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Providing perspectives on recent research into vitamins and nutritionals


HCY2013: Latest Research on Folate and Neural Tube Defects

By Julia Bird

This week, TalkingNutrition will be covering the latest research on the B vitamins and other nutrients involved in one carbon metabolism.

The effect of folate fortification on reducing neural tube defects (NTDs) is a nutrition success story. The first two speakers, Professor Patrick J. Stover from Cornell University, Dr Jim Mills from the Eunice Kennedy Shriver National Institute of Child Health and Human Development both highlighted research that showed a drop in neural tube defects by around one third in the United States and Canada after folic acid fortification of cereals was introduced (see critical review from Osterhues and colleagues for background). Even so, some research questions still remain that may impact how neural tube defect prevention programs are implemented in the coming years. These include:

·         What red blood cell folate concentration offers the highest protection against NTDs?

·         We know that improving folate status works in reducing risk of NTDs, however what is the exact mechanism?

·         What is the best means to improve folate status in various populations: fortification vs. supplementation vs. education?

·         How can women at higher risk of bearing children with NTDs be more effectively targeted?

·         How do genetics and environment interplay to affect risk of NTDs?

·         Are there any intended and negative side-effects of population-level fortification?

The first two points are personally of interest to me as a nutrition researcher. Firstly, the recommendations for red blood cell folate levels to prevent NTDs are considerably higher than for prevention of folate deficiency. While folate deficiency is likely at red blood cell folate levels of 305 nmol/L and sub-clinical deficiency at 340 nmol/L, the level needed for NTD prevention is three times higher at around 900 nmol/L (Green, 2011). This level is based on epidemiological research. Unfortunately, the low absolute prevalence of NTDs and variable response to folic acid supplementation makes it difficult to conduct dose-response studies to sufficiently answer the question via intervention studies. Luckily, computational power can help out here. Dr Crider from the CDC and her research group developed a complex model based on an epidemiological study carried out in China involving around 250,000 women and 247 cases of neural tube defects, and a dose-response study that looked at varying doses of folate and status in 932 women (Crider et al.). After crunching the numbers, the results showed that higher levels of red blood folate were protective against NTDs, and that the highest risk of NTDs was found levels were below the cut-off for sub-clinical deficiency (340 nmol/L). Women with levels over 1000 nmol/L had the lowest incidence of an NTD-affected pregnancy. These numbers agree with the previously published data and can be further used to develop guidelines for targeting women of childbearing age.

My other interest is in developments that clarify the mechanisms behind how folate can prevent NTDs. Up until now, we know that folate supplementation works. The problem is that the exact mechanism is a little elusive. Two main theories are being researched, the first one involves the greater incorporation of uracil into DNA during folate deficiency leads to greater DNA breakage, and the second proposes that the inability to methylate homocysteine to methionine in folate deficiency alters gene expression and genome stability. Both theories lead to failure of cells to divide, differentiate and position themselves correctly during a critical window of development that occurs between days 23 and 28 of pregnancy when the neural tube closes. Dr Stover elaborated in detail about how enzymes involved in folate metabolism affect whether uracil is incorporated into DNA, and where they are specifically located within the cell, which is discussed in more detail in publications from his work group (MacFarlane and Andersonare the lead authors). There is still more work to do in this area, however finding the exact mechanism may help to reduce NTDs further.

A cross-cutting theme running through these presentations is the role of genes and environment on disease risk. Recent developments in gene sequencing and information technologies have opened the door to this exciting new area of nutrigenomics and personalized medicine.


Anderson DD, Woeller CF, Chiang EP, Shane B, Stover PJ. Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis. J Biol Chem. 2012 Mar 2;287(10):7051-62. doi: 10.1074/jbc.M111.333120. Epub 2012 Jan 10.

Crider KS, Zhu JH, Hao L, Yang QH, Yang TP, Gindler J, Maneval DR, Quinlivan EP, Li Z, Bailey LB, Berry RJ. MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am J Clin Nutr. 2011 Jun;93(6):1365-72. doi: 10.3945/ajcn.110.004671. Epub 2011 Apr 20.

Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr. 2011 Aug;94:666S-72S.

MacFarlane AJ, Anderson DD, Flodby P, Perry CA, Allen RH, Stabler SP, Stover PJ. Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA. J Biol Chem. 2011 Dec 23;286(51):44015-22. doi: 10.1074/jbc.M111.307629. Epub 2011 Nov 4.

Osterhues A, Ali NS, Michels KB. The role of folic Acid fortification in neural tube defects: a review. Crit Rev Food Sci Nutr. 2013;53(11):1180-90. doi: 10.1080/10408398.2011.575966.