rs3135506 — APOA5 S19W

APOA5 — Triglyceride Metabolism

APOA5 (Apolipoprotein A5) plays a key role in regulating triglyceride levels. Discovered in 2001¹¹ Discovered in 2001
Pennacchio et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science, 2001 through comparative sequencing of the APOA1/C3/A4 gene cluster, APOA5 was found to strongly influence plasma triglyceride concentrations in both humans and mice.

The Mechanism

The S19W variant (rs3135506) causes a serine-to-tryptophan substitution at position 19 (p.Ser19Trp) in the signal peptide²² The signal peptide is a short amino-acid sequence that directs a newly made protein for secretion out of the cell of the APOA5 protein. This disrupts the signal peptide function, reducing APOA5 secretion into the bloodstream by approximately 50%. Since APOA5 normally lowers triglycerides by stimulating lipoprotein lipase activity and inhibiting VLDL production, reduced secretion leads to higher triglyceride levels.

The Evidence

The ICARIA study³³ ICARIA study
Loria et al. Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia. BMC Med Genet, 2010 demonstrated that APOA5 S19W carriers have an independent, additive triglyceride-raising effect. Carriers of the rare allele show significantly higher levels of large VLDLs (+133%) and small dense LDLs (+34%), creating a proatherogenic lipid profile.

Guardiola et al.⁴⁴ Guardiola et al.
Guardiola et al. APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis. Atherosclerosis, 2015 confirmed that this variant predisposes carriers to atherogenic dyslipidemia and subclinical atherosclerosis — measurable thickening of artery walls even before symptoms appear.

High triglycerides are an independent risk factor for cardiovascular disease and pancreatitis⁵⁵ Very high triglycerides (above roughly 500 mg/dL) can trigger acute pancreatitis, a serious inflammation of the pancreas.

Practical Implications

The C allele is found in about 6% of Europeans and up to 14% of Hispanics, but is rare (<2%) in East Asian and African populations. Dietary interventions — especially limiting refined carbohydrates and increasing omega-3 intake — are the primary management strategy.

Interactions

Triglyceride-raising effects are additive when combined with variants in LPL and APOE genes. If you also carry APOE E4 (rs429358), your overall cardiovascular risk is compounded.