FOLIC ACID #63

FOLIC ACID LEVELS LINKED TO RISK OF CORONARY DEATH #63

Canadian research has linked low blood levels of the B vitamin, folic acid, to increased odds for fatal coronary heart disease. A study of more than 5,000 people found that those in the quarter of the group with the lowest folate levels were 69 percent more likely to die of a coronary problem than those in the quartile with the greatest stores of the vitamin. The study underscores the need for clinical trials to determine whether increasing folic acid intake can prevent heart disease, says Meir Stampfer, M.D., Dr. P.H. of the Harvard School of Public Health, in an editorial accompanying the report. The study was published in the June 26, 1996 issue of JAMA (Vol 275, pp. 1893 -1896).

The research, led by Howard Morrison, Ph.D., of the Cancer Bureau in Ottawa, Ontario, involved men and women, aged 35 to 79, who reported no history of coronary heart disease. The subjects' blood levels of folic acid were measured from 1970 to 1972. The group was then followed through 1985. During the 15-year period, the researchers identified 165 people who died of coronary heart disease. The data show that as folic acid levels dropped, risk of death rose in a stepwise fashion. Folate appeared most protective in women and in people under age 65. An interesting finding in all age groups was that risk increased even when folic acid levels were considered normal. This observation suggests the need to redefine the norms, note the authors.

According to Morrison and his group, the study has two advantages over previous work implicating folate shortages in coronary heart disease. By using subjects who were participants in a national nutrition survey, the researchers were able to link vitamin levels and disease in a representative population sample. Earlier studies of folate and heart disease risk involved either white males or the elderly. The study also correlates low folate levels with actual death from heart disease, rather than with a finding like carotid artery obstruction, which only predicts risk of death.

Citing studies that link low folate levels or intake with risk of neural tube defects, cervical dysplasia and rectal cancer, as well as heart disease, the researchers note that about half of U.S. adults consume less than the newly lowered RDA of 200 mcg. An estimated 88 percent ingest less than the amount (400 mcg), which is needed to produce low, stable homocysteine levels. Although the scientists urge bolstering the diet with such folic acid sources as vegetables and legumes, they suggest that some people may need supplements. In his editorial urging clinical trials of folate supplementation, Stampfer says that, because this low cost approach offers no profit incentive, the National Institutes of Health should fund folate trials. "If proven effective, lowering the homocysteine level could prevent tens of thousands of cases of cardiovascular disease each year at very low cost and with few (if any) adverse effects," he says.

One study out of the University of California, Berkeley, shows that a low-folate diet can cause nicks in genes, resulting in chromosome breaks (B.C. Blount et al., Proceedings of the National Academy of Sciences, 94:3290-5, 1997). Those chromosome breaks could contribute to cancer and other diseases.

When the cell lacks enough folate to synthesize thymine, its biochemical precursor, uracil, builds up in the cell's DNA instead. Then the cell's repair mechanisms remove the uracil, resulting in nicks. "When you have two opposing nicks in the DNA, the chromosome falls apart," says Bruce N. Ames, a professor of biochemistry and molecular biology at UC-Berkeley who co- authored the study.

About 10 percent of the United States population (and about 50 percent of its poor minority population) does not receive enough folates-worrisome because even light deficiencies can cause genetic damage. The UC-Berkeley study also shows that increasing folate in the diet prevents this cellular damage. "Folate deficiency is going to be a great cause of cancer in the United States," predicts Ames.

He also thinks that broken chromosomes could lead to brain damage and affect cognitive function, although the evidence is less clear. "B12 deficiency, which also appears to cause uracil misincorporation into DNA, seems to knock out glial cells surrounding nerves in the periphery."

The relationship between folate deficiency and cellular damage arose accidentally. In 1988, James T. MacGregor, now the director of the Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research, stumbled upon it while studying cellular division. He used pieces of chromosomes left over as a marker for the process. One subject's blood cells contained an abundance of the micronuclei. "We were quite surprised to find this one individual who had 15 times as much as everyone else."

MacGregor and colleagues followed that subject for a year and found that the elevated level of micronuclei was due to a moderate folate deficiency. When the subject received folate supplements, the number of micronuclei found in his blood soon decreased (R.B. Everson et al., Journal of the National Cancer Institute, 80:525-9, 1988).

MacGregor has a new study in press with a population of 22 that should strengthen the argument that a poor diet can result in genetic damage. "The effects on genetic damage could be way bigger than people thought." However, scientists need to better understand the biochemical reactions that lead to genetic damage, and they need to conduct randomized clinical trials. Other questions remain, as well.

The same biochemical processes resulting in birth defects like spina bifida may also be responsible for other diseases, says Benjamin C. Blount, a visiting fellow at the Centers for Disease Control and Prevention's (CDC's) National Center for Environmental Health in Atlanta. "It could be that the birth defect mechanism is the same as the one for cancer, or it could be totally different."

Blount also wonders how the folic cofactor involved in cancer differs from ones associated with heart disease. Low folate levels could contribute to one but not the other in the same subject. The reason for this discrepancy remains unknown. However, one answer could lie in variances in individual genetic makeup. "By studying people with different inborn errors in metabolism, we'll be able to study these subtle differences," he says.

Eric B. Rimm, an associate professor of epidemiology at the Harvard School of Public Health, agrees that genetic variation may affect folate levels and diseases related to them. He and a team of Harvard colleagues are searching for that link. They also want to establish a more conclusive cause-and-effect relationship between folate deficiency and both cancer and heart disease. "Right now, there really aren't any published reports linking folic acid directly," Rimm says.

The search for direct links of folate deficiency to cancer, heart disease, and brain damage could be complicated by the elemental role folate plays in the body's numerous biochemical reactions. "Folate provides a chemical building block, an essential chemical necessary for the body's basic biochemical needs," explains Meir J. Stampfer, a professor of epidemiology at the Harvard School of Public Health. Because folic acid comes into play early in metabolism and bonds many other chemicals together, it may be difficult to discern just how its absence may add to one disease but not another.

Stampfer has helped establish epidemiological evidence linking folate deficiency to both heart disease (L. Chasen et al., Journal of the American College of Nutrition, 15:136-43, 1996) and colon cancer (J. Chen et al., Cancer Research, 56:4862-4, 1996). But he acknowledges the need for clinical randomized trials to more definitively establish a cause-and-effect relationship.

Scientists may not have to wait long. Stampfer and his Harvard colleagues have begun work on such studies, including a randomized trial of vitamin therapy in people who have survived a nondisabling stroke. In particular, the study will examine the role of folates in preventing recurrences. Stampfer predicts that other research groups are taking on the same sorts of problems and results should begin to emerge in the next several years. "These randomized trials are going to be very strong," he comments. "There's going to be a flood of new data. It's going to enhance our ability to reduce the risk of these diseases."

Carol J. Boushey, an associate professor in the department of animal science, food and nutrition at Southern Illinois University, agrees that clinical randomized trials will provide more understanding about how folate deficiency is related to diseases. But she says enough epidemiological data have accumulated to convince her of the link between folate deficiency and heart disease. Boushey and colleagues conducted a meta-analysis of 27 studies relating increased homocysteine with arteriosclerotic vascular diseases and 11 studies of folic acid deficiency's effects on homocysteine. She found that, as in other studies, higher folic acid intake reduces homocysteine (C.J. Boushey et al., JAMA-Journal of the American Medical Association, 274:1049-57, 1995; Hot Papers, The Scients, Sept. 15, 1997, page 12). 

One of the studies she examined directly related folate deficiency with heart disease. However, increased homocysteine levels have been repeatedly linked to heart disease. "I believe the association is there," Boushey says. "I'm comfortable promoting a high-folate diet. But many individuals are skeptical until you do the randomized trials."

Although scientists lack a definitive answer on how folate deficiency leads to heart disease, they are beginning to get some ideas, according to Katherine L. Tucker, an associate professor of epidemiology at the Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center at Tufts University. Folic acid lowers blood levels of homocysteine, an amino acid that, in high levels, has been associated with heart disease, hypertension, and stroke.

"When there's a deficiency, the homocysteine cannot move to the next step and clear. So it accumulates in the blood," Tucker states. She says that accumulation may contribute to the narrowing of the arterial walls by somehow making them more susceptible to plaque buildup. Tucker has seen this buildup and subsequent narrowing in ultrasounds of folate-deficient individuals participating in the longitudinal Framingham Heart Study. That study, initiated in 1948, continues to establish risk factors for heart disease. An analysis of questionnaires of 747 subjects in that study who were also tested for folate showed that those with the lowest folate intake had the highest homocysteine levels.

As evidence linking folate deficiency to disease and genetic damage builds, scientists are questioning the federal government's decision in 1987 to lower the recommended daily allowance of folic acid from 400 µg per person to 200 µg. The Dietary Reference Committee has been actively discussing the RDA of folates and other B vitamins, confirms Carol Suitor, senior program officer with the Institute of Medicine's Food and Nutrition Board. She predicts that the committee will make its recommendations public in April 1998.

Research by Tucker and her colleagues challenges the rationale that led to the folate RDA reduction-that higher levels of folic acid mask anemia in the elderly population, an early stage of B12 deficiency (K.L. Tucker et al., JAMA, 276:1879-85, 1996). Without that warning and subsequent action, the argument goes, B12 deficiency can cause progressively worse neurological problems, including dementia. However, Tucker says that anemia may not be the best indicator for B12 deficiency. Therefore, the benefits of increasing daily folic acid intake greatly outweigh the risks.

Godfrey P. Oakley, Jr., director of the division of birth defects and developmental disabilities at CDC, favors bumping the folate RDA back up to 400 µg. If Boushey's conclusions are correct, that decision could prevent about 50,000 yearly deaths due to heart attack in the U.S. "That's more people than who would die in automobile crashes," Oakley says.

He calls the move from an RDA of 400 µg to 200 µg of folate a day "an absolute disaster" and wouldn't be surprised if that decision were reversed when the Dietary Reference Committee makes its April announcement. In the meantime, FDA's move to fortify every 100 grams of flour with 140 µg of folic acid by the end of 1998 will automatically put more folate into people's diets. Oakley advocates women take more than 400 µg of folic acid a day because diseases with the strongest link to folic acid deficiency-neural tube defects such as spinal bifida-are passed on during the earliest months of pregnancy. In 1993, 2,400 children were born with neural tube defects. Oakley estimates that folic acid supplementation of 700 µg a day would eliminate 75 percent of neural tube defects.

Scientists agree that the recent research has fundamentally changed the way they look at vitamins in a relatively short period. Until the late 1980s, people associated vitamins mostly with growth, according to MacGregor. Then, the research shifted to the role of vitamins and birth defects. The newest wave of research linking vitamin deficiency with genetic damage is just beginning to take hold, but MacGregor thinks it perhaps has the strongest implications.

Blount agrees. "When I first started in this field in 1989, there was still a lot of questions about birth defects." Now that the correlations between folic deficiency and birth defects have been established, more scientists are searching for an understanding of why it exists.

"We do not know how the folate is working," says John Lloyd, director of developmental biology at Jefferson Medical College in Wilmington, Del. "It could be that these mothers are actually methionine-deficient. Or it could be that they are Vitamin B12-deficient. They are all viable hypotheses at the moment."

Lloyd echoes other scientists who say pinpointing the cause may be difficult because of the folic acid's intricate chemical interactions with other chemicals. Folic acid promotes homocysteine to methionine, but that conversion depends on B12. "Perhaps it will be experimental work on animals that will help sort this out," Lloyd says.

While scientists continue to unravel the biochemical reactions and government agencies debate the merits of changing the RDA and supplementation level, most scientists agree that the U.S. diet could be improved to deliver folic acid naturally. "We don't eat enough fresh fruit and vegetables," Stampfer says. "We eat too much fast food and junk food-food that doesn't have these vitamins."