Heterozygosity for the MTHFR polymorphism, which is present in 38% of the population, increases the risk of neural tube defects. Most studies of MTHFR C677T and neural tube defects and other conditions have focused on the risk associated with T allele homozygosity. The possibility that heterozygosity might also increase neural tube defect risk has gone unrecognised except for a small study in which an association between CT and these malformations was thought to be due to the higher than expected proportion of CC control subjects.4
The combined CT and TT genotypes account for about 26% of neural tube defects in Ireland. Folate or folic acid is estimated to be involved in about 50% to 70% of these defects. Thus up to a half of the folate related neural tube defects may be explained by this single genetic variant.
These findings have two important implications. Firstly, MTHFR C677T heterozygosity needs to be considered as a risk factor for other conditions where homozygosity has been shown to be associated with increased risk, for example, ischaemic heart disease.5
Secondly, the population at risk, and the population that will benefit from food fortification, is much larger than previously believed. Based on pooled data from published studies, about 59% of the European population and 53% of the North American population have either CT or TT genotypes.1
Both the lower folate and increased homocysteine concentrations associated with CT and TT genotypes can be corrected by folic acid, even in relatively small doses. Therefore, our study provides new data underscoring the importance of public health intervention programmes of folic acid supplementation and food fortification targeted at all women of childbearing age to prevent neural tube defects. Such intervention may also turn out to have other public health benefits—for example, in the prevention of cardiovascular disease.