rs116843064 — ANGPTL4 ANGPTL4 E40K

ANGPTL4 E40K — The Triglyceride-Lowering Variant

Angiopoietin-like protein 4 (ANGPTL4¹¹ ANGPTL4
a secreted protein that normally shuts off lipoprotein lipase, the enzyme responsible for clearing triglycerides from the bloodstream) acts as a brake on fat clearance. The E40K variant at rs116843064 partially disables this brake. Carriers of the K40 allele (the minor A allele) have less ANGPTL4-mediated LPL inhibition, leading to faster triglyceride clearance after meals and persistently lower fasting triglyceride levels throughout life. This is one of a small number of naturally occurring human variants in the ANGPTL family with a clearly protective cardiovascular phenotype.

The Mechanism

ANGPTL4 is secreted from the liver and adipose tissue and inhibits lipoprotein lipase (LPL)²² lipoprotein lipase (LPL)
the enzyme anchored to capillary walls that hydrolyzes triglycerides in VLDL and chylomicrons, releasing fatty acids for tissue uptake by promoting its dissociation from the capillary wall. The E40K substitution (p.Glu40Lys) alters the N-terminal coiled-coil domain of ANGPTL4, reducing its inhibitory potency against LPL. With less ANGPTL4-mediated inhibition, LPL remains more active — it clears more triglyceride-rich lipoproteins from circulation, leaving lower fasting and postprandial TG levels. This variant is classified as a partial loss-of-function: it reduces, but does not abolish, ANGPTL4 activity, distinguishing it from complete LOF mutations.

The Evidence

The most definitive evidence comes from two large-scale genetic studies. The 2016 NEJM paper from the MI Genetics and CARDIoGRAM Exome Consortia³³ 2016 NEJM paper from the MI Genetics and CARDIoGRAM Exome Consortia
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. NEJM, 2016 analyzed 72,868 CAD cases and 120,770 controls and found the E40K variant specifically associated with a 14% reduced odds of coronary artery disease (OR 0.86, P=4.0×10⁻⁸). Complete LOF mutations in ANGPTL4 in the same study produced even larger effects (OR 0.47 for MI, and 35% lower triglyceride levels in carriers).

A 2024 phenome-wide analysis by Gagnon et al.⁴⁴ Gagnon et al.
Gagnon E et al. Impact of loss-of-function in angiopoietin-like 4 on the human phenome. Atherosclerosis, 2024 used FinnGen (309,154 participants) and UK Biobank whole-exome data (488,278 participants) to confirm the E40K signal: OR 0.84 for CAD (P=3.6×10⁻²¹) and OR 0.91 for type 2 diabetes (P=2.8×10⁻⁵). Critically, a phenome-wide scan of 1,589 diseases found no significant risk increases attributable to E40K — the variant does not appear to trade cardiovascular benefit for harm elsewhere.

Triglyceride reductions are well-quantified across multiple cohorts. Talmud et al.⁵⁵ Talmud et al.
Talmud PJ et al. ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk. Arterioscler Thromb Vasc Biol, 2008 pooled 5 cohorts (n=13,527) and found K40 carriers had 20.4% lower fasting triglycerides (P<0.0001). In the Look AHEAD trial of 2,601 adults with type 2 diabetes, Smart-Halajko et al.⁶⁶ Smart-Halajko et al.
Smart-Halajko MC et al. ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial. BMC Med Genet, 2011 found K40 carriers had 0.33 mmol/L (~17%) lower TG than E40 homozygotes (P=0.001). Higher HDL-cholesterol in K40 carriers has also been reported, consistent with the reciprocal relationship between TG clearance and HDL-C levels.

The evidence is rated strong: consistent replication across large independent cohorts, a clear molecular mechanism via LPL de-inhibition, genome-wide significant association with hard cardiovascular outcomes, and phenome-wide safety data. It falls short of established because ANGPTL4 genotyping is not yet incorporated into clinical lipid management guidelines.

Practical Actions

For the rare individual carrying one or two A alleles, the E40K variant provides a durable biological advantage in TG metabolism. Dietary fat composition still matters: while overall TG clearance is enhanced, the variant does not override the acute postprandial TG spike from very high saturated fat loads. Omega-3 fatty acid supplementation (EPA/DHA) works through a partially overlapping pathway — both E40K and high-dose omega-3s reduce VLDL-TG — so carriers may derive additive benefit from omega-3 intake if baseline TG is in the borderline range.

Because triglyceride levels influence remnant lipoprotein particle burden and are an independent cardiovascular risk factor, the 17–20% TG reduction from E40K is clinically meaningful and worth monitoring through standard lipid panels to confirm phenotypic expression.

Interactions

ANGPTL4 E40K operates in the same triglyceride-clearance pathway as APOA5 (rs3135506), which also modulates LPL activity. A carrier of both E40K and the APOA5 S19W variant (which raises TG) might see partially opposing effects — the combined phenotype would depend on effect magnitudes at each locus. Similarly, the APOC3 promoter variants (rs2854116) that elevate ApoC-III and inhibit LPL are in the same downstream pathway: carrying ANGPTL4 E40K alongside an APOC3 TG-raising variant would likely attenuate but not fully overcome the APOC3 effect. No formal published compound analysis exists for these specific genotype combinations, so these remain pathway-level interactions rather than quantified compound effects.

The companion ANGPTL4 variant T266M (rs1044250) has an independent but weaker TG-lowering effect (~10% reduction) and operates through a different structural domain of the protein. Carriers of both E40K and T266M may have additive TG lowering, though compound heterozygosity at these two positions is rare.