The Reduced Folate Carrier (RFC-1) 80A&gt;G Polymorphism and Maternal Risk of Having a Child with Down Syndrome:  A Meta-Analysis

Coppedè, Fabio; Lorenzoni, Valentina; Migliore, Lucia

doi:10.3390/nu5072551

Cited by 18 publications

(12 citation statements)

References 40 publications

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“…The present results concerning the RFC1 80G>A polymorphism are in accordance with those of previous studies of Down syndrome conducted among Brazilian populations [Biselli et al, 2008;Fintelman-Rodrigues et al, 2009;Brandalize et al, 2010;Zampiere et al, 2012]. In contrast, a recent meta-analysis of nine independent case-control studies concluded that the maternal RFC1 80G>A polymorphism might be associated with increased risk of giving birth to a child with DS, especially among carriers of the GG genotype [Copped e et al, 2013].…”

Section: Discussionsupporting

confidence: 91%

Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome

Bispo

Santos

Barros

et al. 2015

American J of Med Genetics Pt A

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Folate metabolism dysfunction can lead to DNA hypomethylation and abnormal chromosomal segregation. Previous investigations of this association have produced controversial results. Here we performed a case-control study in patients with Turner syndrome (TS) to determine the effects of genetic polymorphisms of folate pathway genes as potential risk factors for somatic chromosomal nondisjunction. TS is a useful model for this investigation because patients with TS show a high frequency of chromosome mosaicism. Here we investigated the possible association of polymorphisms of the MTHFR gene with TS risk, which has been previously investigated with controversial results. We also examined the effects of MTR, RFC1, and TYMS gene polymorphisms in TS for the first time. The risk was evaluated according to allelic and genotype (independent and combined) frequencies among 70 patients with TS and 144 age-matched healthy control subjects. Polymorphism genotyping was performed by PCR, PCR-RFLP, and PCR-ASA. The polymorphisms MTHFR 677C>T and 1298A>C, MTR 2756A>G, RFC1 80G>A, and TYMS 2R/3R-alone or in combinations-were not associated with the risk of chromosomal aneuploidy in TS. In conclusion, our present findings did not support a link between impaired folate metabolism and abnormal chromosome segregation leading to somatic nondisjunction in TS patients.

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Section: Discussionsupporting

confidence: 91%

Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome

Bispo

Santos

Barros

et al. 2015

American J of Med Genetics Pt A

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“…In 2006, we observed a borderline significant increased maternal risk of birth of a child with DS for carriers of the combined RFC1 80GG/ MTHFR 677TT genotype, and a reduced risk for carriers of RFC1 80(AA or AG)/ MTHFR 1298AA genotypes (Coppedè et al, 2006 ). Subsequent studies evaluating the possible contribution of this polymorphism to the maternal risk of having a DS child were conflicting (Table 1 ), but two recent meta-analyses (Yang et al, 2013 ; Coppedè et al, 2013c ) suggest that it could represent an independent maternal DS risk factor with ORs ranging from 1.1 to 1.3 according to the model under investigation (Table 2 ). Moreover, despite that its functional role is still controversial, the RFC1 80G>A polymorphism has been associated with reduced red cell folate concentrations among healthy women (Stanisławska-Sachadyn et al, 2009 ), and with reduced serum folate concentrations in MDS (Zampieri et al, 2012b ).…”

Section: Polymorphisms Of Folate Pathway Genes and Maternal Risk Of Bmentioning

confidence: 99%

“…Moreover, despite that its functional role is still controversial, the RFC1 80G>A polymorphism has been associated with reduced red cell folate concentrations among healthy women (Stanisławska-Sachadyn et al, 2009 ), and with reduced serum folate concentrations in MDS (Zampieri et al, 2012b ). However, less than 1.000 MDS were available for those meta-analyses, and subgroup stratification yielded inconclusive results likely because of the small case-control cohorts in each ethnic group (Coppedè et al, 2013c ; Yang et al, 2013 ). However, RFC1 80G allele frequency resulted higher in Caucasian and Brazilian MDS (ranging between 49.0% and 54.0%) than in Asian ones (36.0–36.5%) (Coppedè et al, 2013a ).…”

Section: Polymorphisms Of Folate Pathway Genes and Maternal Risk Of Bmentioning

confidence: 99%

The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects

Coppedè

2015

Front. Genet.

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Almost 15 years ago it was hypothesized that polymorphisms of genes encoding enzymes involved in folate metabolism could lead to aberrant methylation of peri-centromeric regions of chromosome 21, favoring its abnormal segregation during maternal meiosis. Subsequently, more than 50 small case-control studies investigated whether or not maternal polymorphisms of folate pathway genes could be risk factors for the birth of a child with Down syndrome (DS), yielding conflicting and inconclusive results. However, recent meta-analyses of those studies suggest that at least three of those polymorphisms, namely MTHFR 677C>T, MTRR 66A>G, and RFC1 80G>A, are likely to act as maternal risk factors for the birth of a child with trisomy 21, revealing also complex gene-nutrient interactions. A large-cohort study also revealed that lack of maternal folic acid supplementation at peri-conception resulted in increased risk for a DS birth due to errors occurred at maternal meiosis II in the aging oocyte, and it was shown that the methylation status of chromosome 21 peri-centromeric regions could favor recombination errors during meiosis leading to its malsegregation. In this regard, two recent case-control studies revealed association of maternal polymorphisms or haplotypes of the DNMT3B gene, coding for an enzyme required for the regulation of DNA methylation at centromeric and peri-centromeric regions of human chromosomes, with risk of having a birth with DS. Furthermore, congenital heart defects (CHD) are found in almost a half of DS births, and increasing evidence points to a possible contribution of lack of folic acid supplementation at peri-conception, maternal polymorphisms of folate pathway genes, and resulting epigenetic modifications of several genes, at the basis of their occurrence. This review summarizes available case-control studies and literature meta-analyses in order to provide a critical and up to date overview of what we currently know in this field.

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“…A significant risk was found for the 80GG genotype in NTD cases and mothers, whereas the heterozygous genotype of mothers and both the heterozygous and homozygous genotypes of the fathers do not appear to be significant NTD risk factors. In a separate study, a meta-analysis was conducted on a total of 930 mothers of children with Down's syndrome (DS) and 1240 control mothers showing an increase in the maternal risk for the G allele (Coppedè et al 2013). This analysis suggests that the maternal RFC1 80A.G polymorphism may be associated with an increased risk of having a birth with DS, particularly among carriers of the GG genotype.…”

Section: Genetic Variation In 1c Metabolism Alters Cell Physiologymentioning

confidence: 99%

One-carbon metabolism and epigenetic regulation of embryo development

Sinclair

2015

Reprod. Fertil. Dev.

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One-carbon (1C) metabolism consists of an integrated series of metabolic pathways that include the folate cycle and methionine remethylation and trans-sulfuration pathways. Most, but not all, 1C metabolic enzymes are expressed in somatic cells of the ovary, mammalian oocytes and in preimplantation embryos. The metabolic implications of this, with regard to the provision of methyl donors (e.g. betaine) and 1C cofactors (e.g. vitamin B12), together with consequences of polymorphic variances in genes encoding 1C enzymes, are not fully understood but are the subject of ongoing investigations at the authors' laboratory. However, deficiencies in 1C-related substrates and/or cofactors during the periconception period are known to lead to epigenetic alterations in DNA and histone methylation in genes that regulate key developmental processes in the embryo. Such epigenetic modifications have been demonstrated to negatively impact on the subsequent health and metabolism of offspring. For this reason, parental nutrition around the time of conception has become a focal point of investigation in many laboratories with the aim of providing improved nutritional advice to couples. These issues are considered in detail in this article, which offers a contemporary overview of the effects of 1C metabolism on epigenetic programming in mammalian gametes and the early embryo.

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The Reduced Folate Carrier (RFC-1) 80A>G Polymorphism and Maternal Risk of Having a Child with Down Syndrome: A Meta-Analysis

Cited by 18 publications

References 40 publications

Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome

Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome

The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects

One-carbon metabolism and epigenetic regulation of embryo development

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