Genetic variation in genes of folate metabolism and neural-tube defect risk

Linden, Ivon J. M. van der; Afman, Lydia A.; Heil, Sandra G.; Blom, Henk J.

doi:10.1079/pns2006495

Cited by 108 publications

(103 citation statements)

References 113 publications

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“…The genes that encode the proteins/enzymes related to folate uptake and metabolism include many polymorphisms, among which MTHFR C677T, CBS 844ins68, GCPII H475Y, MTR A2756G, and MTRR A66G are known to affect folate and vitamin B12 intake (Uauy et al 2014). Genetic polymorphisms related to the folate pathway have been shown to be associated with functional implications and specific conditions including NTDs (van der Linden et al 2006), cardiovascular disease (Klerk et al 2002), and some types of cancers, such as colorectal, breast, and lung cancers (Lee 2009). To date, most studies have shown that the MTHFR C677T genotype is related to biomarkers, such as serum folate, tHcy concentration, and folate intake.…”

Section: Genetic Polymorphisms Related To Folate and Thcy Metabolism mentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

134

102

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Moderate hyperhomocysteinemia‐induced low folate status is an independent risk factor for cardiovascular disease, dementia, and depression. Folate is an essential cofactor in the one‐carbon metabolism pathway and is necessary in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. In the folate cycle and homocysteine metabolism, folate, vitamin B12, vitamin B6, and vitamin B2 are important cofactors. Many enzymes are involved in folate transport and uptake, the folate pathway, and homocysteine (Hcy) metabolism, and various polymorphisms have been documented in these enzymes. Serum folate and total Hcy (tHcy) levels are influenced by folate intake and genetic polymorphisms in 5,10‐methylenetertahydrofolate reductase (MTHFR) such as C677T. The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, with a frequency of approximately 15% in Japanese populations. Individuals with the TT genotype have significantly higher tHcy levels and lower folate levels in serum than those with the CT and TT genotypes. However, administration of folic acid has been shown to eliminate these differences. Moreover, data have suggested that interventions based on genotype may be effective for motivating individuals to change their lifestyle and improve their nutrition status. Accordingly, in this review, we discuss the effects of MTHFR C677T polymorphisms on serum tHcy and folate levels with folic acid intervention and evaluate approaches for overcoming folic acid deficiency and related symptoms.

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Section: Genetic Polymorphisms Related To Folate and Thcy Metabolism mentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

134

102

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“…The methionine synthase reductase (MTRR) 66A>G variant has emerged as a possible genetic risk factor for NTDs. Other potential candidates are the MTHFR 1298A>C, methylene-tetrahydrofolate dehydrogenase (MTHFD) 1958G>A and transcobalamin 776C>G variants 64 . Unfortunately, most single nucleotide polymorphisms (SNPs) tested have not been shown to be associated with NTD risks of substantial magnitude 64 .…”

Section: Other Candidate Genesmentioning

confidence: 99%

“…Other potential candidates are the MTHFR 1298A>C, methylene-tetrahydrofolate dehydrogenase (MTHFD) 1958G>A and transcobalamin 776C>G variants 64 . Unfortunately, most single nucleotide polymorphisms (SNPs) tested have not been shown to be associated with NTD risks of substantial magnitude 64 . This indicates that many of the candidate genes studied so far might not be important in the mechanisms underlying the link between folate and NTD risk.…”

Section: Other Candidate Genesmentioning

confidence: 99%

“…Inspired by the identification of the MTHFR 677C>T variant, we and others have systematically explored many genes involved in folate metabolism, in individuals with NTDs or their mothers (for reviews, see REFS 44,[60][61][62][63][64] ). The methionine synthase reductase (MTRR) 66A>G variant has emerged as a possible genetic risk factor for NTDs.…”

Section: Other Candidate Genesmentioning

confidence: 99%

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Neural tube defects and folate: case far from closed

Shaw²,

et al. 2006

Self Cite

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Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ~50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.Neural tube defects (NTDs) are complex congenital malformations of the CNS. Anencephaly and spina bifida are the most common and severe forms of NTD, with a prevalence of about 1 in 1,000 births, although this varies throughout the world 1 . Infants with anencephaly are stillborn or die shortly after birth, whereas infants with spina bifida can survive but are likely to have severe lifelong disabilities and are at risk of psychosocial maladjustment. The estimated lifetime medical costs are high; for example, in California, USA, the costs for children born with spina bifida exceed US$81 million per year 2 .It has been known for more than 20 years that women can reduce their risk of having an NTDaffected pregnancy by taking folic acid supplements. However, the underlying mechanisms byCorrespondence to H.J.B. H.Blom@cukz.umcn.nl. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2010 November 2. Neurulation and neural tube defectsNeurulation has long fascinated scientists, as evidenced by a devoted literature that extends back hundreds of years. The process of neurulation occurs during early embryogenesis, starting with the formation of the neural plate from specialized ectodermal cells and culminating in the closure of the neural tube (FIG. 1), the precursor of both the CNS and most of the PNS. Considered most simply, the neural plate develops bilateral neural folds, which elevate and fuse at the midline to create the neural tube. Subsequent development, together with vesiculation within the tube, gives rise to the brain and spinal cord. Further details of this complex process are beyond the scope of this review (for reviews, see REFS 4,5 ).Neurulation seems to be highly complex and tightly regulated. The development and closure of the neural tube is usually completed by 28 days post-conception. This means that by the time a woman finds out that she is pregnant, the neural tube is almost completely closed. For the neural tube to close properly, genes that regulate various morphogenetic activities must function cooperatively. These activities include programmed cell death, neural crest...

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“…We previously demonstrated that nutrient deficiency is an important independent risk factor for birth defects (Zhang et al 2008a), and lower plasma concentrations of folate and vitamin B12 are related to an increased risk of NTDs in high-risk populations (Zhang et al 2009). Many polymorphisms in folate pathway genes have been investigated and shown to be associated with NTD risk (Zhu et al 2003;van der Linden et al 2006;Boyles et al 2006). However, none of the known folate pathway gene variants contribute substantially to the population burden of NTDs.…”

Section: Introductionmentioning

confidence: 99%

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

Wang

Guo

et al. 2013

Genes Nutr

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The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 lmol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG ? GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant.

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Genetic variation in genes of folate metabolism and neural-tube defect risk

Cited by 108 publications

References 113 publications

Genetic polymorphisms and folate status

Genetic polymorphisms and folate status

Neural tube defects and folate: case far from closed

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

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