Open access Review BMJNPH: first published as 10.1136/bmjnph-2020-000167 on 12 December 2020. Downloaded from Genetic variants for personalised management of very low carbohydrate ketogenic diets Lucia Aronica ,1,2 Jeff Volek,3 Angela Poff,4 Dominic P D'agostino4 To cite: Aronica L, Volek J, ABSTRACT into the basic science of ketones and their Poff A, et al. Genetic variants The ketogenic diet (KD) is a low- carbohydrate, high- applications across broad disciplines. Ketones for personalised management fat, adequate- protein diet proven to be effective for demonstrate pleiotropic actions affecting of very low carbohydrate the reversal of obesity, metabolic syndrome and type ketogenic diets. BMJ gene expression and pathways regulating 2 diabetes, and holding therapeutic potential for the Nutrition, Prevention & Health inflammation, oxidative stress, immune func- prevention and treatment of other chronic diseases. 2020;3:e000167. doi:10.1136/ tion, membrane health, cell signalling and bmjnph-2020-000167 Genetic and dynamic markers of KD response may help to 7 identify individuals most likely to benefit from KD and point antioxidant status that manifest in reversal of ► Additional material is to individuals at higher risk for adverse health outcomes. metabolic disease and extended healthspan. published online only. To view, Here, we provide a clinician-friendly review of state-of- the- The most remarkable therapeutic evidence please visit the journal online art research on biomarkers of KD response for a variety of KDs is the rapid and sustained reversal of (http:// dx. doi. org/ 10. 1136/ of outcomes including weight loss, body composition and bmjnph- 2020- 000167). obesity, metabolic syndrome (MetS) and type cognitive performance drawing data from both intervention 2 diabetes in a plethora of recent published 1Nutrition Science, Metagenics trials and case reports of rare inborn errors of metabolism. research. Preclinical and other evidence Inc, Gig Harbor, Washington, USA We also present a selection of the most promising point to KDs as a promising therapeutic inter- 2Medicine, Stanford University, candidate genes to evaluate in future studies and discuss vention in other chronic diseases including Stanford, California, USA key aspects of study design and variant interpretation 3Human Sciences, The Ohio that may help accelerate the implementation of these Alzheimer’s disease (AD) and certain type of 8 State University, Columbus, biomarkers in clinical practice. cancers. KD induces a metabolic switch from Ohio, USA using glucose to using fat as primary fuel 4 Medicine Molecular for the body. There are different variations Pharmacology & Physiology, of KD with the most commonly used proto- University of South Florida, INTRODUCTION http://nutrition.bmj.com/ cols recommending 30–50 g or less of dietary Tampa, Florida, USA As the field of precision medicine is gaining traction, nutrition research is experiencing a carbohydrate or 25–30 g of ‘net carbs’ (calcu- Correspondence to lated by total carbohydrate minus fibre) per Dr Lucia Aronica, Medicine, ‘gold rush’ for biomarkers that may enable 9 10 Stanford University, Stanford, CA the selection of personalised dietary interven- day. Beta- hydroxybutyrate (BHB) and 94305, USA; tions to maximise an individual’s likelihood acetoacetate are the two main ketone bodies lucia. aronica@ metagenics. com of successful response. These biomarkers in blood that are produced from partial include both genetic factors and dynamic oxidation of fatty acids. Both ketone bodies Received 7 September 2020 biomarkers that respond to lifestyle factors and fatty acids are important sources of on September 28, 2021 by guest. Protected copyright. Revised 4 November 2020 such as physiological markers,1 epigenetics energy for the brain, heart, muscle, kidney Accepted 15 November 2020 and transcriptomics,2 metabolomics3 and and other tissues when glucose availability Published Online First 4 is limited such as during periods of carbohy- 12 December 2020 the microbiome. The use of biomarkers of dietary response would be of particular clin- drate restriction and fasting or when energy ical relevance for the selection and individ- demands are increased, such as during illness ualised risk–benefit analysis of therapeutic or vigorous exercise. diets, such as the ketogenic diet (KD), which A personalised lifestyle approach to KD provide alternative or complementary thera- would enable to maximise both therapeutic pies to standard- of- care treatments. effectiveness and long- term safety for patients. KD is a low- carbohydrate, high- fat, adequate- Although KD has proven to be effective and protein diet that was historically used to treat safe for most people in trials up to 2 years,11 epilepsy and diabetes a century ago prior the degree of therapeutic response in terms © Author(s) (or their to the discovery of insulin and antiseizure of weight loss, metabolic changes and neuro- employer(s)) 2020. Re- use medications.5 6 The latest scientific evidence logical effects varies across individuals.8 12 In permitted under CC BY- NC. No showing that ketones are both preferred fuels addition to physiological factors such as sex commercial re- use. See rights and permissions. Published by and potent signalling molecules has dramat- and age, this variability likely reflects the BMJ. ically increased the number of investigations interaction of genetic and lifestyle-related Aronica L, et al. bmjnph 2020;3:e000167. doi:10.1136/bmjnph-2020-000167 363 BMJ Nutrition, Prevention & Health BMJNPH: first published as 10.1136/bmjnph-2020-000167 on 12 December 2020. Downloaded from factors including diet, insulin resistance (IR) and activity SNPs based on recent guidelines for the interpretation of level. As KD and personalised nutrition are becoming nutrigenetic variants.15 more and more popular, genetic variants for the predic- tion of KD response are increasingly discussed in media SNPs associated with weight loss and body composition articles, blog posts and direct to consumer genetic outcomes reports. However, most of these variants have not been A study in 86 adults (53 overweight men and 33 evaluated in intervention trials of KD, which can mislead normoweight/overweight women) found that SNPs and confuse consumers and their health practitioners. in genes encoding for the metabolic enzymes gastric The main aim of this review is to provide clinicians lipase (LIPF, rs814628-G), hepatic glycogen synthase and patients with a snapshot of clinically tested common (GYS2, rs2306179- C), cholesteryl ester transfer protein single-nucleotide polymorphisms (SNPs) for the predic- (rs5883- T) and galanin (rs694066-G) were significantly tion of KD response, ranked by their strength of scientific associated with a greater weight loss in response to KD evidence. These SNPs have been identified in interven- (8%–13% CHO, 60%–63% fat and 28%–30% protein) tion trials testing the effects of KD on various outcomes over a period of 4–12 weeks.16 including weight loss, body composition and cognitive Another study compared the effects of KD (n=93, CHO performance. In addition, we also provide a list of rare ~12%) vs a low fat diet (LF, n=70, fat ~25%) on weight mutations with strong effects on KD response, either as a loss and body composition, and the association of these therapeutic indication or contraindication, and present effects with genetic variants. The minor G allele of the a selection of the most promising candidate genes and rs5950584 SNP in the promoter region of the angiotensin approaches to evaluate in future studies. Finally, we II receptor type 2 (AGTR2) gene was associated with a discuss the importance of establishing common standards greater reduction in body fat percentage in response to of study design and variant interpretation and delineate KD (CHO ~12%).17 The AGTR2 gene has been impli- the steps we need to take towards the implementation of cated in the accumulation of fat and development of practice- based guidelines. muscle cell IR induced by high fat, hypercaloric feeding in mice.18 The AGTR2 gene is X- linked, thus men can have only one of either the T (major) or the G (minor) allele, while women may have zero, one or two copies COMMON SNPS ASSOCIATED WITH METABOLIC OR of either allele. This means that the effect of this gene NEUROLOGICAL OUTCOMES IN INTERVENTION STUDIES OF KD variant on fat loss with KD may be more prevalent and/ OR KETOGENIC AGENTS or stronger in men than in women. The major G allele in Genetic variation may influence KD response by affecting the rs322695 SNP of the RARB gene was associated with the body’s ability to process and use carbohydrates or greater reductions in body fat percentage within both the fats. While rare mutations (frequency <1%) can produce KD and LF groups. The RARB gene encodes the retinoic http://nutrition.bmj.com/ strong effects on phenotype, common (SNPs, minor allele acid receptor beta, a thyroid–steroid hormone receptor frequency ≥1%) result in more subtle effects that depend which regulates energy production in the liver through on the interaction with other genetic variants and environ- modulation of gene expression. This observation is note- mental factors. Genome- wide association studies (GWAS) worthy in light of the putative role of the retinoic acid have identified many SNPs associated with interindi- system in IR.19 Other genetic variants were associated vidual differences in the response to high fat food intake. with a greater reduction in body fat percentage within However, most of these GWAS were observational studies the LF group only. These include the major G allele of based on populations that consumed diets high in both the rs12691940 SNP in the HNMT gene, which has been on September 28, 2021 by guest. Protected copyright. fats and carbohydrates, often referred as to obesogenic implicated in appetite regulation in mice,20 and the major high-fat diets (oHFD).13 oHFD- associated SNPs, such as G allele of the rs2838549 SNP in the PFKL gene, which those in the PPARA gene,14 are commonly but mislead- produces a key regulatory enzyme for glycolysis known as ingly listed as a contraindication to KD in many genetic hepatic phosphofructokinase.