Nutrigenomics

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Wednesday, July 02, 2008

Taking Vitamins Based on Your Genome

Newly discovered genetic variations could predict who needs more folic

acid.

By Singer

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 <http://mcb.berkeley.edu/labs/rine/people.html> , a biologist at

the University of California, Berkeley, who led the new research in

collaboration with Jasper Rine

<http://mcb.berkeley.edu/labs/rine/labpage.html> , 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

<http://www.pnas.org/cgi/content/abstract/105/23/8055?maxtoshow= & HITS=10

& hits=10 & RESULTFORMAT= & fulltext=marini+rine & searchid=1 & FIRSTINDEX=0 & reso

urcetype=HWCIT> .

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

<http://www.bruceames.org/> , 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 <http://www.chori.org/> and the Joint Genome Center

<http://www.jgi.doe.gov/> , 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 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

<http://www.bruceames.org/SAskree_CV.pdf> , 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.

Copyright Technology Review 2008.

S. Kalman PhD, RD, CCRC, FACN

Miami Research Associates

Director, Nutrition & Applied Clinical Research

6141 Sunset Drive #301

Miami, FL. 33143

(fax)

www.miamiresearch.com <http://www.miamiresearch.com>