Personalized Nutrition and Precision Medicine: overpromised and underdelivered? Part II: Nutrigenetics.

This article will delve into the field of Nutrigenetics, which I believe still plays a fundamental role in Personalized Nutrition.

Why do I say "still"? Because Nutrigenetics has lost some of its initial allure and has been gradually eclipsed by other "trendier" disciplines, or should I say, by the promotion of tests perceived as more fashionable!

The use and implementation of genetic tests, or any other tests associated with Personalized Nutrition and Medicine, differ greatly from their commercialization.

As much as I agree with the idea of making these tests accessible to a wide audience, I am quite opposed to selling them DTC (direct-to-consumer). Why am I saying this? In light of the complexity of these tests, consumers who attempt to change their diet and/or their supplement regimen based on the results may be confused or misled.

Let us face it: we bombarded the market with a multitude of Nutrigenetics tests that the public was not prepared to interpret, which has hurt the credibility of Nutrigenetics.

Prior to proceeding, I would also like to clarify a point that puzzles me: many companies, even very reputable ones, still refer to their tests as Nutrigenomics instead of Nutrigenetics. The two words are not interchangeable, and to use them as if they were indicates either a poor understanding of basic molecular biology and genetics or a lack of interest in correctly educating the public.

Nutrigenetics is the study of how small variations in the sequence of your DNA (SNPs and INDELs) affect the response of your body to nutrients, bioactive compounds, and even dietary patterns. Nutrigenomics, on the other hand, examines how nutrients and food components influence DNA expression, for example by interfering with or acting directly as transcription factors.

Consequently, as much as I would like to offer a test or device that track and analyzes "live" how your meal influences your DNA expression, we are unable to do so at this time.

Now, by responding to some common criticisms, I will explain why Nutrigenetics remains an essential component of Personalized Nutrition and Precision Medicine. Critics often make the following comments:

1. "Genetics doesn't dictate your destiny so it's useless to focus on genetic predisposition. Rather, we should study how the body is functioning in real time through methods such as transcriptomics, proteomics, or metabolomics". First of all, it is interesting to notice that this criticism usually comes from clinicians who struggle to grasp genetic fundamentals. Due to this reason, they believe that moving the target downstream will facilitate their work. It does not work that way! We all know the central dogma of biology and nobody who is serious enough in this field believes that genetics alone will provide all the answers. However, even if you could offer your patients a comprehensive transcriptomics, proteomics, and metabolomics panel (can you?), you would have to begin with genetics, as this will always influence the way the code is expressed. Let me provide an example. You have two patients with similar pathologies, let's say T2D and obesity, with very similar metabolomics signatures, like an overexpression of asparagine and histidine. One of the two patients responded well to a low-fat diet while the other did not. The nutrigenetic analysis would have revealed, for example, that one of the patients is homozygous for the most relevant variants in PPAR gamma, PLIN or FTO, while the other does not carry any variants of relevance. You can predict who will respond better if you know at the beginning of an intervention which are their weakest points and their tendency to respond to specific macronutrients or active compounds. This provides you the opportunity to make changes and personalize your approach. Therefore, what is the less personalized and more generic approach? Recommending a low fat diet to everyone or a reducing fat intake only for those who would respond well to this change? Yes, genetics is just the alphabet, but you can't pretend to read if you don't start with the ABC!
2. "The field of nutrigenetics studies only a small number of variants, while thousands of variants may have an impact on the health of individuals. In addition, many of these variants are not associated with major diseases, which makes them irrelevant." To begin with, we do not randomly select a few genetic variants, but rather focus on those that have been identified as relevant in GWAS. It is also possible that many are in linkage disequilibrium, so we avoid genotyping them all if it is not necessary. Therefore, the choice has a scientific rationale. In nutrigenetics, variations that predispose an individual to disease are examined rather than pathogenic variants. Here is the biggest difference, and perhaps the biggest misunderstanding. A simple question for you: how many individuals will develop cancer because of a very specific, inherited form of the disease, such as Lynch syndrome, PJS, or MEN? What can be done to prevent the remaining 90% of sporadic cancers? Nutrigenetics does not merely examine variation in EFAs metabolism or homocysteine recycling. In addition, we investigate variants that influence sodium sensitivity, the way you detoxify xenobiotics, inflammation, circadian rhythms, neurotransmitters metabolism, and so on. All of these biological processes constitute the basis of any disease in humans. I would like to ask once again: what is more personalized and real precision nutrition and medicine? Identify a unique genetic variation that causes a rare disease or take into account all the key elements contributing to 90% of the cases?
3. "While your argument may seem convincing, you do not present any RCTs to support the scientific basis of the relevance of these SNPs and interventions based on these small variants". This is probably my "favorite" criticism because it illustrates the wide gap between an old paradigm and the medicine of the future. To begin with, we do have RCTs that demonstrate the effectiveness of nutrigenetic interventions. It is true that there are fewer of them, and their relevance or effectiveness may appear to be lower than what you find in clinical trials in which one arm receives a placebo while the other receives a drug. What is the reason for this discrepancy? This is due to the fact that dietary or supplement interventions require long-term observation and cannot be based on a single indicator. An RCT cannot be discarded as ineffective if it considers only one endpoint, such as weight loss after a few weeks. Because the end point may not be evident for 6 months, 5 years or 20 years, we may not be able to find one specific biomarker to demonstrate that an intervention has been successful. It is a preventative rather than a reactive approach in medicine.

To conclude, Nutrigenetics is not obsolete, but should be supplemented with multiomics testing and novel forms of tracking. However, ignoring this part will result in an incomplete puzzle and a truncated reasoning process.