Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome — meta-analysis

Abstract

<jats:title>Abstract</jats:title><jats:p>Folate metabolism deficiency has been related to increased occurrence of maternal non-disjunction resulting in trisomy 21. Several polymorphisms in genes coding for folate metabolism enzymes have been investigated for association with the maternal risk of Down syndrome (DS) yielding variable results. We performed a meta-analysis of case-control studies obtained through the PubMed database. The studies on polymorphisms in the MTHFR, MTRR, MTR, RFC1 and CBS genes were included. The summary OR demonstrated a statistically significant increased risk of giving birth to a child with DS in mothers carrying the mutant allele of the MTHFR/C677T gene polymorphism (both genetic models) and in mothers homozygous for the mutant allele of the MTRR/A66G polymorphism (recessive genetic model). Analyses of other polymorphisms, MTHFR/A1298C, MTR/A2756G, RFC1/A80G, and CBS/844ins68, resulted in borderline or no statistical significance. In conclusion, our meta-analysis showed the significance of genetic alterations in the folate metabolism genes in maternal susceptibility to DS offspring. Our results suggest that the importance of folate supplementation to women in reproductive age in prevention of non-disjunction be revised. Further genetic studies on a combined effect of multiple folate metabolism genes is recommended. Additionally, more thorough studies on the haplotype analyses of genes is recommended as well, especially in populations that have not yet been investigated thus far.</jats:p>

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

“…A brief look at Table 1 clearly shows the heterogeneity of the case-control studies, so far available, in terms of maternal age at delivery, with few studies performed only in women aging less than 35 years [19,21,26], others performed in matched case-control cohorts including both women aging more or less than 35 years at delivery [20,25,27], and even studies performed in unmatched case-control cohorts with a significant prevalence of aged MDS than aged control mothers [24,29]. Despite this, all those papers have been included in previous meta-analyses of the literature [15,16,17], such a heterogeneous group of available data renders almost impossible to assess the contribution of the maternal age effect in a meta-analysis. In addition, data from individual case-control studies are conflicting, including authors observing an increased effect of the RFC-1 80GG genotype with increasing maternal age [20], and others suggesting an increased maternal risk for a DS birth in young women carrying the RFC-1 80GG genotype [21].…”

“…Unfortunately, most of those studies have been conducted in small cohorts of less than, or about, 100 case mothers each, and were often underpowered to evaluate the independent contribution of each studied polymorphism to the maternal risk for trisomy 21 in the offspring [14]. Meta-analyses of published data have been performed to overcome the limits of small case-control cohorts, revealing that both the methylenetetrahydrofolate reductase ( MTHFR c.677C>T) and the methionine synthase reductase ( MTRR c.66A>G) polymorphisms (both genes are involved in folate metabolism) might represent independent maternal risk factors for the birth of a child with DS [15,16,17]. Other polymorphic genes participating in one-carbon metabolism have been studied less extensively than the two previous ones, and results are still borderline or inconclusive for most of them [15].…”

“…A meta-analysis [15] of four genetic association studies [19,20,22,25], for a total of 354 MDS and 644 control mothers, was performed in 2009 to address the role of the RFC-1 80A>G polymorphism as a maternal risk factor for the birth of a child with DS, and showed a trend toward an association under the dominant model (GG + AG vs . AA) with an odds ratio (OR) of 1.32 (95% CI = 0.95–1.82) [15], suggesting the need of additional studies to further address the contribution of this polymorphism to the maternal risk of having a DS child.…”

“…AA) with an odds ratio (OR) of 1.32 (95% CI = 0.95–1.82) [15], suggesting the need of additional studies to further address the contribution of this polymorphism to the maternal risk of having a DS child. Since several additional papers have been published in recent years, including studies in Asian [21,23], European [27], and Brazilian populations [24,26,29], we performed the present meta-analysis of the genetic association studies that investigated the RFC-1 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.…”

Advances in the genetic aspects linking folate metabolism to the maternal risk of birth of a child with Down syndrome

“…Similarly, a significant pooled OR was found for the heterozygote CT, in both fixedeffects (OR = 1.26; 95% CI: 1.10-1.43) and random-effects model (OR = 1.28; 95% CI = 1.08-1.51) 10 , and stratification of data by latitude, showed association mainly in Sub-Tropical regions 10 . Also, Medica et al 14 14 . Taken overall, these data suggest a modest contribution of the MTHFR c.677C>T polymorphism to the maternal risk for having a child with DS 10,11 .…”