More than 2,000 years ago, Hippocrates wrote: "Leave your drugs in the chemist's pot if you can heal the patient with food." Scientists may finally be catching up with the Father of Medicine. One of the newest fields of nutrition science, known as nutritional genomics, is dedicated to understanding the interaction between diet and the genome. The goal is to use food to prevent disease by identifying genetic predispositions for chronic conditions that can be mitigated by the proper dietary intake. Researchers in the field warn that they need to collect much more evidence before nutrigenomic, or nutrigenetic, dieting becomes a reality.

"What we are seeing now is the very, very beginning," says Jose Ordovas at Tufts University, Boston. Ordovas is widely respected by academic and corporate leaders alike as having conducted some of the most elegant gene-diet interaction experiments to date. "Nutrigenomics has established proof of concept, but that's...


Grimaldi and Genelex cofounder Howard Coleman both point to the MTHFR (methylenetetrahydrofolate reductase) gene as one of the best examples of how and why nutrigenetic-based dieting works. Ordovas, on the other hand, says the diet-influenced expression of MTHFR illustrates only how and why nutrigenetic dieting might work in the future. Large (and costly) intervention studies assessing the preventative benefit of folic acid therapy in healthy individuals are still needed.

Most people have a cytosine (C) at MTHFR base pair 677, but about 10% of northern and 15% of southern Europeans have thymine (T) instead. Homozygosity for the C677T polymorphism is a known cause of moderate hyperhomocysteinemia, particularly among those whose folic acid intake is low. Experts agree that the evidence for folic acid intake and MTHFR variability together influencing hyperhomocysteinemia is undeniable. Ordovas says it's one of the best examples of a known gene-nutrient interaction, whereby one's phenotype is determined by the interaction between genotype and nutrient intake.

The disease-prevention implications of this interaction are less certain. Homocysteine is a key intermediate in methionine metabolism, and researchers have known for years that elevated plasma homocysteine levels are associated with a higher risk of cardiovascular disease (CVD). Whether hyperhomocysteinemia causes CVD, however, or is a consequence of it is unclear.2 "The thing that's missing," says University of Iowa cardiologist Steven Lentz, "is that there is not good evidence yet that treating people with folic acid prevents heart disease. It's an interesting example of a nutrient-genome interaction, but we just don't have enough information yet to be sure that it's clinically useful."

The T allele at base pair 677 has also been associated with a lower risk of colorectal adenomas and colon cancer risk, but only when folate intake is normal, again illustrating a dietary influence on this gene's expression.3 The increased risk of cancer associated with low folate intake is particularly pronounced in individuals older than 60 and is exacerbated by the consumption of moderate levels of alcohol. But again, as with the relationship between MTHFR, folic acid, and CVD, no evidence indicates that treating people with folic acid prevents cancer. Likewise, there are no interventional data for the range of other disorders associated with MTHFR SNPs, from migraines with auras to depression.

Lentz says that about a dozen ongoing clinical trials are aimed at determining the effectiveness of homocysteine-lowering therapy with folic acid in preventing secondary CVD events (i.e., in people with already-diagnosed disease). Results from these studies aren't available yet, and preliminary findings are inconsistent. Until data demonstrate clinical benefit, Lentz says that he will continue using folic acid intervention only in high-risk cases, such as patients with other, nonhomocysteine-related CVD risk factors. He says that he doesn't rely on MTHFR profiling at all in his practice.

Nevertheless, MTHFR tops the list of 19 genes that Genelex assays as part of its personalized nutrition service. Clients are provided a 35-page "CELLF Report," which includes a table of genes tested and whether "variations" were found, suggested nutrition and lifestyle changes based on the DNA profile and questionnaire, and reference materials. The sample report on Genelex's Web site indicates that a variation in MTHFR has been detected (presumably the presence of a T allele) and recommends an increased intake of folate. Information is provided on the physiological importance of folate, homocysteine, and how homocysteine build-up has been linked to heart disease and a variety of other illnesses. Suggestions are made for how to "put advice into action," including eating foods that are rich in folate (e.g., liver, leafy vegetables, citrus fruit, whole grains, wheat germ, and avocados). For an additional $100, clients can talk with the nutritionist on staff., Carolyn katzin, about their results in detail.

MTHFR is one of ten genes that comprise South Africa-based GeneCare's CVD nutritional genetic test. For the equivalent of about $400 US, GeneCare clients can have their CVD genetic profile interpreted and suggested dietary changes formulated. The assay is based on 10 genes that are considered CVD risk factors in the South African population. Results are sent to the client's referring nutritionist or physician.



Can your genes tell you how to focus your diet?

The etiology of CVD is vastly more complicated than its association with folic acid, MTHFR, and hyperhomocysteinemia. Even if scientists were to demonstrate that folic acid decreases CVD risk in individuals homozygous for the T allele, that finding would still not account for the multigenic nature of CVD. It is not difficult to imagine the challenge of formulating a scientifically sound, preventative dietary plan given the dozens of other genes associated with CVD and the multitude of nutrients and other food compounds that interact with and influence the expression of those genes.

One of those other genes is apolipoprotein A-1 (APOA1), which plays a prominent role in lipid metabolism. Ordovas and colleagues analyzed data from the Framingham Offspring Study (a long-term study started in 1971 on the incidence and prevalence of cardiovascular disease) to determine whether and how fat intake might influence the association between the APOA1 75(G/A) polymorphism and HDL, or so-called good cholesterol.4 The researchers found that, among women who derived less than 4% of their dietary energy from polyunsaturated fatty acids (PUFA), G/G genotypes had higher HDL-cholesterol than A/A genotypes. But among women whose PUFA intake exceeded 8% of their dietary energy, A/A genetypes were better off. Based on this proof-of-concept study, women with the A-allele at the APOA1 75(G/A) polymorphism should benefit from diets containing a high percentage of PUFA (e.g., vegetable oils, fish, nuts). But as with MTHFR, interventional studies have yet to demonstrate that such dieting does actually lower CVD risk.

The multitude of epigenetic modifications that coat the genome further complicates the multigenic etiology of chronic disease. Epigenetic modifications are heritable changes in gene expression that have little to do with DNA sequence. Duke University's Randy Jirtle, professor of radiation and oncology, says such changes are key to understanding the relationship between diet and chronic disease. In particular, cystosine methylation, a common epigenetic mechanism, is highly susceptible to dysregulation by nutrients (and other environmental components) during early development.5. Early nutrients is so important in mammals, Jirtle says, that "by the time you go to the doctor and say 'I'm pregnant,' all this is done. So, in reality, you really have to be thinking about your diet and nutrition long before you know you are pregnant." This raises yet another question about the preventative effectiveness of nutrigenomic dieting in adults, unless the dieter is thinking a generation ahead.



Nutrigenomics companies send personalized reports like this one to their clients.

Scientists are not the only experts calling for more data, Among ethicists, "there are concerns that the advice or products the public receives are as efficacious as claimed," says David Castle, University of Guelph, Ontario. Castle is currently serving on an international advisory council for the Ethics and Nutritional Genomics Project Canada. He says that consumers want to know that what they are buying is effective. But if the lack of intervention studies is any indication, efficacy is precisely where nutritional genetics falls short. Consumers are either unaware of this shortcoming or they are pursuing what they know is scientifically premature advice. Coleman says Genelex sells about 50 kits each week, while Grimaldi reveals that Sciona has sold about 10,000 assays in the past year. GeneCare managing director Maritha Kotze estimates that she's prepared about 50 evaluations over the past month and says that service is becoming more popular light of increasing publicity. GeneCare was recently awarded the equivalent about $775,000 (US) for product development from Cape Biotech, a government-sponsored biotechnology development initiative.

Coleman describes his company's clientele as "middle or upper income individuals who either have a personal or family history of chronic disease or weight management issues. They have made a commitment to make health their priority." Katzin says that many of her clients are baby boomers whose parents have had a chronic illness, and they are concerned about their own aging process. Many, she says, have already had complete blood work done and are looking for "more information."

Even the skeptics agree that something about obtaining a personalized set of dietary guidelines, interventional evidence notwithstanding, motivates people to become more conscientious, healthier eaters. Today's personalized plans can't offer the specificity that nutrigenomic dieting may one day provide, but few would argue that "eat more leafy greens" is bad advice. Grimaldi estimates that about 75% of Sciona's customers follow their individualized plans for at least a year. That's impressive, given that only 13% to 15% of UK adults consume the recommended five daily portions of fruits and vegetables.

But better diet adherence pales in comparison to the promise of nutrigenomics. "Wouldn't that be sad," quips Jirtle, "if this is the most important scientific advance we've made?"

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