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

Down syndrome is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives fr om the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, ma ternal 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) ge ne may be maternal risk factors for Down syndrome. The present study was un dertaken 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 recen tly associated with increased risk of neural tube defects and might also co ntribute 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 i nteractions. The results are consistent with the preliminary observation th at the MTHFR 677C-->T polymorphism is more prevalent among mothers of child ren with Down syndrome than among control mothers, with an odds ratio of 1. 91 (95% confidence interval [CT] 1.19-3.05). In addition, the homozygous MT RR 66A-->G polymorphism was independently associated with a 2.57-fold incre ase in estimated risk (95% CI 1.33-4.99). The combined presence of both pol ymorphisms 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). T he two polymorphisms appear to act without a multiplicative interaction.