Table 1

SNPs for the selection of KD or exogenous ketone sources as therapeutic option with preliminary evidence from intervention studies

Clinical snapshot
Are these SNPs ready for clinical implementation? These SNPs should be considered as candidate gene variants to evaluate and validate in clinical research rather than established predictors of KD response. The strength of scientific evidence for these SNPs is ‘probable’ or ‘possible’ using a scoring system based on recent guidelines for the interpretation of nutrigenetic variants.15 A strength of evidence score is provided for each SNP in the table. How can clinicians use these SNPs? Rather than as a predictive test, clinicians may use these SNPs to set possible/probable expectations with patients for target outcomes such as weight loss, seizure reduction, or cognitive performance and develop an individualised protocol to achieve those goals (eg, macronutrient composition, total energy intake, use of exogenous ketone sources, duration of the intervention, etc). These SNPs may also be used as an explorative tool in clinic-based research for the design of personalised weight loss strategies using KD. Please refer to the ‘KD response in intervention studies’ column for further details. How can clinicians help accelerate the clinical implementation of these SNPs? Clinicians can contribute to the building of a nutrigenomics knowledge base and accelerate the clinical implementation of these SNPs by testing them in clinic-based research, keeping records of their research data, and promoting the establishment of curated databases of nutrigenetic SNPs where they can submit their research data.
SNPs associated with weight loss/body composition outcomes in intervention studies of response to KD
Effect allele	Allele frequency	Enzyme function	Outcome	Response to KD
LIPF rs814628-G		Gastric lipase is secreted by the mucosa of the stomach and hydrolyzes dietary triglycerides in the gastrointestinal tract. It is responsible for 30% of fat digestion in humans. The minor G allele of this SNP determines an amino acid change in the protein sequence (Ala161 >Thr), with possible decrease in enzymatic function.	Weight loss	Individuals with the minor G allele lost more weight than those homozygous for the major A allele in response to KD (8%–13% CHO, 60%–63% fat and 28%–30% protein) over a period of 4–12 weeks in a study in 86 adults. This suggests that decreased gastric fat breakdown on KD may enhance weight loss.16 Strength of evidence: Possible.
GYS2 rs2306179-C		Hepatic glycogen synthase two catalyses the formation of glycogen from glucose in the liver. The minor C allele of this SNP is an intronic variant with unknown consequences on protein function.	Weight loss	Carriers of the minor C allele lost more weight than those homozygous for the major T allele in response to KD (8%–13% CHO, 60%–63% fat and 28%–30% protein) over a period of 4–12 weeks in a study in 86 adults. This suggest that the hepatic glycogen response to carbohydrate restriction may influence the weight loss response to KD.16 Strength of evidence: Possible.
CETP rs5883-T		CETP regulates the reverse cholesterol transport, a process by which excess cholesterol is removed from peripheral tissues and returned to the liver. CETP may mediate the triglyceride lowering and remodelling effects of LDL and HDL observed with low carbohydrate diets (PMID: 15 930 434).	Weight loss	Carriers of the minor T allele lost more weight than those homozygous for the major C allele in response to KD (8%–13% CHO, 60%–63% fat, and 28%–30% protein) over a period of 4–12 weeks in a study in 86 adults. This suggest that the weight loss response to KD may depend on the metabolism of circulating lipoproteins.16 Strength of evidence: Possible.
GAL rs694066-G		Galanin is an appetite hormone that stimulates food consumption, particularly fat intake. The minor A-allele of this SNP is an intronic variant with unknown consequences on protein function.	Weight loss	GG genotype increased weight loss compared with those who carried the minor A allele in response to KD (8%–13% CHO, 60%–63% fat, and 28%–30% protein) over a period of 4–12 weeks in a study in 86 adults. This suggest that a role of fat-mediated appetite hormones in determining the response to carbohydrate restriction.16 Strength of evidence: Possible .
AGTR2 rs5950584-G		The angiotensin 2 receptor is located primarily in the brain, adrenal medulla, heart and uterus where it counterbalance the effects of angiotensin II, a potent vasopressor hormone and a primary regulator of aldosterone secretion. In mice, AGTR2 has been implicated in the accumulation of fat and development of insulin resistance induced by high fat, hypercaloric feeding.	Weight loss response and reduction of body fat	The minor G allele was significantly associated with a greater reduction in body fat percentage in response to KD with ~12% of total energy from carbohydrates in a study with 93 adults.17 Given that the AGTR2 gene is X-linked, its effects on fat loss with KD may be more prevalent and/or stronger in men than in women. Strength of evidence: Possible.
SNPs associated with neurological outcomes in intervention studies of response to KD/exogenous ketone sources
Effect allele	Allele frequency	Enzyme function	Outcome	Response to KD/exogenous ketone sources
CDY1L rs12204701-A		CDY1L is a chromodomain protein and histone acetyltransferase acting as gene repressor and critical for the maintenance of cell identity. It has been implicated in seizure‐related neurodevelopmental disorders.	Seizure reduction	The A allele of rs12204701 may alter the levels or function of CDYL1 with effects on gene expression regulation in the brain. Drug resistant epileptic patients with AA and AG genotype may experience lower (<50%) seizure reduction in response to KD with lower blood BHB (−10%), free carnitine (−23%), and lower acetylcarnitine (12%). Strength of evidence: Probable.
APOE rs429358-C		ApoE is the principal cholesterol carrier in the brain and helps clear both cholesterol and triglycerides from the bloodstream. There are at least three alleles of the APOE gene, called e2, e3, and e4, which produce three protein isoforms that differ in only two amino acid sites ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158) and ApoE4 (Arg112/Arg158). These structural differences result in different effects on lipid and glucose metabolism and chronic disease risk. The e4 allele, which is found in 30% of the general population, is associated with a 4-fold to 15-fold increase in Alzheimer’s disease (AD) risk in the context of a Westernised lifestyle.	Cognitive performance	Ketones may function as an alternative fuel for neurons,21 bypass the defects in cerebral glucose metabolism, and improve cognitive symptoms in AD patients. KD and MMKD may improve cognitive performance, AD biomarkers, and MetS in both e4 carriers and e3 homozygous.28 29 With regard to exogenous ketone sources, e4 carriers experience smaller improvements in cognitive performance on MCT supplementation compared with e4 non-carriers, despite showing prolonged elevations of BHB levels (24% higher levels 2 hours after MCT administration). This suggests that e4 carrier may have a lower ability to utilise exogenous ketone sources, and thus derive cognitive benefits, compared with e4 non-carriers. Strength of evidence: Probable.31 32

SNP identification numbers (noted as “rs…") are the unique SNP identifiers from the NCBI dbSNP database.
AGTR2, angiotensin II receptor type 2; APOE, apolipoprotein E; BHB, beta-hydroxybutyrate; CDYL1, chromodomain Y‐like protein 1; CETP, cholesteryl ester transfer protein; GAL, galanin; GYS2, glycogen synthase 2; HDL, low-density lipoprotein; KD, ketogenic diet; LDL, low-density lipoprotein; LIPF, lipase F; MetS, metabolic syndrome; MMKD, modified Mediterranean-ketogenic diet; NCBI, National Center for Biotechnology Information; SNP, single-nucleotide polymorphism.