Genetic basis for folate deficiency in neural tube defects strengthened

17 May 2005

A brief report published in the Online First electronic version of BMJ (which releases papers in advance of their publication in the print journal) links a common genetic polymorphism with an increased risk of neural tube defects in babies. The gene in question encodes a folate dependent enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR); the common genetic variant, C677T, substitutes an alanine residue in place of a valine at position 222 in the enzyme, with an associated decrease in levels of enzyme activity. The effect of decreased enzyme activity is reduced levels of folate in the tissues, and increased levels of homocysteine in the plasma. This polymorphism may be homozygous (TT genotype) or heterozygous (CT genotype); these genotypes are present in around 10% and 38% of the population, respectively. The TT genotype affects enzyme activity, folate and homocysteine levels more markedly than the heterozygous CT form, and has previously been associated with an increased risk of neural tube defects such as spina bifida in pregnancy, as well as a modestly increased risk of cardiovascular disease. The BMJ paper reports an Irish study to investigate whether the heterozygous CT genotype is also associated with an increased risk of neural tube defects [Kirke, PN et al. (2004) BMJ, doi:10.1136/ bmj.38036.646030.EE] .

DNA from 395 individuals with neural tube defects spina bifida aperta or encephalocele, and 855 randomly selected newborn controls was genotyped for the MTHFR polymorphism. From their results, the authors calculated that both the TT and CT genotypes were associated with a small increased risk of neural tube defects; although the increased risk associated with the heterozygous genotype (around 50%) was lower than that for the homozygous TT genotype (around 150%), it was nevertheless proposed to represent a significant fraction of neural tube defects in the population, because the CT genotype is more common. Taken together, the authors propose that the TT and CT genotypes may account for over a quarter of all neural tube defects in Ireland. They claim that the potential adverse effect of these genotypes on neural development in foetuses can be corrected by maternal folic acid supplementation in pregnancy, leading them to suggest that these results underline the importance of taking folic acid prior to conception and in the early stages of pregnancy. They also argue that fortification of foods (such as bread) with folic acid may have additional public health benefits, by reducing the risk of cardiovascular disease in as much as half of the population.

Comment: This study confirms and extends previous work rather than identifying a novel gene-disease association, but is interesting to consider that even a mildly increased level of risk, if affecting a large proportion of the population, may be significant in public health terms. It is also a good example of how environmental changes (taking folic acid in early pregnancy when the neural tube of the foetus is developing) may in some cases balance out genetic effects, although in fact this study does not present any evidence connecting maternal folic acid supplementation directly with foetal MTHFR genotype and risk of neural tube defects. The maternal genotype with respect to the MTHFR polymorphism may also be relevant, and additional environmental and foetal genetic factors probably also influence neural tube formation.

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