Association of solute carrier family 19 member 1 (SLC19A1) A80G polymorphism with the maternal risk for having a child with Down syndrome: A systematic review and meta-analysis.

Impairments in folate metabolism have long been suspected to contribute to chromosome 21 aneuploidy and Down syndrome (DS). Indeed, several studies have investigated the role of a functional polymorphism in the reduced folate carrier gene, known as either SLC19A1 or RFC-1 A80G polymorphism (rs1051266), as a maternal risk factor for having a child with DS. We searched for available case-control studies investigating this association and included 16 independent studies, for a total of 1958 DS mothers and 2750 control mothers. We performed random-effects meta-analyses to summarize the results on the association between the presence of this polymorphism and the risk of giving birth to a DS child, and reported odds ratios (ORs) with 95% confidence intervals (CIs) as measures of association. We also performed a trial sequential analysis (TSA) to clarify the robustness of the meta-analyses. Under the recessive model (GG vs AA+AG), the association was significant (OR=1.29, 95% CI: 1.03-1.61), also when including only studies with Hardy-Weinberg equilibrium (HWE) in control mothers (OR=1.38, 95% CI: 1.09-1.75). Additionally, significant associations emerged from allelic contrast (G vs A; OR=1.21, 95% CI: 1.02-1.43) and homozygote comparison (GG vs AA; OR=1.47, 95% CI: 1.04-2.07) when considering only the studies in which controls were in HWE. Results from TSA indicate that the number of studies might be sufficient to support the observed associations. The present meta-analysis suggests that the RFC-1 A80G polymorphism is associated with a slight yet significant increase in the risk of having a child with DS, especially in homozygous GG mothers.