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Currently Recommended Folate Intake May Be Insufficient For Large Group Of People

NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

A study of Irish women indicates that current dietary standards for the nutrient folate--known to prevent a devastating class of birth defects and possibly cardiovascular disease--do not take into account the increased folate requirements of a large minority of people genetically at risk for folate deficiency.

The study, published in the May 31 issue of The Lancet, shows that a much greater number of women than was previously believed are genetically at risk for an enzyme defect that causes a vitamin deficiency that predisposes them to having children with a neural tube defect--a debilitating class of birth defects affecting the brain and spinal cord.

The study was conducted by a group of Irish and American researchers led by Anne Molloy, PhD, of Trinity College in Dublin, Ireland. Funding was provided by the National Institute of Child Health and Human Development (NICHD), The Health Research Board of Ireland, and the Irish Heart Foundation.

"This challenges the assumption underlying the Recommended Daily Allowance--that virtually everyone can take the same amount of a vitamin and do fine," said James L. Mills, MD, one of the U.S. members of the research team and Chief of NICHD's Pediatric Epidemiology Section.

Dr. Mills added that the study he and his colleagues conducted focused solely on women, but the same genetic defect, present in men, might also increase the risk for heart disease, stroke and cancer of the colon.

Neural tube defects (NTDs) are a class of birth defects affecting the brain or spinal cord. They occur in about one per thousand pregnancies in the U.S. each year. Among the most common NTDs are spina bifida, in which a piece of the spinal cord protrudes from the spinal column, causing paralysis below the protrusion, and anencephaly, a fatal condition in which the brain fails to develop normally.

Currently, the National Academy of Sciences' recommended daily allowance (RDA) for folate is 400 micrograms per day for pregnant women and 180 micrograms for other adult women and 200 micrograms for male adults. The results of the current paper suggest that people having two copies of the abnormal gene may need more folate than these guidelines specify to compensate for their genetic deficiency. Additional studies will be needed, however, to determine exactly how much additional folate they would require.

In 1995, Drs. Molloy and Mills, as well as several other authors of the current paper, reported that people who had two copies of an abnormal variation in the gene for 5,10 methylenetetrahydrofolate reductase were more likely to have a neural tube defect than were people who did not have the abnormal gene or had only one copy of the gene. The gene manufactures one of many enzymes involved in the complex set of chemical reactions that use folate to convert the amino acid homocysteine to the amino acid methionine. In addition to the link to NTDs, higher homocysteine levels have also been associated with increased risk for cardiovascular disease (although it remains to be seen whether the relationship is causal).

In the current paper, the researchers showed that a large number of women who had two copies of the aberrant gene also had lower than normal levels of folate in their red blood cells. To conduct their study, the researchers measured the folate levels of a group of Irish women having either one or two copies of the abnormal gene, as well as women who did not have the abnormal gene. In all, 242 pregnant women and 318 non-pregnant women took part in the study. The research was conducted in Ireland because NTD rates are higher there than in many other countries.

For the pregnant group, the researchers found that 20 women had two copies of the abnormal gene, 108 had one abnormal gene and one normal gene, and 114 had two normal genes. For the non-pregnant group, 41 women had two copies of the abnormal gene, 129 had one copy each of the normal and abnormal gene, and 148 had two normal genes.

Next, the researchers tested the folate levels from red blood cell samples taken from all the women and found that the women having two abnormal copies of the gene had significantly lower folate levels than any of the other women in the study.

The study's authors reported that their finding does not directly prove that individuals having two copies of the abnormal gene have a higher folate requirement than other individuals, but that it nonetheless has far reaching implications.

"These results suggest that a substantial minority of people in general populations may have increased folate needs," the authors wrote. "Future studies may show the presence of other common genetic variants that interact with particular nutrients and place doubts on the validity of assuming 'normality' for nutrient requirements in any general population."

The authors noted that the percentage of people having two copies of the abnormal gene varies from population to population, ranging from 5 percent to 15 percent.

"A section of the population that includes women at risk of having a baby affected by a neural tube defect is, therefore, at a disadvantage," they wrote. "Thus, this study calls for future reviews of the dietary reference values for folate to include recommendations for increased intake in this group, especially during childbearing years."

The authors noted that the enzyme for 5,10 methylenetetrahydrofolate reductase is only one of many enzymes dependent on folate in the complex set of chemical reactions that use the vitamin to convert the amino acid homocysteine to the amino acid methionine. This probably means that there are many other aberrant genes--yet to be discovered--that increase the risk for neural tube defects.

"If genetic variants that cause altered nutrient status are common, as this study suggests, there may be no such thing as a 'normal' population with respect to nutrient requirements, as was assumed when dietary reference values were established," the researchers concluded.

Other authors of the paper were D.G. Weir, A.S. Whitehead, and D. Ramsbottom, also of Trinity College; S. Daly, Coombe Women's Hospital, Dublin; P.N. Kirke, Health Research Board, Dublin; and Mary Conley, NICHD


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