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Biomedicine

Taking Vitamins Based on Your Genome

Newly discovered genetic variations could predict who needs more folic acid.

Newly discovered genetic variations can impair an enzyme whose malfunction has been linked to birth defects and heart disease–but added nutrients can reverse the effect, according to new research. The findings could signify a step forward for nutrigenomics, a growing field examining how our diet and genes interact to affect our health. Scientists hope that nutrigenomics research will one day help people overcome some of their genetic foibles with personally tailored cocktails of vitamins.

The daily vitamin dosages recommended by the U.S. Department of Agriculture “are based on studies done 60 years ago, and are based on the assumption that everyone is biochemically the same,” says Nick Marini, a biologist at the University of California, Berkeley, who led the new research in collaboration with Jasper Rine, another Berkeley biologist. “We also think compliance would be better if an individual knew they personally needed more of a particular vitamin.”

The human genome codes for approximately 600 enzymes that must interact with vitamins or minerals in order to function properly. Scientists have known for years that some rare and severe metabolic disorders, caused by misspellings in the genes for vitamin-dependant enzymes, can be treated with vitamins. But research linking such genetic variations to more subtle health effects, which might affect a much broader swath of the population, is only just beginning.

In a pilot study published in June, scientists focused on an enzyme called MTHFR, or methylenetetrahydrofolate reductase, which converts the B vitamin folate (also called folic acid) from one form into another. Folate plays many roles in maintaining human health: it’s been linked to preterm birth and birth defects, as well as to cardiovascular disease, stroke, and colorectal cancer. The U.S. Food and Drug Administration mandated the addition of the vitamin to cereals and other grains in 1993.

Previous research suggested that variations in the MTHFR enzyme may make some people more susceptible to the effects of folate deficiency. A common genetic variant that produces a weakened version of the enzyme increases risk of birth defects and possibly of heart disease, although it’s not clear why. About 12 percent of people of European descent have two copies of that variation.

Marini and his colleagues sequenced the MTHFR gene in 564 people of different ethnicities and found four new variants that also impair enzyme function. In a unique step, the researchers then rigged a molecular system to measure how efficiently the different forms of the enzyme could churn out their molecular products. They added the human gene sequences to yeast cells, which were engineered such that their growth rate depended on how well the enzyme was working. Three of those sequences performed poorly: the yeast cells containing them grew more slowly than their counterparts when fed limited amounts of folate. But the same yeast grew at normal rates when given the vitamin in excess, suggesting that higher doses of folate might help people who are genetically susceptible to health problems linked to B-vitamin deficiency. The findings were published in the Proceedings of the National Academy of Sciences.

Nutrigenomics has received a bad rap in recent years, largely because companies have been offering individually tailored cocktails of supplements based on unproven research. But research like Marini’s begins to provide a way to more rigorously analyze vitamins’ impact. The work is unique because it provides an easy way to assess gene function, something that hasn’t been done much in nutrigenomics, says Bruce Ames, a biochemist at Berkeley who helped pioneer the study of vitamins in metabolism and human health. Ames, who was not involved in the research, adds that analysis in more complex systems will likely be needed to determine optimal dosages. “In the future, scientists may take a cell from an actual person and grow it in culture to determine if a bit extra of this vitamin or that vitamin can help,” he says.

Marini, Rine, and their colleagues are now following up their research in humans to try to better understand the enzyme’s role in birth defects. In collaboration with the Children’s Hospital Oakland Research Institute and the Joint Genome Center, in Walnut Creek, CA, the scientists will sequence the gene in 250 children with neural-tube defects and 250 normal children to see whether the poorly functioning variants appear more often in the former. “This could be incredibly important for shedding light on birth defects,” says Gary Shaw, the research director for the California Research Division of the March of Dimes, who is based at the Children’s Hospital Oakland Research Institute.

The Berkeley research has been enabled by new technologies, such as inexpensive gene sequencing, that allow scientists to search for a multitude of rare variants unlikely to be detected with other genetic tools. “We think that low-frequency variations, which would only be identified through sequencing, are important,” says Marini. For example, scientists have long known that there is a genetic component to neural-tube defects, because a woman who gives birth to one affected child is likely to have another. “But it’s been difficult to pinpoint the genetic cause, probably because it’s linked to low-frequency variants,” says Marini.

The findings might also shed light on a growing controversy over folate and heart disease. The MTHFR enzyme breaks down homocysteine, an amino acid that has been linked to heart disease in some studies but not others. An ineffective enzyme causes homocysteine to build up in the blood. It’s possible that only people who have both an ineffective enzyme and low levels of folate sustain high levels of the amino acid long enough to cause harm, says Syed Hussein Askree, a postdoctoral researcher in Ames’s lab. Because most studies examine people with a range of genotypes and diets, that link may have gotten lost.

Ultimately, Marini and his collaborators hope to take a much broader look at our nutritional requirements. Based on the rate of rare genetic impairments within the MTHFR region, the researchers calculated that everyone harbors about 250 disadvantageous mutations amid the 600 enzymes that require vitamins or minerals to function. That might mean we’re missing out on a lot of vitamins.

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