The Problem with Nutrigenomics

"Personalized nutritional counseling is a burgeoning field. Several companies, including Vitagene, Nutrigenomix and DNAFit, are already offering individualized dietary counseling.  Their efforts are based mostly on genetic testing, but scientists have only just begun to explore the links between DNA and good nutrition. “I think companies offering personalized dietary advice are probably running ahead of the evidence,” said John Mathers, director of the Human Nutrition Research Center at Newcastle University in Britain." [NYTimes Blog]

Introduction

Science skeptics have recently reviewed these services, and found plenty of quackery. [Science Based Medicine] [Skeptical Raptor]

However, there is some research to back up the idea that genetic testing can provide insights into metabolic disorders.  There may be as many as 200 SNPs for which there are proven metabolic effects, and only a subset of these alter nutrient requirements in a significant portion of the population [e.g., the rs1801133 MTHFR SNP and folate requirement in 15–30% of the population (Solis et al., 2008) and the rs12325817 PEMT SNP and choline requirement in 20–45% of the population (da Costa et al., 2006)].

What do genetic testing services measure?

The human genome consists of about 3 billion nuceleotide bases, each of which is either A,C, T, or G.  A reference genome based on the similarities of all genotyped humans has been assembled, along with a corresponding reference database of all of the point "mutations" where individuals differ from that baseline.  So far, scientists have documented about 150 million of these single nucleotide polymorphisms, called SNPs.  The average person doesn't have all of these differences, however; most people have about 3 millions SNPs that differentiate them from the reference human genome.   Since 3 million is about 0.1% of the 3 billion base pairs, most humans differ from each other by about 0.1% of our DNA. Ancestry genomic testing services like 23andme test for a few hundred thousand SNPs for $100-$200.  For $1000-10,000 a complete genomic sequence can be obtained.  (there are about 3 billion bases total.  

Examples: MTHFR – metabolic pathways and nutrigenomics

In humans, SNPs in the gene MTHFD1 increase the demand for betaine as a methyl-donor, thereby increasing the dietary requirement for choline. Another SNP in the gene PEMT prevents the activation of this gene by estrogen, thereby decreasing endogenous production of phosphatidylcholine (a source of choline) in the liver and increasing the dietary requirement for choline. [Choline: Critical Role During Fetal Development and Dietary Requirements in Adults. Ziesel]

But note that it is not so simple.  There are several forms of the MTHFD1 gene, for example MTHFD1L and MTHFD2. If MTHFD1 is commonly mutated, it may be a pseudogene.

Complexities interpreting SNPs

No simple test can unravel the intricacies of the human genome, and consumers should be suspicious of anyone claiming to be able to interpret measurements of tens of thousands of genes, with millions of genetic variations, some of which have effects on hundreds or thousands of the small molecules of metabolism (and perhaps on thousands of peptides or proteins involved in metabolism).

[A grand challenge for nutrigenomics.  Steven Zeisel. 2010.]

Mistakes in genomics data

Note that 23andme data, like any large genome scan, can have mistakes in it.  For example, the Enlis genomics blog found more than 500 likely mistakes in a sample of 23andme raw data!  (Enlis)

Furthermore, many important nutritional SNPs are not testing by 23andme.

Solution: Metabolic Testing
There is a genetic test for MTHFR variations. But there’s also a cheaper and more accurate way to test for whetherMTHFR variations are causing disease. We simply check the levels of homocysteine in the blood...In other words, the homocysteine levels determine our actions, not the MTHFR test results.[Cleveland Clinic]

Metabolic Pathways

Say you want to know what the possible effects of taking a supplement might be.  You could research the supplement on the two high-quality websites that report supplement interactions based on human trials:

Examine.com

The Mayo Clinic - not as many supplements covered.

It would be great if there were reliable "trip reports" from patients on the effects and side-effects of drugs, but unfortunately side-effects are not reliably reported.

If you wanted more basic information, you could consult a metabolic pathway interaction diagram.  Note that the study of genetics and proteomics still has a long way to go:  we don't know what most of the essential genes even do, nor do we know the function of xx% of all genes.  No network diagram is complete....

SigmaAldrich offers a searchable poster:



According to this, NAC can increase glutathione, but also homocysteine. Important information from the network!




Biochemical-pathways.com has even more information.  Note that because the network diagram is again a poster, single compounds (e.g. cysteine) can occur in different places on the diagram.




Metacyc is the most detailed, but only shows one "pathway" at a time.


KEGG is another very good resource with drop-down menus to explore individual pathways.

A long list of other resources.

New Paper Continues Confirmation of Age-Defying Diet

In the last 15 years a number of research groups around the world have converged on an explanation for how dietary restrictions can lead to lifespan extension. These teams have narrowed the search to a handful of compounds.*  The central candidate, by far, is an essential amino acid called methionine, found in high amounts in meat and fish, but in very low amounts in most plant foods.

Reducing consumption of this single amino acid extends lifespan by 15-44% in every laboratory animal tested to date. This effect is sufficient to completely explain previous results that found dietary restriction of total calories led to lifespan extension. Turns out it wasn't the calories -- it was the methionine.

Methionine restriction reduces visceral fat with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Methionine restriction also prevents age-associated increases in serum lipids.(source)

A new paper published this month by Koziel et al confirms previous methionine restriction results in human cell culture, mice, rats, fruit flies, and yeast. Koziel et al used human cell culture to specifically examine mitochondrial function and showed that oxidative stress is reduced by this dietary intervention.  This work supports the traditional free radical theory of aging-by-oxidative stress.

Methionine is an interesting amino acid because it promotes growth, including muscle and bone development. It is essential, and that is the point: restriction appears to promote a healthy stress-response that can confer adaptive resilience to senescence.  Other researchers have postulated that methionine restriction causes an increase in autophagy, the process whereby cells break down and recycle unused or damaged cell components. Instead of the free radical theory of aging, this theory would postulate that Methionine restriction induces a starvation-type response where cells begin to recycle their constituents at an increased pace. In this theory, "stress" is a good state to be in, because it puts cells in an active phase of self-repair. Cite: 1 and 2.

* The two other most promising age-defying compounds are rapamyacin (an antibiotic with a plethora of strange and powerful effects throughout the body) and resveratrol.  

3D Protein Structures!

http://www.rcsb.org/pdb/home/home.do