Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects.

BACKGROUND Impaired one-carbon metabolism is thought to be associated with the risk of neural tube defects (NTDs); however, the role of methylation in NTDs remains unclear. Long interspersed nucleotide element-1 (LINE-1) constitutes 17-25% of the human genome. LINE-1 hypomethylation correlates with global DNA methylation levels in cancerous cells, but limited information is available on LINE-1 methylation in NTDs. OBJECTIVE We determined whether LINE-1 methylation patterns were associated with neural tube development and the possible relations between DNA methylation and key maternal metabolites involved in folate-mediated one-carbon metabolism. DESIGN Global methylation, maternal plasma folic acid, vitamin B-12, and total homocysteine (tHcy) concentrations were assessed in 48 NTD and 49 control samples by immunoassay, and LINE-1 methylation levels were evaluated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS Methylation levels of genomic DNA and LINE-1 decreased significantly in the neural tissue of NTD samples. The risk of NTDs increased with decreasing levels of LINE-1 methylation, with an odds ratio of 5.246 (95% CI: 1.519, 18.124; P = 0.009) for the lowest quartile (methylation level < or = 57.94%) compared with the highest quartile (methylation level > or = 60.94%). Compared with control subjects, case subjects had lower maternal plasma concentrations of vitamin B-12. CONCLUSIONS Hypomethylation of LINE-1 and genomic DNA was associated with an increased risk of NTDs. Functional insufficiency of maternal plasma vitamin B-12 was associated with NTDs, although no significant correlation could be established between maternal folic acid, vitamin B, tHcy, and LINE-1 methylation.

• Publication year

  2010

• Venue

  American Journal of Clinical Nutrition

• Publication date

  2010-05-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3945/ajcn.2009.28858PMID 20164316
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Maternal serum vitamin B12, folate and homocysteine and the risk of neural tube defects in the offspring in a high-risk area of China

  2009cited by this paper
• Neural tube defects in Australia: trends in encephaloceles and other neural tube defects before and after promotion of folic acid supplementation and voluntary food fortification.

  2009cited by this paper
• Genome-Wide Hypomethylation in Head and Neck Cancer Is More Pronounced in HPV-Negative Tumors and Is Associated with Genomic Instability

  2009cited by this paper
• Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer

  2009cited by this paper
• LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: A preliminary study

  2009cited by this paper
• Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism.

  2008cited by this paper
• Trends in the postfortification prevalence of spina bifida and anencephaly in the United States.

  2008cited by this paper
• LINE‐1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer

  2008cited by this paper
• Inhibition of methylation and changes in gene expression in relation to neural tube defects.

  2008cited by this paper
• High prevalence of NTDs in Shanxi Province: a combined epidemiological approach.

  2007cited by this paper
• Embryology of neural tube defects: information provided by associated malformations

  2007cited by this paper
• Excess methionine suppresses the methylation cycle and inhibits neural tube closure in mouse embryos

  2006cited by this paper
• DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia.

  2006cited by this paper
• Integrity of the methylation cycle is essential for mammalian neural tube closure.

  2006cited by this paper
• Neural tube defects and folate: case far from closed

  2006cited by this paper
• Analysis of repetitive element DNA methylation by MethyLight

  2005cited by this paper
• Inhibition of transmethylation disturbs neurulation in chick embryos.

  2005cited by this paper
• Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility.

  2005cited by this paper
• Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases.

  2004cited by this paper
• Mobile Elements: Drivers of Genome Evolution

  2004cited by this paper
• 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations are associated with DNA hypomethylation

  2004cited by this paper
• A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements.

  2004cited by this paper
• Retrotransposition-Competent Human LINE-1 Induces Apoptosis in Cancer Cells With Intact p53

  2004cited by this paper
• Cytosine methylation mediates sexual conflict.

  2003cited by this paper
• The genetic basis of mammalian neurulation

  2003cited by this paper
• Chromosomal Instability and Tumors Promoted by DNA Hypomethylation

  2003cited by this paper
• A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status

  2002cited by this paper
• public health issues in infant and child nutrition

  2002cited by this paper
• [Variation of plasma folate levels in adults between some areas and different seasons in China].

  2002cited by this paper
• Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population

  2001cited by this paper
• Retrotransposons as epigenetic mediators of phenotypic variation in mammals

  2001cited by this paper
• Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect.

  2001cited by this paper
• Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation

  2001cited by this paper
• Chemopreventive effects of dietary folate on intestinal polyps in Apc+/-Msh2-/- mice.

  2000cited by this paper
• Folate deficiency diminishes the occurrence of aberrant crypt foci in the rat colon but does not alter global DNA methylation status

  2000cited by this paper
• DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.

  1999cited by this paper
• DNA hypomethylation leads to elevated mutation rates

  1998cited by this paper
• Cytosine methylation and the ecology of intragenomic parasites.

  1997cited by this paper
• Identification of critical CpG sites for repression of L1 transcription by DNA methylation.

  1997cited by this paper
• DNA methylation and genetic instability in colorectal cancer cells.

  1997cited by this paper
• Asymmetric Methylation in the Hypermethylated CpG Promoter Region of the Human L1 Retrotransposon*

  1997cited by this paper
• Is mutated MTHFR a risk factor for neural tube defects?

  1996cited by this paper
• Recent developments in the understanding of the aetiology of neural tube defects.

  1995cited by this paper
• DNA methylation in folate deficiency: use of CpG methylase.

  1993cited by this paper
• Evidence for multi-site closure of the neural tube in humans.

  1993cited by this paper
• Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation.

  1992cited by this paper
• Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.

  1992cited by this paper
• Periconceptional use of multivitamins and the occurrence of neural tube defects.

  1989cited by this paper
• Periconceptional Use of Multivitamins and the Occurrence of Neural Tube Defects

  1988cited by this paper
• Vitamin dificiencies and neural tube defects.

  1976cited by this paper
• Reproductive Biology and Endocrinology Open Access Fundamental Roles of Reactive Oxygen Species and Protective Mechanisms in the Female Reproductive System

  year unknowncited by this paper

• Multi-tissue DNA methylation analysis to identify an appropriate surrogate tissue for a unique neurological tissue specific to spina bifida.

  2026cites this paper
• Associations of arsenic exposure and folate in maternal leukocyte DNA methylation: a case-control study of mothers with spina-bifida affected children

  2026cites this paper
• Excessive DNA Double‐Strand Breaks–Associated 3D Genome Reorganization Contributes to Neural Tube Defects with Folate Deficiency

  2025cites this paper
• Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development

  2025cites this paper
• Novel Variants of IGF2 Gene Are Linked With Neural Tube Defects‐An In Silico to Clinical Approach in West Bengal, India

  2025cites this paper
• Mechanisms of genome instability from cellular folate stress.

  2025cites this paper
• Protective Effect of myo-Inositol Against Decitabine-Induced Neural Tube Defects in Embryonic Zebrafish

  2025cites this paper
• Maternal Myo-Inositol Deficiency Involved Autophagy Impairment by PI3K/Akt/mTOR Signaling in Neural Tube Defects During Pregnancy

  2025cites this paper
• The Role of Folic Acid and Vitamin B12 in Gestational Diabetes Mellitus and Offspring Development: A Narrative Review.

  2025cites this paper
• Epigenetic role of LINE-1 methylation and key genes in pregnancy maintenance

  2024cites this paper
• Ethionine‐induced S‐adenosylmethionine deficiency suppressed H3K27me3 and cell differentiation during neural tube development in mice

  2024cites this paper
• Cycloleucine induces neural tube defects by reducing Pax3 expression and impairing the balance of proliferation and apoptosis in early neurulation.

  2024cites this paper
• Advances in DNA methylation of imprinted genes and folic acid regulation of growth and development.

  2024cites this paper
• Mapping of long interspersed element-1 (L1) insertions by TIPseq provides information about sub chromosomal genetic variation in human embryos

  2024cites this paper
• Maternal non-compliance with recommended folic acid supplement use alters global DNA methylation in cord blood of newborns: A cohort study.

  2024cites this paper
• Characterization of CircRNA-Associated CeRNA Networks in Folate Deficiency-Induced Neural Tube Defects.

  2023cites this paper
• Myelomeningocele: the evolution of care over the last 50 years

  2023cites this paper
• Effect of epigenetic activating of Dlk1-Dio3 imprinted cluster on miR-370 expression due to folate deficiency during nerve development.

  2023cites this paper
• Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

  2023cites this paper
• Embryonic exposure to decitabine induces multiple neural tube defects in developing zebrafish

  2023cites this paper
• Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?

  2023cites this paper
• Exploring epigenomic mechanisms of neural tube defects using multi‐omics methods and data

  2022cites this paper
• Loss‐of‐Function of p21‐Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects

  2022cites this paper
• An effective restoration of one-carbon metabolism in folate-deficient mice with a high-folate corn inbred line

  2022cites this paper
• Alterations in DNA Methylation in Orofacial Clefts

  2022cites this paper
• Homocysteine Metabolism in Pregnancy and Developmental Impacts

  2022cites this paper
• Overview of Neural Tube Defects: Gene–Environment Interactions, Preventative Approaches and Future Perspectives

  2022cites this paper
• Epigenetic Effect of Maternal Methyl-Group Donor Intake on Offspring’s Health and Disease

  2022cites this paper
• Hypermethylation of PI3K-AKT signalling pathway genes is associated with human neural tube defects

  2021cites this paper
• Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

  2021cites this paper
• Parental metal exposures as potential risk factors for spina bifida in Bangladesh.

  2021cites this paper
• Folate deficiency disturbs PEG10 methylation modifications in human spina bifida

  2021cites this paper
• Comprehensive analysis of gene expression and DNA methylation for preeclampsia progression

  2021cites this paper
• Control of LINE-1 Expression Maintains Genome Integrity in Germline and Early Embryo Development

  2021cites this paper
• Magnitude and determinants of neural tube defect in Africa: a systematic review and meta-analysis

  2021cites this paper
• Maternal biomarkers for early prediction of the neural tube defects pregnancies

  2020cites this paper
• Maternal Folic Acid Supplementation Mediates Offspring Health via DNA Methylation

  2020cites this paper
• DNA methylation abnormalities of imprinted genes in congenital heart disease: a pilot study

  2020cites this paper
• Genetic Basis of Neural Tube Defects

  2020cites this paper
• New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation

  2020cites this paper
• Identification of histone malonylation in the human fetal brain and implications for diabetes‐induced neural tube defects

  2020cites this paper
• The effect of folic acid deficiency on Mest/Peg1 in neural tube defects

  2020cites this paper
• TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis

  2019cites this paper
• MGMT is down-regulated independently of promoter DNA methylation in rats with all-trans retinoic acid-induced spina bifida aperta

  2019cites this paper
• Lower S-adenosylmethionine levels and DNA hypomethylation of placental growth factor (PlGF) in placental tissue of early-onset preeclampsia-complicated pregnancies

  2019cites this paper
• Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects

  2019cites this paper
• B-vitamins & one-carbon metabolism

  2019cites this paper
• Analysis of methylation datasets identified significantly changed genes and functional pathways in osteoarthritis

  2019cites this paper
• Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients

  2019cites this paper
• Low Maternal Dietary Folate Alters Retrotranspose by Methylation Regulation in Intrauterine Growth Retardation (IUGR) Fetuses in a Mouse Model

  2019influential citation
• BDE-47 Decreases Progesterone Levels in BeWo Cells by Interfering with Mitochondrial Functions and Genes Related to Cholesterol Transport.

  2019cites this paper
• The effect of folic acid deficiency on FGF pathway via Brachyury regulation in neural tube defects

  2019cites this paper
• Effects of prenatal alcohol exposure on the epigenome, gene expression and development

  2018cites this paper
• MGMT is down-regulated in rats with all-trans retinoic acid-induced spina bifida aperta independently of promoter DNA methylation

  2018cites this paper
• rs10732516 polymorphism at the IGF2/H19 locus associates with genotype-specific effects on placental DNA methylation and birth weight of newborns conceived by assisted reproductive technology

  2018cites this paper
• Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons

  2018cites this paper
• Regulation of the expression of tumor necrosis factor-related genes by abnormal histone H3K27 acetylation: Implications for neural tube defects

  2018cites this paper
• DNA methylation and socioeconomic status in a Mexican-American birth cohort

  2018cites this paper
• Integrated analysis of DNA methylation profiling and gene expression profiling identifies novel markers in lung cancer in Xuanwei, China

  2018cites this paper
• Evaluating LINE-1 methylation in cleft lip tissues and its association with early pregnancy exposures.

  2018cites this paper
• Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

  2018cites this paper
• Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects

  2018cites this paper
• Hypomethylation of GRHL3 gene is associated with the occurrence of neural tube defects.

  2018cites this paper
• Association of long interspersed nucleotide element-1 and interferon regulatory factor 6 methylation changes with nonsyndromic cleft lip with or without cleft palate.

  2018cites this paper
• Associations between genetic variation in one-carbon metabolism and leukocyte DNA methylation in valproate-treated patients with epilepsy.

  2017cites this paper
• Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity.

  2017cites this paper
• Syddansk Universitet Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment A two-step Mendelian randomization study

  2017cites this paper
• Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis

  2017cites this paper
• Interplay Between Maternal Micronutrients, DNA Methylation, and Brain Development

  2017cites this paper
• Folate deficiency disturbs hsa‐let‐7 g level through methylation regulation in neural tube defects

  2017cites this paper
• 171 – Pathophysiology of Neural Tube Defects

  2017cites this paper
• rs10732516 polymorphism at the IGF2/H19 locus associates with a genotype-specific trend in placental DNA methylation and head circumference of prenatally alcohol-exposed newborns

  2017cites this paper
• Altered GNAS imprinting due to folic acid deficiency contributes to poor embryo development and may lead to neural tube defects

  2017cites this paper
• University of Southern Denmark Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment A two-step Mendelian randomization study

  2017cites this paper
• Evaluating LINE-1 methylation in cleft lip tissues and its association with early pregnancy exposures

  2017cites this paper
• Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child’s IQ at age 8, cognitive performance and educational attainment: a two-step Mendelian randomization study

  2017cites this paper
• Prenatal airborne polycyclic aromatic hydrocarbon exposure, LINE1 methylation and child development in a Chinese cohort.

  2017cites this paper
• The interplay between DNA methylation, folate and neurocognitive development.

  2016cites this paper
• Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida

  2016cites this paper
• Prenatal Dexamethasone Exposure Increases the Susceptibility to Autoimmunity in Offspring Rats by Epigenetic Programing of Glucocorticoid Receptor

  2016cites this paper
• Methylome analysis for spina bifida shows SOX18 hypomethylation as a risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development

  2016cites this paper
• Profiling placental and fetal DNA methylation in human neural tube defects

  2016cites this paper
• Does arsenic increase the risk of neural tube defects among a highly exposed population? A new case-control study in Bangladesh.

  2016cites this paper
• Hypermethylation of AKT2 gene is associated with neural-tube defects in fetus.

  2016cites this paper
• Determining the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and genomic DNA methylation level: A meta-analysis.

  2016cites this paper
• DNA methylation in human development : methodologies and analytics for genome-wide studies

  2016cites this paper
• Genome-Wide DNA Methylation Changes During Aging

  2016cites this paper
• Nutri-epigenomic Studies Related to Neural Tube Defects: Does Folate Affect Neural Tube Closure Via Changes in DNA Methylation?

  2015cites this paper
• Gene-specific DNA methylation profiles and LINE-1 hypomethylation are associated with myocardial infarction risk

  2015cites this paper
• Abnormal epigenetic regulation of the gene expression levels of Wnt2b and Wnt7b: Implications for neural tube defects

  2015cites this paper
• Genomic DNA Hypomethylation Is Associated with Neural Tube Defects Induced by Methotrexate Inhibition of Folate Metabolism

  2015influential citation
• DNA methylation aberrations rather than polymorphisms of FZD3 gene increase the risk of spina bifida in a high-risk region for neural tube defects.

  2015cites this paper
• Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

  2015cites this paper
• DNA methylation of LINE-1 and Alu repetitive elements in relation to sex hormones and pubertal timing in Mexican-American children

  2015cites this paper
• DNA methylation analysis of Homeobox genes implicates HOXB7 hypomethylation as risk factor for neural tube defects

  2015cites this paper
• Tissue-Specific Methylation of Long Interspersed Nucleotide Element-1 of Homo Sapiens (L1Hs) During Human Embryogenesis and Roles in Neural Tube Defects.

  2015cites this paper
• Developments in our understanding of the genetic basis of birth defects.

  2015cites this paper
• Levels of PAH-DNA adducts in cord blood and cord tissue and the risk of fetal neural tube defects in a Chinese population.

  2015cites this paper
• Functional variant in methionine synthase reductase intron-1 is associated with pleiotropic congenital malformations

  2015cites this paper
• Neural tube defects.

  2014cites this paper