Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

Pangilinan, Faith; Molloy, Anne M.; Mills, James L.; Troendle, James; Parle‐McDermott, Anne; Signore, Caroline; O’Leary, Valerie B.; Chines, Peter S.; Seay, Jessica M; Geiler-Samerotte, Kerry; Mitchell, Adam; VanderMeer, Julia E.; Krebs, Kristine M.; Sanchez, Angelica; Cornman‐Homonoff, Joshua; Stone, Nicole R.; Conley, Mary; Kirke, Peadar N.; Shane, Barry; Scott, John M.; Brody, Lawrence C.

doi:10.1186/1471-2350-13-62

Cited by 71 publications

(76 citation statements)

References 53 publications

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“…A pesar que nuestros resultados no encontraron asociación entre variantes del gen MTHFR y la EB, consideramos que la vía metabó-lica del folato no puede aún ser excluida del todo como una causa de MM después de la FAF en Chile. Existen variables en otros genes involucrados en esta vía, tales como TYMS, MTHFD1, SHMT1 y MFTC que han sido involucrados en la etiología de la EB en otras poblaciones 31,32 . Por lo tanto, se requiere de nuevos estudios con el fin de aclarar la contribución global de esta vía metabólica en nuestro país, idealmente con tamaños muestrales mayores que permitan detectar riesgos genotípicos menores.…”

Section: Discussionunclassified

Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile

et al. 2014

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Section: Discussionunclassified

Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile

et al. 2014

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“…Inadequate folate status led to several types of birth defects, including certain heart defect, limb malformations, and in particular neural tube defects. Pangilinan et al (2012) reported common genetic variants in 82 candidate genes Pregnancy one-carbon metabolism and DNA methylation selected from 1-C-pathway, including MTHFR, as risk factors for neural tube defects. Other variants are involved in, for example, choline metabolism, reabsorption of vitamin B12, and mitochondrial folate transport.…”

Section: Discussionmentioning

confidence: 99%

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Mil¹,

Bouwland-Both²,

Stolk³

et al. 2014

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Correspondence should be addressed to R P M Steegers-Theunissen; Email: r.steegers@erasmusmc.nl † R P M Steegers-Theunissen is now at Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands AbstractMaternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C metabolism in early pregnancy in association with newborn DNA methylation levels of fetal growth and neurodevelopment candidate genes. The participants were 463 mother-child pairs of Dutch national origin from a large populationbased birth cohort in Rotterdam, The Netherlands. In early pregnancy (median 13.0 weeks, 90% range 10.4-17.1), we assessed the maternal folate and homocysteine blood concentrations, folic acid supplement use, and the MTHFR C677T genotype in mothers and newborns. In newborns, DNA methylation was measured in umbilical cord blood white blood cells at 11 regions of the seven genes: NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR. The associations between the 1-C determinants and DNA methylation were examined using linear mixed models. An association was observed between maternal folate deficiency and lower newborn DNA methylation, which attenuated after adjustment for potential confounders. The maternal MTHFR TT genotype was significantly associated with lower DNA methylation. However, maternal homocysteine and folate concentrations, folic acid supplement use, and the MTHFR genotype in the newborn were not associated with newborn DNA methylation. The maternal MTHFR C677T genotype, as a determinant of folate status and 1-C metabolism, is associated with variations in the epigenome of a selection of genes in newborns. Research on the implications of these variations in methylation on gene expression and health is recommended.

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“…To date, most studies have shown that the MTHFR C677T genotype is related to biomarkers, such as serum folate, tHcy concentration, and folate intake. Other polymorphisms in the folate pathway have been found to be associated with a variety of complex traits and disorders including MTHFR A1298C, MTRR A66G, MTR A2756G, MTHFD1 G1958A, FOLH1 T484C, SLC19A1 A80G, and transcobalamin II ( TCN2 ) C776G, the transport protein of vitamin B12 (Weisberg et al 1998; Gaughan et al 2001; Laverdiere et al 2002; Kluijtmans et al 2003; Dervieux et al 2004; Martinelli et al 2006; Moskau et al 2007; Silva et al 2011; Pangilinan et al 2012; Xie et al 2012). Table 1 summarizes the distribution of serum tHcy, folate, vitamin B6, and vitamin B12 according to polymorphisms related to folate and tHcy metabolism (Hiraoka et al 2004; Hiraoka et al 2009).…”

Section: Genetic Polymorphisms Related To Folate and Thcy Metabolism mentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

136

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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Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

Cited by 71 publications

References 53 publications

Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile

Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Genetic polymorphisms and folate status

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