Keto And Genes: Is This Diet Right For You?

The ketogenic diet is a high-fat, low-carbohydrate, and adequate-protein diet that has been proven to be effective for weight loss, improved metabolic markers, and even brain-protective properties. However, the ketogenic diet may not work for everyone due to individual factors such as genetics.

Genetics play a significant role in how individuals respond to different diets, and certain genetic markers can make a keto diet unsafe or ineffective for weight loss. For example, carriers of genetic variants in the PPARA gene often cannot achieve ketosis, which is crucial for the success of a ketogenic diet. Additionally, the APOE4 gene variant is associated with higher cholesterol levels and an increased risk of Alzheimer's disease, making a low-saturated fat diet more suitable for these individuals.

Other genes that can influence the success of a ketogenic diet include FADS1, FUT2, ACLS1, APOA2, FTO, TCF7L2, and MTHFD1. These genes can impact omega-3 fatty acid synthesis, gut microbiome health, saturated fat metabolism, food cravings, appetite regulation, insulin resistance, and more.

Therefore, understanding one's genetic predispositions and making minor adjustments to the ketogenic diet can optimize its effectiveness and minimize potential health risks.

The APOE gene and its variants

The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream.

There are at least three slightly different versions (alleles) of the APOE gene. The major alleles are called e2, e3, and e4. The most common allele is e3, which is found in more than half of the general population.

The APOE e4 variant is associated with an increased risk of developing late-onset Alzheimer's disease. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk.

The APOE e4 allele may also be associated with an earlier onset of memory loss and other symptoms compared to individuals with Alzheimer's disease who do not have this allele.

The APOE e4 version of the APOE gene can increase the risk of developing a form of dementia called dementia with Lewy bodies.

The APOE e4 allele has been shown to greatly increase the risk of a rare condition called hyperlipoproteinemia type III. Most people with this disorder have two copies of the APOE e2 allele, leading researchers to conclude that the e2 allele plays a critical role in the development of the condition.

The APOE e2 allele has been shown to have a protective effect on cognition after menopause.

The APOE e4 allele is an independent risk factor in age-related mortality and all-cause mortality.

The APOE e4 allele is associated with hypertension and brain hemorrhage risks.

The APOE e2 allele is associated with a lower risk of cognitive decline and a significantly reduced risk of cardiovascular disease.

The FADS1 gene and omega-3 synthesis

The FADS1 gene is responsible for the synthesis of omega-3 long-chain fatty acids. The FADS1 and FADS2 gene cluster is involved in the metabolic pathway of LA and ALA, as well as the enzymes involved in the production of eicosanoids, 5-LO, and cyclooxygenase from AA and EPA.

The FADS1 gene encodes the Δ5 desaturase, which catalyses the addition of a double bond at the Δ5 position. This is a rate-limiting step in the synthesis of polyunsaturated omega-3 and omega-6 fatty acids. The FADS1 gene is located on human chromosome 11 and consists of 12 exons and 11 introns.

Individuals with the FADS1 gene variant should be cautious with saturated fat intake. With reduced genetic function in converting saturated fats into unsaturated fats, a high saturated fat diet may lead to poor implications for metabolism, cholesterol levels, triglycerides, inflammation, and neurological health.

The FADS1 gene has also been associated with cognitive development. Studies have shown that the FADS1 genotype can influence the structure and function of brain substrates, particularly in males. Additionally, maternal FADS1 genotypes have been linked to lower cognitive development in infants, possibly due to lower LC-PUFA status during critical stages of fetal development.

In summary, the FADS1 gene plays a crucial role in omega-3 synthesis and has implications for overall health and development.

The FUT2 gene and gut microbiome health

The FUT2 gene is associated with gut microbiome health and enzyme levels in the gut lining that influence the concentration of vitamin B12 in the blood. The FUT2 gene encodes an α-1,2-fucosyltransferase responsible for the expression of ABO histo-blood-group antigens on mucosal surfaces and bodily secretions. Individuals who carry at least one functional allele are known as "secretors", whereas those homozygous for loss-of-function mutations are known as "non-secretors".

Non-secretor individuals tend to have lower alpha-diversity, which is an unfavourable feature for the host. They also have a higher risk of developing Crohn's disease, which may be due to changes in the intestinal microbiota. The FUT2 gene has been shown to modify the gut microbiome and influence the risk of graft-versus-host disease and bacteremia after hematopoietic stem cell transplantation.

To maintain good gut microbiome health, it is recommended to focus on eating probiotic and prebiotic foods. Probiotic foods include fermented vegetables like sauerkraut and kimchi, aged hard cheese, cottage cheese, and tempeh. Prebiotic foods include asparagus, tomatoes, avocado, Jerusalem artichoke, apples, berries, garlic, onions, and leeks.

The PPARA gene and ketosis

The PPARA gene, also known as the PPAR-alpha gene, is a nuclear receptor protein that plays a role in mediating fatty acid oxidation, lipid metabolism, and glucose production for energy consumption. In other words, it affects the body's ability to use fats as fuel over carbohydrates, making it harder to enter and stay in ketosis.

PPAR-alpha is a transcription factor that, once activated by ligands such as polyunsaturated fatty acids, regulates the metabolism of lipids, carbohydrates, and amino acids. It is part of the subfamily of peroxisome proliferator-activated receptors, which also includes PPAR-delta and PPAR-gamma.

Genetic variants within the PPARA gene have been associated with an increased risk of developing dyslipidemia and cardiovascular disease. These variants influence fasting and postprandial lipid concentrations and can accelerate the progression of type 2 diabetes.

Individuals with certain PPARA gene variants may struggle to achieve ketosis, even when consuming a high-fat diet. This is because their bodies have difficulty breaking down fats into ketones to use as energy. As a result, they may experience increases in cardiovascular risk markers like triglycerides, small dense LDL, and total cholesterol.

Personalizing Your Keto Diet

If you are considering a ketogenic diet, it is important to understand how your body may respond to high amounts of fat. Genetic testing can provide valuable insights and help you personalize your diet to optimize your results.

If you have PPARA gene variants, you may need to take exogenous ketones to achieve a ketogenic state. Regularly checking your ketone levels is essential to ensure you are in ketosis. Additionally, monitoring your cholesterol panel (HDL, LDL, and triglyceride levels) is crucial, as these may be associated with higher triglyceride and cholesterol levels on a high-fat diet.

To support your body's ability to use fats as fuel, focus on getting your fats from polyunsaturated sources such as walnuts, flaxseed, flaxseed oil, and chia seeds. Reducing saturated fat intake, especially from animal-based sources like lard, cheese, and butter, may also be beneficial.

In summary, the PPARA gene plays a crucial role in mediating fatty acid oxidation and lipid metabolism. Certain genetic variants within this gene can make it challenging for some individuals to achieve and maintain ketosis on a ketogenic diet. Personalizing your diet based on your genetic makeup can help optimize your results and minimize potential health risks.

The ACLS1 gene and saturated fat metabolism

The ACSL1 gene plays a vital role in saturated fat metabolism and triacylglycerol (TAG) synthesis. It is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. The protein encoded by this gene converts free long-chain fatty acids into fatty acyl-CoA esters, which are key to lipid biosynthesis and fatty acid degradation.

ACSL1 is involved in fatty acid metabolism and arachidonate biosynthesis. It is located in the mitochondrion outer membrane, peroxisomal membrane, endoplasmic reticulum membrane, and microsome membrane.

ACSL1 is also associated with body mass index quantitative trait locus 11.

ACSL1 gene polymorphisms have been found to influence the risk of metabolic syndrome, with GG homozygotes for rs9997745 displaying increased fasting glucose and insulin concentrations and increased insulin resistance. This risk was modulated by dietary fat consumption, with the risk abolished among individuals consuming a low-fat or high-PUFA diet.

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