Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome

Abstract

Down syndrome is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. A recent preliminary study suggested that abnormal folate metabolism and the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome. The present study was undertaken with a larger sample size to determine whether the MTHFR 677C-->T polymorphism was associated with increased risk of having a child with Down syndrome. Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism. A common polymorphism in this gene was recently associated with increased risk of neural tube defects and might also contribute to increased risk for Down syndrome. The frequencies of the MTHFR 677C-->T and MTRR 66A-->G mutations were evaluated in DNA samples from 157 mothers of children with Down syndrome and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results are consistent with the preliminary observation that the MTHFR 677C-->T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91 (95% confidence interval [CI] 1.19-3.05). In addition, the homozygous MTRR 66A-->G polymorphism was independently associated with a 2. 57-fold increase in estimated risk (95% CI 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an odds ratio of 4.08 (95% CI 1.94-8.56). The two polymorphisms appear to act without a multiplicative interaction.

Figure 1

Overview of the interactive and interdependent reactions involved in cellular one-carbon metabolism, with emphasis on the two major functions of these pathways in DNA metabolism: normal DNA synthesis and normal DNA methylation. These two major functions intersect at the folate/B₁₂–dependent methionine synthase reaction, which generates metabolically active tetrahydrofolate for DNA nucleotide precursor synthesis, and, at the same time, regenerates methionine from homocysteine. Both DNA synthesis and DNA methylation are negatively affected by inadequate folate or B₁₂ intake and/or by mutations in these pathways. Note that an elevation in homocysteine induces the reversal of the SAH hydrolase reaction and causes an elevation in SAH, a potent product inhibitor of the DNA methyltransferase reaction (De Cabo et al. 1995).