Abstract
A common polymorphism (c.80A>G) in the gene coding for the reduced folate carrier (SLC19A1, commonly known as RFC-1) has been associated with maternal risk of the birth of a child with Down Syndrome (DS), but results are controversial. We searched major online databases to identify available case-control studies, and performed a meta-analysis to summarize the data concerning this association. Nine independent case-control studies were identified for a total of 930 DS mothers (MDS) and 1240 control mothers. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using both fixed and random effects models. An increase in the risk of having a birth with DS was observed for carriers of the homozygous GG genotype (OR 1.27, 95% CI 1.04–1.57; p = 0.02, fixed effects model), even after removal from the meta-analysis of published data with deviations from Hardy-Weinberg equilibrium (HWE) in controls (OR 1.26, 95% CI 1.02–1.55; p = 0.03, fixed effects model). Moreover, the pooled OR under the fixed effects model showed an increase in the maternal risk for the G allele (OR 1.14, 95% CI 1.01–1.30; p = 0.03). Present results suggest that the maternal RFC-1 80A>G polymorphism might be associated with an increased risk of having a birth with DS, particularly among carriers of the GG genotype.
Highlights
Green vegetables, fruits, cereals, calf’s liver and beans are the major sources of dietary folates whose metabolism, referred to as one-carbon metabolism, is required for the production of the major intracellular methylating agent S-adenosylmethionine (SAM), and for the synthesis of DNA and RNA precursors [1]
In 1999, James and coworkers observed that impairments of one-carbon metabolism, due to the presence of polymorphic genes, could be maternal risk factors for the birth of a child with Down Syndrome (DS) [11], and subsequent in vitro studies revealed that folate deficiency induces chromosome 21 aneuploidy [12,13]
The main finding of the study was a significant association under the recessive genetic model (GG vs. AG or AA), with an Odds ratios (OR) = 1.27 if all the studies were evaluated, and an OR = 1.26 after removal of the study with Hardy-Weinberg equilibrium (HWE) deviations in controls
Summary
Fruits, cereals, calf’s liver and beans are the major sources of dietary folates whose metabolism, referred to as one-carbon metabolism, is required for the production of the major intracellular methylating agent S-adenosylmethionine (SAM), and for the synthesis of DNA and RNA precursors [1]. In 1999, James and coworkers observed that impairments of one-carbon metabolism, due to the presence of polymorphic genes, could be maternal risk factors for the birth of a child with DS [11], and subsequent in vitro studies revealed that folate deficiency induces chromosome 21 aneuploidy [12,13]. Those papers have stimulated considerable research in the field, and several case-control studies have been performed to investigate the contribution of maternal polymorphisms of genes involved in one-carbon metabolism as risk factors for having a child with DS (reviewed in [14]). 80A>G polymorphism as a maternal risk factor for having a birth with DS, including nine independent case-control studies (Table 1) for a total of 930 MDS and 1240 control mothers
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