Precision medicine for colorectal cancer
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
MTHFR (5,10-methylenetetrahydrofolate reductase) is a pivotal enzyme in folate metabolism catalyzing irreversible conversion of 5,10-methylenetetrahydrofolate (CH2THF) to 5-methyltetrahydrofolate (CH3THF), a cosubstrate for homocysteine remethylation to methionine (Goyette et al., 1994). This enzyme is encoded by MTHFR gene and is located on human chromosome 1 (Goyette et al., 1994). Two nonsynonymous variants, C677T in exon 4 (Ala222Val, rs1801133) and A1298C in exon 7 (Glu 429Ala, rs1801131), have been identified for the MTHFR gene and have been associated with decreased enzymatic activity and altered intracellular folate distribution (Frosst et al., 1995). Despite contradictory data, several clinical studies have demonstrated the potential predictive role of MTHFR genetic variants in toxicity and efficacy of 5-FU (De Mattia and Toffoli, 2009). Since a reduction in MTHFR enzymatic activity could lead to a decrease in intracellular CH3THF concentrations, it is hypothesized that tumors exhibiting the rare MTHFR variants may be more sensitive to 5-FU cytotoxicity compared to patients with a wild-type genotype (Etienne-Grimaldi et al., 2007).
Current and Potential Applications of Pharmacogenetics and Pharmacogenomics
John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb in Moderate to Severe Psoriasis, 2014
Methotrexate reversibly inhibits dihydrofolate reductase, disrupting the folate metabolic pathway and resulting in a blockade in the synthesis of the purine nucleotides and thymidylate, ultimately interfering with DNA synthesis, repair, and cellular replication [52]. Although the pharmacogenetics of methotrexate have not been studied extensively with respect to psoriasis, there has been an abundance of research in patients with rheumatoid arthritis. Several polymorphisms have been identified in methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in the folate pathway [53]. In a study by van Ede et al., patients with the polymorphism C677T, either homozygous or heterozygous for the variant, were found to have increased risk of experiencing elevation of liver enzymes severe enough to warrant discontinuation of the medication [54]. Another polymorphism in MTHFR, A1298C, has been discovered that also leads to an altered form of MTHFR but not to the extent that C677T disrupts the enzyme function [55]. Single-nucleotide polymorphisms (SNPs) in solute carrier family 19 (SLC19A1), which is a folate carrier controlling the influx of methotrexate in cells, have also been implicated in the increased risk of adverse events and discontinuation of methotrexate secondary to toxicity in rheumatoid arthritis patients [56].
Epigenetics and Assisted Reproduction Experimental Studies
Cristina Camprubí, Joan Blanco in Epigenetics and Assisted Reproduction, 2018
Concerning the origin of these anomalies, we know that the epigenome is subject to alterations caused by intrinsic and extrinsic factors (Chapter 6). Variations in the DNA sequence of factors involved in the methylation of DNA during spermatogenesis have been associated with sperm methylome alterations. For instance, some authors have reported DNMT3A and DNMT3L variations in infertile patients with sperm DNA methylation anomalies at imprinted loci (21). A significant number of authors have focused their research in determining the influence on the availability of methyl groups provided by the folate metabolism. A key factor of this process is methylenetetrahydrofolate reductase (MTHFR). MTHFR 677C > T polymorphism has been associated with male infertility, although with controversial results. A recent meta-analysis (22) have suggested that this MTHFR polymorphism is associated with male infertility, except in cases of oligozoospermia. Other factors involved in sperm DNA methylations, such as the specific factor CCCTC-binding factor-like protein (CTCFL/BORIS) has been discarded (23,24). In any case, since the sperm methylome is the result of a complex machinery that involved the participation of a great number of molecules, the uncovering of the genetic factors involved in the occurrence of variations will require well-designed and high-quality studies using throughput methodologies.
The influence of MTHFR genetic polymorphisms on adverse reactions after methotrexate in patients with hematological malignancies: a meta-analysis
Published in Hematology, 2019
Pingli Yao, Xia He, Rong Zhang, Rongsheng Tong, Hongtao Xiao
Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in the folic acid cycle. It can catalyze the reduction of 5-methyl-10-methyl-THF to 5-methyl-THF. The association of MTHFR genetic polymorphism and toxicities after giving MTX has also become a hot issue. In recent years, studies mainly focus on two single-nucleotide polymorphisms: 677C>T (rs1801133) and 1298A>C (rs1801131). The mutation of 677 C/T in MTHFR gene resulted in the substitution of alanine by valine, which can increase the intracellular homocysteine concentration and change the folic acid distribution. Glutamic acid will be replaced by alanine when base A mutates into base C in the MTHFR 1298 site, and it may cause the reduction of MTHFR activity [5]. Related reports showed that patients with MTHFR 677TT are associated with MTX clearance and are associated with the increased risk of mucositis, anemia, and so on [6–8]. There were also partial reports that suggested that the MTHFR genetic polymorphism may not be an accurate predictor for MTX-related toxicity [9,10].
Relationship between MTHFR Gene Polymorphisms and Gastrointestinal Tumors Development: Perspective from Eastern Part of Turkey
Published in Journal of Investigative Surgery, 2022
Ersoy Öksüz, Gökhan Görgişen, Gökhan Oto, Hülya Özdemir, Abbas Aras, Murat Öksüz, İsmail Musab Gülaçar, Muhammet Hamdi Demirkol
Methylenetetrahydrofolate reductase (MTHFR), which is the most important enzyme of folate metabolism and consists of 656 amino acids, converts 5,10 methylenetetrahydrofolate (5,10-methylene THF) into 5-methyl tetrahydrofolate (5-methyl THF). 5-methyl THF provides the necessary methyl group for DNA methylation, methionine synthesis, and remethylation of homocysteine. As 5,10-methylene THF converts into 5-methyl THF, it simultaneously oxidizes into 10-formyl THF, which ensures purine synthesis [8]. Any polymorphism or mutation on the gene coding the MTHFR enzyme causes a reduction in the activity of this enzyme. In serious cases of MTHFR enzyme deficiency, substrates in the MTHFR pathways accumulate, nucleic acid synthesis is affected, and hyperhomocysteinemia and homocystinuria occur due to the reduction in the amount of methyl necessary for biochemical events [9]. As a result of that, homeostasis is disrupted, and stroke, thrombosis, peripheral neuropathy, cardiovascular and cerebrovascular diseases are observed [10]. The most prevalent polymorphisms seen on the gene coding the MTHFR enzyme are C677T and A1298C. The C677T polymorphism changes the 677th nucleotide cytosine (C) into→ thymine (T) in the gene coding the MTHFR enzyme. The A1298C polymorphism causes the 1298th nucleotide to change from adenine (A) into → cytosine (C) [11]. It has been shown that these polymorphisms cause a predisposition to many types of cancer, including esophageal and gastric cancers, in addition to the diseases mentioned above [12–14].
Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population
Published in Systems Biology in Reproductive Medicine, 2018
Razieh Bigdeli, Mohammad Reza Younesi, Erfan Panahnejad, Vahid Asgary, Samaneh Heidarzadeh, Hoda Mazaheri, Samira Louni Aligoudarzi
The homozygous frequencies of mutations in MTHFR C677T or MTHFR 1298A/C were also increased in women with successive pregnancy loss compared to those that belong to the control groups. There are several reports that show the pathogenetic role of hyperhomocysteinemia (HHCY) in women with RPL, although the data regarding this issue in the literature do not show unequivocal results. Some researchers have reported increasing evidence for the relationship that has been observed between HHCY, methylenetetrahydrofolate reductase gene polymorphism C677T (MTHFR C677T) or MTHFR 1298A/C and RPL (Wouters et al. 1993; Sotiriadis et al. 2007; Torabi et al. 2012; Faramand et al. 2016). Considering this from another perspective, some other researchers did not report an association between HHCY or MTHFR C677T or MTHFR 1298A/C and RPL (Hohlagschwandtner et al. 2003; Abu-Asab et al. 2011; Yildiz et al. 2012; Dissanayake et al. 2012). Methylenetetrahydrofolate reductase catalyzes re-methylation of homocysteine and making a methionine. Elevated levels of homocysteine have been observed to be associated with C677T mutations of the MTHFR gene and have been identified as risk factor for thrombosis. The embryo toxic effects have been indicated to show a relation on influencing folic acid on the proliferation belonging to the rapidly dividing embryonic cells (Nadir et al. 2007).
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