Journal Publication

Is Mutated Methylenetetrahydrafolate Reductase (MTHFR) a Risk Factor for Neural Tube Defects? A Pooled Analysis.

by D. L. Posey, M.J. Khoury, J. Mulinare, M.J. Adams Jr., and C.Y. Ou

Three recent studies have suggested that homozygosity for the C677T mutation in the gene coding for a thermolabile 5,10-methylenetetrahydrafolate reductase (MTHFR) is a risk factor for neural tube defects (NTDs) (1-3). We review pooled results from these studies and raise methodologic issues in interpreting these data in relation to the known protective effects of folic acid for NTDs.

These studies are summarized in Table 1. Compared with the homozygous normal genotype, homozygotes for the C677T mutation have an increased risk for NTDs (odds ratio 4.28, 95% C.I. 2.26-8.10), while heterozygotes have an odds ratio of 1.35 (95% C.I. 0.92-2.00). Assuming a causal association with C677T homozygosity, using the Miettinen formula for attributable fraction, we can calculate that 13% of NTD cases can be attributed to the homozygous C677T mutation. Even if C677T heterozygosity is a causal risk factor, an additional 11% of NTD cases may be attributed to the C677T mutation. These attributable fractions fall well below the 50-70% reduction in NTD rates that occur with adequate periconceptional consumption of folic acid (4). Therefore, the protective effect of folic acid in NTDs likely involves additional biologic interactions with other mutations in this gene, other genes as well as other risk factors.

Beyond these calculations, four methodologic issues need to be considered in interpreting the findings from these studies. First, none of these studies used an appropriate control group derived from the same population from which cases arise. The use of convenience controls raises concern over the potential for confounding by race/ethnicity and other NTD risk factors. This is especially significant in the face of variability of the frequency of C677T homozygosity in various populations (e.g. French Canadians) (5). Second, because C677T homozygosity may be associated with a higher risk of morbidity and mortality from vascular disease, the use of prevalent NTD cases rather than incident cases raises the concern that the finding may reflect an effect on intrauterine and postnatal survival rather than a causal role on the genesis of NTDs. Third, it is not clear from these studies whether the MTHFR association is due to the maternal or fetal genotypes or both. Disentangling maternal from fetal effects will be crucial to target periconceptional intervention measures. Finally, none of these studies examined the interaction between MTHFR genotypes and the intake of folate from dietary and supplemental sources. This will be crucial in interpreting the biologic plausibility of the findings.

Thus, it appears from these study results that the C677T mutation is not responsible for a large percentage of NTD cases. Also, before a causal inference can be made, further studies are needed to disentangle the effects of this gene on the cause and survival of NTD cases, maternal from fetal genotypic effects, as well biologic interactions with folic acid and other factors.

 References

1. Ou CY, Stevenson RF, Brown VK, et al. C677T homozygosity associated with thermolabile 5,10 methylenetetrahydrafolate reductase as a risk factor for neural tube defects. Am J Hum Gen 1995;57(suppl):A223.
2. Whitehead AS, Gallagher P, Mills JL, et al. A genetic defect in 5,10 methyltetrahydrafolate reductase in neural tube defects. QJ Med 1995;88:763-6.
3. van der Put NMJ, Steegers-Theunlssen RPM, Frosst P, et al. Mutated methylenetetrahydrafolate reductase as a risk factor for spina bifida. Lancet 1995;346:1070-1.
4. Centers for Disease Control. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992;41(No. RR-14):1-7.
5. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease; a common mutation in methylenetetrahydrafolate reductase. Nature Gen 1995;10:111-3.

Table 1. Pooled analysis of risk of neural tube defects according to MTHFR genotype