Genetic Polymorphisms Involved in Folate Metabolism and Maternal Risk for Down Syndrome: A Meta-Analysis

Abstract

Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I 2 statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS.

Gene Polymorphisms That Predispose Women for Down Syndrome Child Birth

“…Furthermore, when Caucasian samples were stratified by geographic and demographic criteria the estimates revealed that the risk is higher in those of nonresidential European descent (OR = 1.47; 95% CI = 1.02-2.11; dominant model) than in residential European Caucasians (OR = 1.31; 95% CI = 1.01-1.70; dominant model). On contrary, when the study was conducted on the Caucasian from Mediterranean regions no significant association was observed (OR = 1.19; 95% CI = 0.91-1.55; dominant model), which suggests that the manifestation of the effect of MTRR rs1801394 66A > G is also dependent on geographic and dietary factors [33].…”

“…Nevertheless, the meta-analysis conducted in 2009 on 623 DS bearing and 936 control mothers [31], confirmed association of this polymorphism in maternal genome with the elevated risk of having DS baby. Further analyses with stratified data, performed in recent time [32,33], suggest a significant effect in Caucasians under both dominant and recessive genetic models. The estimated score for minor Allele "G" among Caucasian women was 35.8-54.3%, among Brazilian women was from 40.0 to 48.0% and among Asian mothers was from 41.5 to 62.5% [32][33][34].…”

“…Further analyses with stratified data, performed in recent time [32,33], suggest a significant effect in Caucasians under both dominant and recessive genetic models. The estimated score for minor Allele "G" among Caucasian women was 35.8-54.3%, among Brazilian women was from 40.0 to 48.0% and among Asian mothers was from 41.5 to 62.5% [32][33][34]. Furthermore, when Caucasian samples were stratified by geographic and demographic criteria the estimates revealed that the risk is higher in those of nonresidential European descent (OR = 1.47; 95% CI = 1.02-2.11; dominant model) than in residential European Caucasians (OR = 1.31; 95% CI = 1.01-1.70; dominant model).…”

“…The estimated frequency of minor allele 'G' of this polymorphic site in the European and mixed Brazilian populations of women having DS child is 18-21% [37], while the estimate is less than 10% in the Asian women [38]. A large cohort study on Italian population samples [33,37], revealed the MTRR 66A > G polymorphism, but not the MTR 2756A > G one, was associated with increased serum folate levels among the GG carriers women. On the other hand study on Brazilian population has [29] reported association of MTRR AG and GG genotypes with high methylmalonic acid (MMA) concentrations, an indicator of the vitamin B12 status.…”

Choline metabolites

“…There is some heterogeneity in these data as studies have inconsistently reported the association of specific effect alleles (or underlying polymorphisms), so additional work is necessary to clarify the risk variants and their effect size. More recently, meta-analyses have identified associations between MTHFD1 polymorphisms, such as the MTHFD1 G1958A variant, as being associated with increased risk for birth defects [16], [17], [18]. Additionally, two missense mutations, rs7946 and rs897453, in PEMT , an enzyme required for de novo production of choline, have been associated with altered homocysteine levels and neural tube defects, respectively [19, 20].…”