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.”
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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.
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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.
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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.