Down syndrome, or trisomy 21 (T21), is mainly due to abnormal segregation during meiosis, but the exact mechanism of this nondisjunction is unclear. The relationship between chromosomal nondisjunction and folate metabolism has attracted attention because chronic folate and methyl deficiency results in abnormal DNA methylation, DNA strand breaks, and aberrant chromosome segregation. The methyltetrahydrofolate reductase (MTHFR) gene encodes methylenetetrahydrofolate reductase, a key enzyme in folate and homocysteine metabolism. In the MTHFR enzyme, the 2 most important single-nucleotide polymorphisms, C677T and A1298C, can affect folate and total homocysteine status. This meta-analysis was performed to quantitatively assess the effect of the MTHFR C677T and A1298C polymorphisms on the risk of having an infant with T21.
PubMed and Chinese biomedicine databases were searched for articles on the association between MTHFR C677T/A1298C and T21. Case-control studies containing available genotype frequencies of MTHFR C677T and MTHFR A1298C were extracted. For the study control groups, the observed genotype frequencies of MTHFR C677T and A1298C polymorphisms were assessed for Hardy-Weinberg equilibrium using the χ2 test. Strength of association was determined using crude odds ratios and 95% confidence intervals.
Twenty-eight studies examined the association between MTHFR gene polymorphisms and T21, including 2806/4597 cases/controls for MTHFR C677T and 1854/2364 cases/controls for MTHFR A1298C. Ethnicity, country, publication year, author, and number of cases and controls for the MTHFR C677T and MTHFR A1298C genotype were extracted. Variant genotypes in MTHFR C677T were associated with an increased risk of having a child with T21. The association was most notable for carriers of the T genotype (dominant model: odds ratio, 1.305; 95% confidence interval, 1.125–1.514; P = 0, P = 0.003). For MTHFR A1298C gene polymorphism, there was no significant association with T21 offspring.
Maternal age is the only well-established risk factor for T21, but many children with T21 are born to mothers younger than 35 years old, suggesting that other factors are involved. DNA hypomethylation may increase the risk of meiotic nondisjunction associated with the risk of T21. This analysis supports conclusions that the T-carrier genotype has an increased risk of T21, especially for Asians and whites, evidence that the MTHFR C677T polymorphism may be associated with the risk of having a child with T21.