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.

Testing a Relevant SNP?

A new study in Science Magazine by Simonti et al has linked this SNP to a rare condition known as protein-calorie malnutrition (PCM).  The study compared electronic health records (EHR) for 28,000 people with SNPs that are now known to derive from Neandertal DNA.

SNP rs12049593 is in an intron of SLC35F3, which means it does not change the actual structure of the protein, but instead alters the amount of protein produced.  SLC35F3 codes for a protein that helps transport vitamin B1 (thiamine) through the body to the mitochondria, where it can be used to generate and store energy from sugar. The linkage to PCM makes sense, because PCM is characterized by fatigue, malnutrition, and wasting even in the presence of adequate caloric intake.

"Humans depend on diet for their thiamine needs. Very little thiamine is stored in the body and depletion can occur within 14 days. Severe thiamine deficiency may lead to serious complications involving the nervous system, brain, muscles, heart, and stomach and intestines." (Mayoclinic)

"Thiamine is required for the assembly and proper functioning of several enzymes that are important for the breakdown, or metabolism, of sugar molecules into other types of molecules (i.e., in carbohydrate catabolism). Proper functioning of these thiamine–using enzymes is required for numerous critical biochemical reactions in the body, including the synthesis of certain brain chemicals (i.e., neurotransmitters); production of the molecules making up the cells’ genetic material (i.e., nucleic acids); and production of fatty acids, steroids, and certain complex sugar molecules.

Thiamine deficiency can lead to cell damage in the central nervous system through several mechanisms. First, the changes in carbohydrate metabolism, particularly the reduction in a–KGDH activity, can lead to damage to the mitochondria. Because the mitochondria produce by far the most energy required for cellular function, mitochondrial damage can result in cell death through a mechanism called necrosis. Altered carbohydrate metabolism can lead to oxidative stress, characterized by excess levels of highly reactive molecules such as free radicals and/or the presence of insufficient levels of compounds to eliminate those free radicals (i.e., antioxidants, such as glutathione). Oxidative stress can lead to various types of cell damage and even cell death."  (from Role of Thiamine Deficiency in Alcoholic Brain Disease)

Simonti et al state:
"Decreased expression of this transporter in the brain or GI tract could exacerbate malnutrition or its symptoms. It is possible that new dietary pressures may have caused changes in carbohydrate metabolism to be beneficial in early human migrants out of Africa; indeed, there is evidence suggesting that Neandertal-derived genes increase the efficiency of fat digestion. More recently, the reduction of thiamine present in foods from the grain-refining process, as well as an increased intake of simple carbohydrates, make this a potentially harmful allele, because it could reduce thiamine availability although modern diets increase demand."

I am homozygous for the recessive allele of SNP rs12049593.  I have a C where 95% of people have a G or T, courtesy of my Neandertal ancestry.  According to the Simnoti study, I may have some malnutrition symptoms if I do not express the B1 transporter gene.  According to my research, B1 can also passively diffuse if it is ingested at high enough concentrations.

I tested oral administration of 100mg/day of B1, which is more than 6000% of the US RDA but is the only size pill commercially available; apparently, this is a standard doze for supplementing B vitamins.  I weighed myself morning and night for 1 week and did not notice any change in weight.  Subjectively, I noticed some tiredness the first two times I took B1, then I noticed some energy, and after four or five days I do not notice any effect from supplementation.

UPDATE:  Figuring out what allele is variant and which is most common is difficult.  My information above was from 23andme raw data viewer, but when I loaded my data into the excellent Enlis Genome Personal software, I see that I actually have the reference allele, not the rare allele.  So that may explain why I don't respond to supplemental B1.

Tama Hills and Environmental Consciousness in Japanese Anime Films

In 1994 Studio Ghibli produced Pom Poko, (directed by Isao Takahata) a trippy animated film about a community of magical shape shifting raccoons desperately struggling to prevent their forest home from being destroyed by urban development.  The movie draws heavily on traditional Japanese folklore (especially the reputed power of the raccoon's testicles), but the setting is the 1960's rapid conversion of the Tama hills rural farmland into planned suburbs of Tokyo (called Tama New Town).

In 1995, Studio Ghibli came out with a very different film.  Whisper of the Heart is a realistically-animated love story about a teenage girl who loves reading books, and the boy who had previously checked out all of the library books she chooses.  It was set in a peaceful suburb in the hills of West Tokyo.  Specifically, the Tama hills.

Development of Tama Hills, as depicted in Pom Poko.

Scenes from Whisper of the Heart:

Walking along Tama Hills, above Tama River.

Walking along Tama River, toward Tama Hills.

It is difficult to describe the cognitive dissonance these two films create.  The first, a story of animals defending nature against human development, and the second, a human-centered love story set in that very development.

Tama Hills (Tama New Town), Tokyo.  Yes, those are golf courses on the hills.  There is an amusement park, too.

Map.

The main character, Shizuku, in Whisper of the Heart even composes a song, set to the tune of "Country Road".  She and her friend Yuuoko sing it together.

"Konkuriito roodo, doko made mo
Mori wo kiri, tani wo ume
Uesto Toukyou, Maunto Tama
Furusato ha, konkuriito roodo

Concrete Roads, to everywhere
Cutting forests, burying valleys
West Tokyo, Mount Tama
My home town is a concrete road...

(both laugh)"

(transcribed by Nausica.net)

Teenage lovers from Whisper of the Heart, overlooking Tokyo from Tama Hills.

It is possible to visit many of the locations that were used in Whisper of the Heart.

Young raccoon lovers from Pom Poko, overlooking Tokyo from Tama Hills.

More information about locations that inspired Japanese animated films.

Food4me study tested Nutrigenomics...and found no benefits

Food4me is a large online study designed to test whether personalized nutrition advice based on analysis of phenotypes (waist cicrumference, blood markers: glucose, cholesterol, carotenes, n-3 index ) or genotypes (SNPs in genes such as MTHFR, FTO, TCF7L2, APOE E4, FADS1 ) could perform better than standard nutritional advice.  The study recruited more than 1,600 volunteers from across Europe to take part.  Participants performed quantified health self-analyses such as biometric measurements and movement counts. They also used a do-it-yourself blood sampling technique that involves drying blood from a finger prick on absorbent paper, which can then be analyzed for more than 92 metabolic biomarkers in a lab.  They also submitted saliva samples that were checked for more than 36 genetic variants that have been linked to nutritional needs and health outcomes.

"A scientific knowledge base was developed, capturing the current knowledge in the field of nutrition
with a particular focus on the interaction of food consumption, nutrient intakes, biomarkers,
genetic variation to health. SNP information comprises risk allele frequencies as well as gene
symbols and functions. The collected scientific knowledge represented in the data base covers
currently 35 food items, 92 biomarkers, 36 genetic variations, 16 different health outcomes, and
180 established interactions based on scientific publications and an expert assessment."

After one year, the results are in.  Although their internet-based nutritional intervention was associated with positive outcomes, a recent whitepaper concluded that, after testing various diets, there were no improved health outcomes from phenotypic or genetic information.

The researchers state that, "despite enormous efforts over the last decade to identify gene variants that define the susceptibility of an individual to a life-style dependent disease, the outcomes of the large-scale profiling studies are rather disappointing. Although a large number of genes and variants have
been found (there are for example around 60 genes that carry a susceptibility risk to develop
type 2 diabetes mellitus (T2DM)), the effect sizes of each individual gene variant are generally
very low. In almost all cases, the risk-variant increases disease risks by only a very few percent..."

Complex Science: The Role of Vitamin D Receptor (VDR) Genotype Polymorphisms (SNPs)

Vitamin D regulates the expression of hundreds of genes, with widespread hormonal and immune effects.  But whether vitamin D is good for you may depend on your genes.  According to one hypothesis, supplemental vitamin D causes allergies and asthma.  [1]

But the biochemistry is complex.  The main circulating metabolite is 25-hydroxyvitamin D or 25(OH)D, a biomarker of vitamin D status.  The active vitamin D metabolite 1,25(OH)2D3 binds to nuclear vitamin D receptor (VDR), which exists from under 500 to over 25,000 copies per cell in many human tissues including thymus, bone marrow, B and T cells and lung alveolar cells.  Gene expression can be varied over a 100-fold range by subtle modifications of introns and promoter regions outside of the gene[1]

The SNPs that seem to affect VDR are not in the exon; they may affect RNA production in the promoter region. It is unlikely that increased or decreased vitamin D sensitivity is simply mediated by a genetic variation in the VDR. Vitamin D requires several enzymatic steps to be activated, transported and degraded; receptor signalling requires several co-factors and all of these may contribute additive or multiplicative effects on vitamin D sensitivity.

Possibly because of this complexity, progress in this field has been slow.  I reviewed several papers, most of which found very small or no effects from common SNPs.  For example, although most papers found insufficient or deficient levels of vitamin D throughout the population, a case-control study only found a small effect on circulating 25(OH)D from one of the SNPs tested. [2].  A randomized controlled trial found effects from more SNPs, but each contributed very small effect sizes. All SNPs tested had, at most, +/-5% effect on circulating 25(OH)D. : "Three SNPs had statistically significant interactions: rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR, with per allele effect sizes ranging from −4% to +3% differences in [25(OH)]."[3]

These complex and unimpressive results are representative of the difficulties inherent in assaying SNPs for clinically-relevant phenotypes.  Most SNPs slightly modify expression or binding of a protein, such that it takes the combination of dozens or hundreds of different SNPs to create any significant phenotype.  Biochemistry is complex, and it is always possible that other gene or protein interactions can ameliorate or exacerbate any small perturbation from any given SNP.

Citations:
[1] Variants in the vitamin D receptor gene and asthma.  2005.  

[2] Vitamin D levels and vitamin D receptor gene polymorphisms in asthmatic children: a case–control study.

[3] Genetic Variants in CYP2R1, CYP24A1, and VDR Modify the Efficacy of Vitamin D3 Supplementation for Increasing Serum 25-Hydroxyvitamin D Levels in a Randomized Controlled Trial.

Trying to Expose Sham "Nutrigenomics Testing"

Denise Minger published a post about her genetic MTHFR status that convinced me to test mine, but now I'm writing to expose this for scam it is. It took me an embarrassingly long time to realize that there is simply no scientific evidence for the claims on geneticgenie.org, mthfrsupport.com, or any of the other websites that have sprung up around Dr. Yasko's unsupported claims about SNPs and the detox/methylation cycle.  I fell for, and many people are continuing to fall for it.

The idea of correlating individual genetic differences to different nutritional requirements seems scientifically plausible.  But searching Pubmed shows that the claims being made about specific SNPs are not backed up by published scientific research. This scam propagates on plausibility, confusion, and ultimately, apathy.  I was taken in and confused by the veneer of scientific credibility...and when it didn't make sense I assumed I just needed to spend more time on the research.

But there is no research backing up these claims. They can all be traced back to Amy Yasko, who runs a website promoting her personal interpretations and observations.  While she claims not to make any money from sharing her knowledge, she promotes products and testing sold by her husband's company.  Her bibliography appears to include extensive scientific work, but I was unable to locate any of the papers she claims to have published.  She states that she is now "too busy" to publish her results.  I also could not find any confirmation that she is a real doctor (JD or PhD).

The sad truth is that, whether she believes in her own theories or not, this is a classic snake oil supplement gimmick hiding behind a sheen of fake science.  Selling B vitamins as miracle drugs has a long history, because almost everyone feels better with a few B vitamins (that's why they put them in energy drinks).  If you try the more expensive supplements she promotes, you may or may not feel better.  If you do feel better, you're quite likely to promote the gimmick. Most of the people commenting write in to say that they are feeling better, or think that they will when they get their supplement combination dialed in.  If you don't fell better, you might be motivated to try a different high-priced supplement, or you might just give up and stop reading this (or other) blogs.  The result is a huge number of people who appear to have been helped by this approach, and a continuous supply of new customers.

While we all want personally-tailored miracle drugs, maybe the best we can say right now is to eat "whole foods, mostly plants, and not too much"...and skip the overpriced unscientific supplements.

More background on Amy Yasko's nutrigenomics scam.

A brief review of the state of the science for one of Yasko's claims.

My review of the complex problems involved in evaluating Yasko's incomplete metabolic diagrams.