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.

Neural tube defects in Victoria, Australia: potential contributing factors and public health implications

“…41 There is also evidence emerging that there is an association between folate and Down syndrome. 42,43 This genetic predisposition may therefore play a significant role in public health in the not too distant future, if and when screening for it becomes feasible and acceptable in the wider community. Not only may we be able to prevent specific birth defects from forming, but there may also be opportunities to identify those at higher risk of common disorders in adult life.…”

Infant C677T MTHFR polymorphism and severe mental retardation

“…Down syndrome, an important condition leading to mental retardation, has been associated with polymorphisms in genes involved in folate metabolism (James et al, 1999;Hobbs et al, 2000). One gene variant in particular, the C677T/C677T genotype, of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene, has been associated with Down syndrome as well as being a risk factor for other complex congenital anomalies (Botto and Yang, 2000).…”

Frequency of 677C -> T and 1298A -> C polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in Turner syndrome individuals

“…Frosst et al (1995) identified a C to T substitution at nucleotide 677 in the coding region of the MTHFR gene converting an alanine to a valine residue in the gene product and creating a new HinfI restriction site resulting in the MTHFR 677C ® T polymorphism and a reduction in enzyme activity which may lead to a decrease in the levels of SAM, inhibition of methyltransferase and subsequent DNA hypomethylation. The importance of the stable methylation of pericentromeric DNA for chromosomal stabilization and segregation has been supported both by clinical and experimental data (reviewed by Hobbs et al, 2000). Therefore, in homozygosis, the 677C ® T mutation may be a contributing risk factor to somatic chromosomal non-disjunction.…”

“…Defects in folic acid metabolism because of mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been considered as a possible cause of chromosomal non-disjunction by hypomethylation (James et al, 1999;Hobbs et al, 2000). The MTHFR gene is located on the short arm of chromosome 1 (1p36.3) and has 11 exons (Goyette et al, 1994) which code for a cytosolic flavoprotein that catalyzes the reduction of 5,10-methylenetetrahydrofolate (5,10-methyleneTHF) to 5-methyltetrahydrofolate (5-methylTHF), the predominant circulating form of folic acid (Weisberg et al, 1998).…”