Can Genes Influence the Way People Respond to a Ketogenic Diet?

The ketogenic diet (KD) is a low-carbohydrate, high-fat, adequate-protein diet that has proven to be effective for the reversal of several chronic conditions including obesity, metabolic syndrome, and type-2 diabetes (T2DM) in trials of up to two years.¹ However, the degree of therapeutic response to KD varies across individuals.^2,3 For example, some KD dieters lose more weight than others, and, while most of them improve their blood lipids, so-called “high responders” experience abnormal increases in low-density lipoprotein cholesterol (LDL-C). Many factors underlie this variability of response to KD including physiological factors (sex, age, hormones), lifestyle factors (activity level, diet quality, stress, etc.), and their interaction with genetic factors.

Genes can affect many aspects of how people respond to KD, including:⁴

• Ketone production, uptake, and clearance
• Cholesterol production, uptake, and clearance
• Weight loss
• Cognitive performance
• Seizure reduction
• Keto adaptation (long-term physiological responses to KD)

But do we actually know which genes make people more likely to succeed or fail on KD? Can we trust what health news and direct-to-consumer genetic services tell us about these predispositions? How can clinicians evaluate the validity and utility of this information to develop personalized lifestyle interventions for their patients?

In a recent study, researchers have reviewed what we know about the genetic variants that affect the response to KD in clinical studies and their possible use in personalized care.⁵ The authors focused exclusively on genetic data from intervention studies in which the participants either followed a KD protocol with a carbohydrate restriction sufficient to induce ketosis or were administered ketogenic agents such as medium-chain triglycerides (MCT). For each genetic association, a strength of evidence score was calculated based on the number, type, and size of the supporting studies. Based on these criteria, the following genetic variants were found to affect the response to KD or ketogenic agents with sufficient evidence from clinical studies:

• 5 genetic variants were associated with greater weight loss in response to KD: gastric lipase (LIPF, rs814628-G), hepatic glycogen synthase (GYS2, rs2306179-C), cholesteryl ester transfer protein (CETP, rs5883-T), and galanin (GAL, rs694066-G)
• 1 genetic variant was associated with greater reduction in body fat percentage in response to KD: angiotensin II receptor type 2 (AGTR2, rs5950584-G)
• 1 genetic variant was associated with greater cognitive improvement in response to MCT-based agents in patients with Alzheimer’s disease (APOE, rs429358-T)
• 1 genetic variant was associated with greater seizure improvement in epileptic patients: chromodomain Y ligand 1 (CDYL1, rs12204701-G)

The researchers also addressed one of the questions clinicians care most about: Can genes help us predict which patients may be “hyperresponders” to KD and design personalized management plans for those patients? Some individuals may be more likely to be “hyperresponders” to KD if they carry certain genetic variants that lead to higher LDL-C in response to high fat intake. However, these genetic variants are not always a contraindication to KD and warrant a case-by-case evaluation based upon screening for additional cardiovascular risk factors such as family history, high LDL particle number, high triglycerides, low high-density cholesterol (HDL), and high coronary calcium score. While patients at high cardiovascular risk may need to avoid or discontinue KD, those at low risk may consider adopting a KD protocol with low saturated fats, high unsaturated fats, and limited consumption of red meat in order to lower their LDL.

Finally, the researchers present a selection of the most promising candidate genes to evaluate in future studies and discuss key aspects of study design that may help accelerate the implementation of these biomarkers in clinical practice.

This study was supported by Metagenics and published on December 12, 2020, in the journal BMJ Nutrition, Prevention, and Health.

What are the key takeaways?

• Genetic variants may affect a patient’s response to a ketogenic diet (KD).
• Only a few genetic markers of KD response have been validated in clinical trials. These markers may be used in conjunction with other risk factors and biological variables to develop personalized KD interventions.

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Citations

1. Athinarayanan SJ et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. Front Endocrinol. 2019;10:348.
2. Ludwig DS et al. Dietary fat: from foe to friend? Science. 2018;362:764–770.
3. Westman EC et al. Low-carbohydrate nutrition and metabolism. Am J Clin Nutr. 2007;86:276–284.
4. Ruano G et al. Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction. Nutr Metab. 2006;3:20.
5. Aronica L et al. Genetic variants for personalized management of very low carbohydrate ketogenic diets. BMJ Nutr Prev Health. 2020.