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If you carry the ANGPTL4 E40K variant (a specific change in the angiopoietin-like protein 4 gene), your body is unusually efficient at clearing fats from your blood. That translates into naturally lower triglycerides, higher HDL cholesterol, and a meaningfully reduced risk of coronary artery disease and type 2 diabetes. This is one of the clearest examples in human genetics of a single variant that confers lifelong cardiovascular protection.
The variant is rare. Only about 2 to 3 out of every 100 people of European ancestry carry it, and it is less common in other populations. But knowing your status matters: it tells you something fundamental about how your metabolism handles dietary fat and whether your baseline cardiovascular risk is lower than standard charts would predict.
Bayesian fine-mapping, a statistical method that identifies which genetic change is actually responsible for an observed effect, confirms with 99.99% probability that E40K is the causal variant driving these benefits. This is not a marker that happens to sit near the real cause. It is the cause.
Your body uses an enzyme called lipoprotein lipase (LPL) to break down triglycerides circulating in your blood. Think of LPL as the cleanup crew that pulls fat out of your bloodstream and delivers it to muscles and fat tissue for use or storage. ANGPTL4 (angiopoietin-like protein 4) normally acts as a brake on that cleanup crew, slowing it down.
The E40K variant (a substitution of glutamic acid for lysine at position 40 in the protein) destabilizes the ANGPTL4 protein after your cells release it. The brake still gets made, but it falls apart before it can do much braking. The result: your LPL runs more freely, clearing triglyceride-rich particles from your blood faster and more completely.
Mendelian randomization studies, which use genetic variation to test cause-and-effect relationships, confirm that the cardiovascular benefits of E40K track closely with enhanced LPL activity (correlation of 0.82) rather than with changes in another fat-processing enzyme called hepatic lipase (correlation of -0.10). The protection comes specifically from better triglyceride clearance, not from some unrelated metabolic shift.
This variant follows a dosage pattern: the more copies you carry, the stronger the effect. Because the variant is rare, the vast majority of people carry zero copies. A small percentage carry one, and homozygotes (two copies) are extremely uncommon. In a study of 42,930 participants, only 17 people were homozygous.
| Genotype | What It Means for Triglycerides | What It Means for HDL Cholesterol | Heart Disease Risk | Type 2 Diabetes Risk |
|---|---|---|---|---|
| G/G (no copies) | Baseline levels | Baseline levels | Population average | Population average |
| G/A (one copy, carrier) | About 13% lower than non-carriers | About 7% higher than non-carriers | About 19% lower risk | About 9% lower risk |
| A/A (two copies) | Substantially lower than carriers | Substantially higher than carriers | Greatest reduction | Greatest reduction |
Sources: DiscovEHR study (Dewey et al.); Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia; Gagnon et al.
What this means for you: if you carry one copy, your triglycerides are naturally about 13% lower and your HDL cholesterol about 7% higher than someone without the variant. Your risk of coronary artery disease drops by roughly one-fifth (OR 0.81, 95% CI: 0.70 to 0.92), and your type 2 diabetes risk falls by about 9% (OR 0.91, 95% CI: 0.87 to 0.95). LDL cholesterol is not significantly affected.
If you are a non-carrier (G/G), this result does not indicate elevated risk. It simply means you have the standard version of the ANGPTL4 gene and the usual level of LPL inhibition. Your triglyceride metabolism is governed by the same factors as the general population: diet, exercise, other genetic variants, and metabolic health.
One legitimate concern about reduced ANGPTL4 function is that in mice, complete loss of this protein on a high-fat diet causes severe abdominal lymph node inflammation with abnormal fat accumulation. This finding raised early safety questions about whether blocking ANGPTL4 in humans could cause similar problems.
Human data are reassuring. A comprehensive scan of 1,589 diseases in 309,154 people from the FinnGen study found that E40K carriers, including homozygotes, did not have a significantly increased risk of any disease after statistical correction for multiple comparisons. Electronic health record reviews also found no increased rates of abdominal lymph node problems or other abdominal disorders in carriers.
Because this is a genetic variant, your genotype itself does not change over your lifetime. You either carry the E40K variant or you do not. However, the downstream effects of the variant, particularly your triglyceride and HDL cholesterol levels, are influenced by the same factors that affect these biomarkers in everyone.
The E40K variant provides human genetic validation for targeting ANGPTL4 to treat cardiometabolic disease. However, whole-body ANGPTL4 inhibition is not currently viable as a therapy because of the complications seen in animal models. Research is now focused on liver-specific ANGPTL4 inactivation, either alone or combined with therapies targeting a related protein called ANGPTL3, as a potentially safer strategy for lowering triglycerides.
If you are a non-carrier interested in the same metabolic benefits that E40K carriers enjoy naturally, the actionable path is familiar: reducing triglycerides through dietary changes, physical activity, weight management, and, when appropriate, pharmacological therapies like fibrates or omega-3 fatty acids. These interventions enhance the same LPL-mediated triglyceride clearance pathway that E40K activates genetically.