hyperdiploidy subgroup (n=35, p=0.002, OR=0.28, 95%CI=0.12–0.65). The combined effect of RFC 80GA and AA genotypes with MTHFR 677CC wild type also decreased risk of childhood ALL in Chinese (p=0.05, OR=0.47, 95%CI=0.22–1.0). In the Malay cohort, the MTHFR 677 CT and TT genotypes played a protective role only in the TEL-AML1 subgroup (n=27) as compared to CC wild type (p=0.05, OR=0.24, 95%CI=0.06–1.0). However, interestingly MTHFD1 1958GG wild type decreased risk of childhood ALL as compared to MTHFD1 1958GA or AA genotypes (p=0.02, OR=0.54, 95%CI=1.11–3.05) when combined with MTHFR 677CC genotype. Haplotype analysis of TSER variants showed no significant effect in the 2 races. Using a candidate pathway approach, we showed that polymorphisms in the folate pathway significantly modified the risk of developing childhood ALL especially the MTHFR, MTHFD1 and RFC1. This effect may arise from different genes of the same pathway and this may be different for different races. This supports a pathway way rather than a single-gene approach towards elucidation of cancer risk in childhood ALL.

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Niclot, Sidonie, Quentin Pruvot, Caroline Besson, Daniel Savoy, Elisabeth Macintyre, Gilles Salles, Nicole Brousse et al. « Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas ». Blood 108, n^o 1 (1 juillet 2006) : 278–85. http://dx.doi.org/10.1182/blood-2005-04-1567.

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The incidence of follicular lymphoma (FL) in industrialized countries has been increasing since the 1950s. Polymorphisms in genes encoding key enzymes controlling folate-methionine metabolism, including methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS or MTR), serine hydroxymethyltransferase (SHMT), and thymidylate synthase (TS or TYMS), modify the risk of various cancers and possibly FL. This study specifically looks for an association between MTHFR, MTR, TYMS, and SHMT polymorphisms and the risk of FL. We carried out a case-control study with 172 patients diagnosed with FL and 206 control subjects. We report that the risk of FL was doubled by the association of one mutant allele at both MTHFR polymorphisms. Individuals with MTR 2756AA had 2-fold higher risk of FL, and subjects not having at least one TYMS 2R allele showed a 2-fold higher risk of FL. The MTR 2756AA genotype conferred a greater multivariate-adjusted relative risk of FL, and the risk was multiplied by almost 5 in the TYMS2R(-)/MTR 2756AA combination. In conclusion, common polymorphisms in key enzymes of the folate-methionine metabolism pathway result in an increased risk of FL and suggest that inadequate intake of dietary folate and other methyl donor nutrients may contribute to the development of this malignancy. (Blood. 2006;108:278-285)

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COCOLOS, Andra-Maria, et Catalina POIANA. « Differentiated Thyroid Cancer Genetic Mechanisms - Focus on Vitamin D Receptor and Methylenetetrahydrofolate Reductase Gene Polymorphisms ». Medicina Moderna - Modern Medicine 29, n^o 1 (30 mars 2022) : 7–13. http://dx.doi.org/10.31689/rmm.2021.29.1.7.

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Thyroid cancer is the most frequent endocrine cancer representing 1-1.5% of all cancers. Approximately 90% of these are differentiated thyroid carcinomas (DTC) with a favorable prognosis and cure rate. DTC has recently witnessed an increase in incidence with a relatively stable mortality rate, mostly due to intensive screening. Despite being considered indolent and the 10-year survival rate being above 90%, local or distant recurrence can be observed in up to 20% of cases. Mutations in BRAF, RET, RAS, NTRK1, PAX8-PPARG are commonly found in DTC but studies show that genetic alterations with apparently no correlation to DTC might improve or aggravate prognosis. Vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms is consider to be one of these factors, due to the fact that it exerts immunological and antineoplastic functions throught its antiproliferative and prodifferentiating actions. FokI gene polymorphism has been associated with later stage and negative prognosis in different studies. Also, polymorphisms of genes involved in folate metabolism (MTHFR, MTR, RFC1) may be incriminated in carcinogenesis, folate being an extremely important factor in DNA synthesis. Studies suggest that through correction and avoidance of incriminated neoplastic agents, thyroid cancer incidence, evolution and prognosis might improve significantly. For this to be possible we need to be aware of the molecular pathways these environmental factors use to exert their carcinogenic effects.

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Petrone, Igor, Paula Sabbo Bernardo, Everton Cruz dos Santos et Eliana Abdelhay. « MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer : A Review ». Genes 12, n^o 4 (17 avril 2021) : 587. http://dx.doi.org/10.3390/genes12040587.

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Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.

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Martinelli, Marcella, Luca Scapoli, Paolo Carbonara, Ilaria Valentini, Ambra Girardi, Francesca Farinella, Gabriella Mattei et al. « Idiopathic pulmonary fibrosis and polymorphisms of the folate pathway genes ». Clinical Biochemistry 46, n^o 1-2 (janvier 2013) : 85–88. http://dx.doi.org/10.1016/j.clinbiochem.2012.10.009.

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Chango, Abalo, Nathalie Fillon-Emery, Clotilde Mircher, Henri Bléhaut, Daniel Lambert, Bernard Herbeth, S. Jill James, Marie-Odile Réthoré et Jean Pierre Nicolas. « No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers ». British Journal of Nutrition 94, n^o 2 (août 2005) : 166–69. http://dx.doi.org/10.1079/bjn20051490.

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The cause of the non-disjunction leading to trisomy 21 remains unclear. Recent evidence has suggested that 5, 10-methylenetetrahydrofolate reductase (MTHFR) and/or methionine synthase reductase (MTRR) might contribute to the maternal risk of trisomy 21. The purpose of the present study was to analyse these findings among the French population and to investigate whether common polymorphisms in genes of the folate and homocysteine pathway, including the MTHFR 677C>T, MTHFR 1298A>C, the methionine synthase (MTR) 2756A>G, the cystathionine β-synthase (CBS) 844Ins68 and the reduced folate carrier (RFC-1) 80G>A polymorphisms, contribute to the risk of trisomy 21. The risk was studied by analysing independent and combined genotypes in 119 case mothers and 119 control mothers. The MTHFR 677T, MTHFR 1298C, MTR2756G, MTRR66G, CBSIns68+ and the RFC-1 80G allele frequencies were not significantly different among French case mothers, compared with control mothers. The risk of having a child with trisomy 21 did not appear to be linked to polymorphisms in genes associated with folate and homocysteine metabolism.

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Zanrosso, Crisiane W., Mariana Emerenciano, Flavio Ramos, Alexandre Figueiredo, Isis Q. Magalhaes, Edinalva Leite, Vanessa Cavalcanti, Maria TC Muniz et Maria S. Pombo-de-Oliveira. « Little Evidence of the Protective Role of MTHFR Genetic Polymorfism in Acute Leukaemia and Down Syndrome in Brazil. » Blood 104, n^o 11 (16 novembre 2004) : 4427. http://dx.doi.org/10.1182/blood.v104.11.4427.4427.

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Abstract Immunomolecular and genetic markers are great tools to understand the pathway of leukemogenesis. Because of acute leukemias (ALs) commonly arise as result of DNA damage and/or DNA translocations, the polymorphism of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) have been associated to reduced enzyme activity and altered distribution of cellular folate metabolites. We have determined the prevalence of MTHFR mutations C677T and A1298C in 227 children with AL from different regions of Brazil and 279 region-matched subjects as the control group. PCR-RFLP method was applied using HinfI and MboII restriction digestion to determine the MTHFR 677 and 1298 respectively. Odds ratio (OR) and 95% confidence intervals (95%CI) were used as statistics standard methods. There were 202 acute lymphoblastic leukemias (ALL) and 65 acute myeloid leukemias (AML) from three different regions of Brazil. The frequencies of the 677CC, 677CT and 677TT genotype were 57%, 33%, 10% in the ALL cases; and 51%, 40%, 9% in the controls, respectively. Whereas the frequencies of MTHFR 1298AA, 1298AC and 1298CC were 52%, 40%, 8% in the ALL cases and 61%, 32%, 7% in the controls, respectively. Also, we analyzed separately a group of Down syndrome (DS) cases that include (i) DS with AL and, (ii) DS without AL. The frequencies of the 677CC, 677CT and 677TT genotype were 2,16%, 2,37%, 0% in the DS with AL cases, and 4,31%, 3,02%, 0,22% in the DS without AL, respectively. Whereas the frequencies of MTHFR 1298AA, 1298AC, 1298CC were 2,94%, 1,05%, 0,84% in the DS with AL and 4,83%, 2,10%, 0,63% in the DS without AL, respectively. There were no differences of MTHFR C677T frequencies in both groups in overall analysis. However, the frequency of MTHFR 677 and MTHFR 1298 genotypes differ between cases and controls in different regions of Brazil (p<0.04). The overall analysis indicates that MTHFR C677T and A1298C may confer a protective effect against childhood acute leukemia only in distinct group of cases. Region OD IC (95%) p South 0.41 0.045–3.59 0.69 Southeast 0.78 0.265–2.33 0.84 Northeast 1,02 0.385–2.65 0.69

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Almekkawi, Ahmad K., Marwa W. AlJardali, Hicham M. Daadaa, Alison L. Lane, Ashley R. Worner, Mohammad A. Karim, Adrienne C. Scheck et Richard E. Frye. « Folate Pathway Gene Single Nucleotide Polymorphisms and Neural Tube Defects : A Systematic Review and Meta-Analysis ». Journal of Personalized Medicine 12, n^o 10 (29 septembre 2022) : 1609. http://dx.doi.org/10.3390/jpm12101609.

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Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In this review we examine single nucleotide polymorphisms (SNPs) of the genes in the folate pathway associated with NTD. We reviewed the literature for all papers discussing both NTDs and SNPs in the folate pathway. Data were represented through five different genetic models. Quality assessment was performed using the Newcastle–Ottawa Scale (NOS) and Cohen’s Kappa inter-rater coefficient assessed author agreement. Fifty-nine papers were included. SNPs in MTHFR, MTRR, RFC genes were found to be highly associated with NTD risk. NOS showed that high quality papers were selected, and Kappa Q-test was 0.86. Our combined results support the notion that SNPs significantly influence NTDs across the population, particularly in Asian ethnicity. Additional high-quality research from diverse ethnicities is needed and meta-regression analysis based on a range of criteria may provide a more complete understanding of the role of folate metabolism in NTDs.

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Skibola, Christine F., Matthew S. Forrest, Fabio Coppedé, Luz Agana, Alan Hubbard, Martyn T. Smith, Paige M. Bracci et Elizabeth A. Holly. « Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma ». Blood 104, n^o 7 (1 octobre 2004) : 2155–62. http://dx.doi.org/10.1182/blood-2004-02-0557.

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Abstract Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R] → double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)-6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL. (Blood. 2004;104: 2155-2162)

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Vohra, Manik, Anu Radha Sharma, Bobby Paul, Manoj K. Bhat, Kapaettu Satyamoorthy et Padmalatha S. Rai. « In silicocharacterization of functional single nucleotide polymorphisms of folate pathway genes ». Annals of Human Genetics 82, n^o 4 (25 mars 2018) : 186–99. http://dx.doi.org/10.1111/ahg.12231.

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