Study: Nutrigenomics far outperforms Keto for weight loss.
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#01 – Ketogenic Diets: the Good, the Bad and the Genetic with Dr. Aaron Gardner

Are you considering a ketogenic diet? Learn the benefits, potential risks, implications for heart health, how to choose supplements that aid ketosis, how genetics affect the way high fat diets impact different people and whether a ketogenic is a good solution for APOE4 carriers.

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Ok, welcome to the first episode of the Gene Food podcast, a deep dive into the implications of ketogenic and high fat diets for different genotypes. Aaron and I are fascinated by a study that came out last year, called the Retterstol study, which measured biomarkers for 30 healthy adults before and after going on a diet very high in fat and low in carbohydrate. The results confirm what we believe to be true here at Gene Food, which is there is no one size fits all when it comes to nutrition. The rise in LDL-C on the high fat diet prescribed in the study varied between just 5% in some participants to 107% in others! Clearly genetics play a big role in how our bodies respond to high fat diets and that’s what we get in today’s episode.

Because I know many of our listeners will be interested, here is a link to the study Aaron mentioned regarding ketone ester supplements vs. ketone salts.

The conversation is a bit on the technical side, but bear with us, this is episode #1, so we are working out the kinks as we go.

This Episode Covers:

  • Are you in ketosis? How to measure ketones and make sure you’re getting the benefits of a ketogenic diet;
  • The protective effect of ketones and the research of Dr. Veech at Harvard [4:00];
  • The GSTP1 gene, glutathione, SOD2 and endogenous antioxidants and ketones as an antioxidant [6:40];
  • Dangers of damaging gut health with excessive keto, cycling in and out of ketosis [7:30];
  • Ketone supplements and exogenous ketones, ester vs salts supplements, MCT oil, VDR genes and high fat diets [11:30];
  • Retterstol study and the variability in responses to high fat diets, including carnivore diet blood work [20:54];
  • LDL receptor, LDL particle saturated fat, cholesterol and the risk for heart disease [27:10];
  • PCSK9, LDLR and LDL-C levels [39:30];
  • PPAR the difficulty of generating ketones and the importance of testing [48:00];
  • FTO the “obesity gene” an high fat diets [53:00];
  • APOE4, Alzheimer’s and ketogenic diets: what is the best diet for APOE4? Vegan vs. high fat / low carb, Rhonda Patrick protocol [57:30];

Genetic Notes:


proprotein convertase subtilisin/kexin type 9

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What it does

Binds to LDL receptor causing the receptor to internalise into the cell, meaning it can’t traffic any more LDL.

If you block PCSK9 function, more DL receptors are present on the cell surface and so more LDL is absorbed. This is the function of PCSK9 inhibitors alirocumab and evolocumab.

Berberine is thought to be a “natural” inhibitor of PCSK9, but the mechanism is unclear, and positive associations are limited to animal models.


rs11206510 – R46L  (C allele is minor and protective)

Minor allele is protective against myocardial infarctions, reduces LDL cholesterol levels by 15%.

Only about 10% of people carry the protective allele, most people don’t.


What it does

Low density lipoprotein receptor (LDLR) binds circulating low density lipoproteins (LDL) and is encoded for by the LDLR gene.

Increased LDLR function is associated with greater clearance and therefore reduced serum LDL.



The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C, and lower risk of CHD.


Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L. This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82).

PPAR alpha

What it does

PPAR-alpha is a transcription factor that increases fat breakdown in the liver by altering the expression of other genes. Importantly PPAR-alpha is activated under conditions of calorie restriction and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.

Results in increase in fatty acid uptake, trafficking etc, also downregulates immune responses.


Rs1800206 – C > G

Associated with higher TG, cholesterol, LDL, apoA1 and apoB

The G allele was associated with greater plasma concentrations of TG and apoC3 in subjects consuming a diet low in PUFAs (<6% of energy), whereas when PUFA intake was high, carriers of the G allele had lower TG and apoC3, indicating a significant dose-response relationship between PUFA intake and serum TG concentrations depending on the genotype . Additionally, dietary fat intake interaction has effects on the peak particle diameter of LDL, a risk factor for cardiovascular diseases. G carriers with higher saturated fat intakes had smaller peak particle diameters of LDL than those with lower intakes.

Furthermore, in healthy white men from Quebec, carriers of the G allele had lower apoA1 concentrations after a high PUFA diet (P = 0.02). In addition, subjects that followed a low-fat diet for 8 wk and then were supplemented daily with 5 g of fish oil for 6 wk showed a significant genotype-diet interaction on the plasma C-reactive protein concentration.

Some evidence in mouse models that G is associated with impaired fasting response, i.e. you don’t go into ketosis.


What it does

See our FTO gene page.


Rs17817449 T > G

Rs1121980 G > A


What it does

See our CETP gene page.


rs708272 – TaqIB

rs2303790 – D442G

Both reduce CETP levels, and activity resulting in higher HDL-C levels ~4.5% increase, and higher apolipoprotein A-I levels. There is a weak association with a beneficial effect protecting against CAD.

For the latter there is a stronger effect, but may just be a study population effect as very rare. Confusing but a meta analysis of all available studies described the weak protective effect.

APOE4, Diet and Alzheimer’s

See our APOE gene page for detail on the APOE4 polymorphism.

The ketogenic diet (also known as keto diet) is a very low-carb, high-fat eating pattern.

There is a lot of research into its effects on brain health, particularly Alzheimer’s.

Our brains use glucose (carbs) as their main fuel source. If glucose is not available, the brain can switch to using ketones.

In Alzheimer’s disease, the ability of the brain to use glucose for energy is impaired. However, its ability to use ketones remains equal to that of a healthy brain (R). This is why a ketogenic diet may aid those already suffering from Alzheimer’s, but be contraindicated as a preventative measure. 

Both animal and human trials have shown ketogenic diets have slight beneficial effects in mild-to-moderate Alzheimer’s disease. Studies that directly supplement ketones in the form of MCT oils (maybe even coconut oil) have also been promising (R)(R)

Unfortunately, early studies indicate that cognitive improvements from MCT supplementation are weaker in those with APOE4 variations. This suggests a ketogenic diet and MCTs may not be as effective in APOE4 carriers (R) (R)

Additionally, it’s especially difficult to adhere to long-term ketogenic diets because they are so restrictive, and it may increase the risk for heart disease in some populations.

John O'Connor

John O'Connor is the founder of Gene Food, a nutrigenomic startup helping people all over the world personalize nutrition. John is the host of the Gene Food Podcast and a health coach trained at Duke's Integrative Medicine Program. Read his full bio here.

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  1. Fascinating stuff, thank you for the comment Micheal. The parasite / Alzheimer’s protective angle is not one we have researched, but we will add it to the list for a blog post in the near future. Thank you for putting these issues on our radar.

  2. Heather Rae, INHC says:

    Low level chronic inflammation is root cause of cellular dysfunction/illness, a reason to look at ability clear hydroxyl radicals, peroxynitrite, and overall function of detoxification pathways. And … what *is* the role of microbiome, pre/pro-biotics …?

  3. Heather Rae, INHC says:

    Thank you for doing the podcasts. I look forward to more! I am a certified functional genetic analyst, and integrative nutrition coach for which bio-indivduality is the over-arching theme. I live between VietNam and US (northeast) and I am interested in race, geography, sunlight, heat effects on nutri-genomics. I have done a Thermo Fisher (NGRI) DNA test – we load it into analytical software with other test results and sign/symptom questionaire. I have APoE4 (homozygous) … this conversation is personal and professional.

    • Hey Taylor,

      Thanks for listening. We have submitted the feed to iTunes and Google podcasts, just waiting for the show to be approved. So, yes, subscribing via Google podcasts will be possible in short order.

  4. Markus says:

    Years ago when I was eating a low-carb/ketogenic paleo diet, my cholesterol skyrocketed to >400 mg/dl. In addition, I had poor lipid metabolism and mitochondrial function according to a Genova NutrEval-analysis.

    Later on I discovered that I’m APOE4/4, heterozygous FTO and PPARA.

    Now, eating a more plant-based, higher carbohydrate diet, my cholesterol is 150 and my mitochondrial markers have improved significantly.

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