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Maternal risk for Down syndrome is modulated by genes involved in folate metabolism.

ABSTRACT: Studies have shown that the maternal risk for Down syndrome (DS) may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B_{12} status) concentrations. The polymorphisms transcobalamin II (TCN2) c.776C>G, betaine-homocysteine S-methyltransferase (BHMT) c.742A>G, methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) c.677 C>T and the MTHFR 677C-1298A-1317T haplotype modulate DS risk. The polymorphisms MTHFR c.677C>T and solute carrier family 19 (folate transporter), member 1 (SLC19A1) c.80 A>G modulate folate concentrations, whereas the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) c.66A>G polymorphism affects the MMA concentration. These results are consistent with the modulation of the maternal risk for DS by these polymorphisms.

SUBMITTER: Zampieri BL

PROVIDER: S-EPMC3826801 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Maternal risk for Down syndrome is modulated by genes involved in folate metabolism.

Zampieri Bruna Lancia BL Biselli Joice Matos JM Goloni-Bertollo Eny Maria EM Vannucchi Hélio H Carvalho Valdemir Melechco VM Cordeiro José Antônio JA Pavarino Erika Cristina EC

Disease markers 20120101 2

Studies have shown that the maternal risk for Down syndrome (DS) may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B<formula>_{12}</formula> status) concentrations. The polymorphisms transcobalamin II (TCN2) c.776C>G, betaine ...[more]

PMID: 22377700

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Project description: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.

Dataset Information

Maternal risk for Down syndrome is modulated by genes involved in folate metabolism.

Publications

Maternal risk for Down syndrome is modulated by genes involved in folate metabolism.

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