Dietary fat plays a central role in human metabolism, and individuals vary widely in how effectively they absorb, transport and utilise different types of fat. The ketogenic diet (“keto”), which is extremely high in fat and very low in carbohydrates, relies on shifting the body into ketosis—a metabolic state in which fat becomes the primary fuel source. While some people thrive on this diet, others experience elevated cholesterol, digestive issues or changes in blood sugar control. These highly individual responses are influenced not only by lifestyle, but also by genetics.

Modern nutrigenomic testing analyses specific genes involved in fat metabolism, insulin regulation, inflammation and lipid transport. These tests do not diagnose disease; instead, they identify genetic variants—also known as single nucleotide polymorphisms (SNPs)—which are natural differences in the DNA sequence. A variant can slightly increase or decrease the efficiency of an enzyme or transporter. Some variants are considered “neutral,” while others predispose individuals to higher triglycerides, increased LDL cholesterol, altered omega-3 needs, or poorer metabolic responses to very high-fat diets such as keto.

Understanding these variants allows us to predict who is more likely to respond positively to a high-fat diet and who may be genetically predisposed to adverse effects. For example, some genes increase fat absorption in the gut, others alter cholesterol clearance in the liver, and others determine how effectively the body converts plant-based fatty acids into long-chain omega-3s.

Seven key genes—FABP2, PPARG, APOE, APOA5, CETP, FADS1 and CD36 can influences lipid metabolism and modify physiological responses.

FABP2 – Intestinal Fatty Acid Binding Protein 2

Role:

FABP2 encodes an intestinal fatty-acid–binding protein that transports long-chain fatty acids inside enterocytes. It acts as a “lipid chaperone”, directing fats towards oxidation or chylomicron assembly.

Key SNP:

Ala54Thr (rs1799883) – G→A substitution causing an alanine→threonine change at codon 54. The Thr54 protein has higher affinity for long-chain fatty acids.

Metabolic impact:

Thr54 carriers show:

• Increased intestinal fat absorption and post-prandial triglycerides

• Higher fasting free fatty acids and insulin; lower insulin sensitivity

• Greater risk of dyslipidaemia, metabolic syndrome and type 2 diabetes, particularly in Asian populations and with high-fat diets

Nutrition strategy:

• Avoid very high-fat / high–saturated-fat diets (including strict keto).

• Favour Mediterranean-style, moderate-fat patterns with more MUFA (olive oil, nuts) and omega-3s.

• Increase fibre to slow fat absorption; prioritise regular exercise for insulin sensitivity.

PPARG – Peroxisome Proliferator-Activated Receptor-γ

Role:

PPAR-γ is a nuclear receptor that controls adipocyte differentiation, lipid storage and insulin sensitivity. It is also the pharmacological target of thiazolidinedione (TZD) anti-diabetic drugs.

Key SNP:

Pro12Ala (rs1801282) – Proline→alanine at codon 12 of the PPARG2 isoform.

Metabolic impact:

• Ala12 reduces receptor activity but is paradoxically protective, associated with ~20% lower type 2 diabetes risk and better insulin sensitivity.

• Pro/Pro genotype is linked to higher BMI, visceral adiposity, insulin resistance and metabolic syndrome, especially with high-fat diets.

Nutrition strategy:

• For Pro/Pro: minimise saturated fats, overall calorie excess and central obesity.

• Emphasise Mediterranean-style diet rich in olive oil, nuts and omega-3s; regular exercise.

• Ala carriers tend to respond particularly well to MUFA-rich patterns.

APOE – Apolipoprotein E

Role:

ApoE mediates clearance of triglyceride-rich lipoproteins and is central to cholesterol transport and neuronal lipid delivery.

Key isoforms (via rs429358 & rs7412):

• ε3 – neutral, most common

• ε4 – higher LDL-C, pro-inflammatory; major genetic risk factor for late-onset Alzheimer’s disease and increased cardiovascular risk

• ε2 – lower LDL-C overall but can predispose to type III hyperlipoproteinaemia in ε2/ε2 homozygotes

Metabolic impact:

• ε4 carriers: higher LDL-C, stronger LDL response to saturated fat and dietary cholesterol, greater atherosclerosis and Alzheimer’s risk.

• ε2 carriers: generally lower LDL but higher remnant/triglyceride risk in some contexts.

Nutrition strategy:

• ε4: aggressively limit saturated fat and cholesterol, avoid high-fat keto diets; adopt a high-fibre Mediterranean pattern with abundant vegetables, legumes and fish; prioritise DHA/EPA and antioxidants; regular exercise and vascular risk control.

• ε2: monitor triglycerides and remnant cholesterol; avoid very high-fat/high-sugar diets.

APOA5 – Apolipoprotein A-V

Role:

ApoA-V is a potent regulator of plasma triglycerides; it enhances lipoprotein lipase (LPL)–mediated clearance of triglyceride-rich lipoproteins.

Key SNP:

−1131T>C (rs662799) in the promoter.

Metabolic impact:

The C allele is associated with:

• Higher fasting and post-prandial triglycerides

• Lower HDL-C

• Higher risk of metabolic syndrome, NAFLD, pancreatitis (at very high TG) and cardiovascular disease, especially in obesity.

Nutrition strategy:

• Focus on triglyceride management: weight reduction, limiting added sugars, refined carbs and alcohol (particularly binge drinking).

• Prefer MUFA and omega-3–rich fats (olive oil, nuts, oily fish).

• Consider omega-3 (EPA/DHA) supplementation for persistent hypertriglyceridaemia.

• Maintain high fibre intake and regular physical activity.

CETP – Cholesteryl Ester Transfer Protein

Role:

CETP transfers cholesteryl esters from HDL to apoB-containing lipoproteins (VLDL/LDL) in exchange for triglycerides, influencing HDL-C and LDL composition.

Key SNPs:

• Taq1B (rs708272)

• I405V (rs5882) and −629C>A (rs1800775) – often in linkage disequilibrium.

Metabolic impact:

• “Low-CETP” alleles (e.g. Taq1B B2, −629A, 405V) → higher HDL-C, sometimes modestly lower LDL-C and reduced CHD risk.

• “High-CETP” genotypes → lower HDL-C, more atherogenic lipid profiles and higher coronary risk.

Nutrition strategy:

For low HDL / high CETP genotypes:

• Prioritise exercise, weight management and a Mediterranean pattern rich in MUFA/PUFA and very low in trans fats.

• Replace saturated fats with olive oil, nuts and fish.

• Discuss pharmacotherapy (e.g. statins ± niacin) with a physician if risk is high.

FADS1 – Fatty Acid Desaturase 1

Role:

FADS1 encodes Δ5-desaturase, catalysing key steps in conversion of essential fatty acids to long-chain omega-6 (AA) and omega-3 (EPA) PUFAs.

Key SNPs:

Commonly rs174546 / rs174547 in the FADS1 gene cluster.

Metabolic impact:

• Low-activity (minor) alleles → reduced conversion of LA/ALA to AA/EPA/DHA; lower levels of long-chain PUFAs, potentially lower AA-driven inflammation but higher risk of EPA/DHA insufficiency if fish intake is low.

• High-activity (major) alleles → higher AA (more pro-inflammatory signalling), sometimes higher LDL-C and blood pressure, particularly with high omega-6 intake.

Nutrition strategy:

• Low-activity genotypes: ensure direct EPA/DHA intake (2–3 servings oily fish/week or supplements); don’t rely solely on plant ALA.

• High-activity genotypes: moderate omega-6 vegetable oils; increase omega-3 intake to rebalance AA:EPA ratio.

• For everyone: aim for a lower omega-6:omega-3 ratio via Mediterranean / whole-food patterns.

CD36 – Fatty Acid Translocase / Taste Receptor

Role:

CD36 is a membrane transporter for long-chain fatty acids in intestine, muscle, adipose tissue and also acts as a fat-taste receptor on the tongue and a scavenger receptor for oxidised LDL on macrophages.

Key SNP:

rs1761667 (−31118G>A) in the promoter.

Metabolic impact:

• A allele → reduced CD36 expression; lower oral fat sensitivity, altered fat preference, and in several cohorts higher habitual fat intake, BMI and central adiposity; possible effects on triglycerides and insulin resistance.

• CD36 also contributes to foam cell formation in atherosclerotic plaques via uptake of oxidised LDL.

Nutrition strategy:

• For low-taste / A carriers: be mindful with portion sizes of high-fat foods; enhance flavour with herbs/spices rather than extra fat.

• Emphasise protein, fibre and high-quality fats (olive oil, nuts, fish) to support satiety and cardiometabolic health.

• Regular endurance exercise improves muscle fatty-acid uptake and oxidation and helps counter insulin resistance.

• A generally antioxidant-rich Mediterranean pattern helps reduce oxidised LDL burden.

  
  

  
  

  If you’d like to understand your own genetic profile, optimise your health goals, or identify the most suitable dietary approach for your body, you can book a consultation with me to review your test results and create a tailored nutrition plan.

  
  

Reference list:

• Altshuler, D. et al. (2000) ‘The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes’, Nature Genetics, 26(1), pp. 76–80.

• Bajit, H. et al. (2020) ‘Single-nucleotide polymorphism rs1761667 in the CD36 gene is associated with orosensory perception of a fatty acid in obese and normal-weight subjects’, Journal of Nutritional Science, 9, e24.

• Baum, L., Tomlinson, B. and Thomas, G.N. (2003) ‘APOA5 −1131T>C polymorphism is associated with triglyceride levels in Chinese men’, Clinical Genetics, 63(5), pp. 377–379.

• Carlquist, J.F. et al. (2003) ‘The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease’, American Heart Journal, 146(6), pp. 1007–1014. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0002870303005015.

• Chistiakov, D.A. et al. (2010) ‘The PPARγ Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects’, Diabetes & Vascular Disease Research, 7(1), pp. 56–62. Avaailable at: https://pubmed.ncbi.nlm.nih.gov/20368233/

• Garcés Da Silva, M.F. et al. (2018) ‘Postprandial hypertriglyceridemia is associated with the variant 54 Threonine FABP2 gene’, Journal of Cardiovascular Development and Disease, 5(3), p. 47. Available at: https://doi.org/10.3390/jcdd5030047.

• Guo, S.-X. et al. (2016) ‘Associations of CETP Taq1B polymorphism with the composite ischemic cardiovascular disease risk and HDL-C concentrations: A meta-analysis’, International Journal of Environmental Research and Public Health, 13(9), p. 882. Available at: https://doi.org/10.3390/ijerph13090882.

• Juan, J. et al. (2018) ‘Joint effects of FADS1 polymorphisms and dietary polyunsaturated fatty acid intake on circulating fatty acid proportions’, American Journal of Clinical Nutrition, 107(5), pp. 826–833. Available at: https://doi.org/10.1093/ajcn/nqy042.

• Masson, L.F., McNeill, G. and Avenell, A. (2003) ‘Genetic variation and the lipid response to dietary intervention: a systematic review’, American Journal of Clinical Nutrition, 77(5), pp. 1098–1111. Available at: https://doi.org/10.1093/ajcn/77.5.1098.

• Pennacchio, L.A. et al. (2001) ‘An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing’, Science, 294(5540), pp. 169–173. Available at: https://doi.org/10.1126/science.1064852.

• Pepino, M.Y. et al. (2012) ‘The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects’, Journal of Lipid Research, 53(3), pp. 561–566. Available at: https://doi.org/10.1194/jlr.P021022.

• Schaeffer, L. et al. (2006) ‘Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids’, Human Molecular Genetics, 15(11), pp. 1745–1756. Available at: https://doi.org/10.1093/hmg/ddl117.

• Vimaleswaran, K.S. et al. (2006) ‘Thr54 allele carriers of the Ala54Thr variant of FABP2 gene have associations with metabolic syndrome and hypertriglyceridemia in urban South Indians’, Metabolism, 55(9), pp. 1222–1226. Available at: https://pubmed.ncbi.nlm.nih.gov/16919542/.

• Weggemans, R.M., Zock, P.L. and Katan, M.B. (2001) ‘Apolipoprotein E genotype and the response of serum cholesterol to dietary fat, cholesterol and cafestol’, Atherosclerosis, 154(3), pp. 547–555. Available at: https://pubmed.ncbi.nlm.nih.gov/11257255/.