QUANTITATIVE ASSESSMENT: A meta-analysis by Arno Motulsky's lab illustrated the relationship between homocysteine levels and folic acid intake.
Comments by Arno G. Motulsky, Department of Medicine, University of Washington
Researchers have known for some time that elevated levels of the amino acid homocysteine (hyperhomocysteinemia) may be associated with arteriosclerotic vascular diseases, such as heart attacks and strokes. Scientists also have observed that individuals with hyperhomocysteinemia often have low levels of the vitamin folic acid. To clarify the relationship between folic acid and homocysteine levels, the authors of this paper compiled the results of 27 previous studies relating homocysteine levels to arteriosclerotic vascular disease and 11 studies of folic acid effects on homocysteine levels.
"In this meta-analysis [see story on page 1], we were trying to find out what the relationship was of high homocysteine levels to coronary heart disease, to cerebrovascular disease, and to peripheral vascular disease," says Arno G. Motulsky, a professor of medicine and genetics at the University of Washington. The implications were just as the researchers had suspected: Hyperhomocysteinemia was indeed a great risk factor for vascular disease.
The team then made a quantitative assessment of the percentage of coronary heart disease ascribable to hyperhomocysteinemia. From these results and from estimates of the effect of folic acid on homocysteine levels, they calculated the number of deaths due to coronary heart disease that might be prevented by increasing the amount of folic acid in the diet through food fortification, dietary change, and folic acid supplements.
The reasoning was simple: "Assuming that vascular disease is associated with hyperhomocysteinemia, and since folic acid will bring down homocysteine levels, it's reasonable to infer that, in fact, by giving folic acid you might reduce the frequency of coronary heart disease," Motulsky explains. He does acknowledge, however, that this hypothesis has not yet been tested in clinical trials.
According to Motulsky, the paper's high number of citations is due to "the importance of the problem, the showing quite clearly of a somewhat novel risk factor, and, most excitingly, the possibility of being able to do something about [it]." He also credits widespread interest in folic acid as a potential preventive agent.
In the two years since the paper's publication, the Food and Drug Administration (FDA) has, in fact, decided to fortify food with folic acid as a preventive measure-but not in an attempt to prevent vascular disease. Rather, FDA officials were trying to reduce the number of birth defects in the United States. Scientists have determined that increasing the amount of folic acid in the food of pregnant women in the first few weeks of pregnancy prevents at least half of neural tube defects occurring in embryos-defects that lead to debilitating conditions like spina bifida (Notebook, The Scientist, April 29, 1996, page 30). Motulsky calls the potential dual effect of folic acid food fortification an "exciting possibility."
The University of Washington team is now focusing on the folic acid-related enzyme methylenetetrahydrofolate reductase (MTFR). Homozygotes for a variant of this enzyme (10 percent to 15 percent of the Caucasian population) have high homocysteine levels. "But what's most exciting to me as a geneticist concerned with genetic-environmental interactions," adds Motulsky, "is that this genetic variant appears to require suboptimal folic acid nutrition to cause high homocysteine levels. Both genetic and environmental factors are involved."