ApoE2 carriers have lower Lp(a), with APOE the second most important gene after LPA in determining Lp(a) levels, a mechanistic review (Curr Atheroscler Rep 2022)

Original title: Genetic and Mechanistic Insights into the Modulation of Circulating Lipoprotein (a) Concentration by Apolipoprotein E Isoforms

Curr Atheroscler Rep · 30 March 2022 · 6

Chemello K, Blom DJ, Marais AD, Lambert G, Blanchard V

This review examines how apolipoprotein E (apoE) isoforms modulate circulating Lp(a). While the LPA gene accounts for up to 90% of the variance in Lp(a) concentration, genome-wide association studies identify APOE as the second most important modulating locus. Carriers of the apoE2 variant, especially epsilon2/epsilon2 homozygotes, consistently show reduced Lp(a) levels; this genotype can also predispose to dysbetalipoproteinaemia, a disorder of sharply elevated cholesterol and triglycerides, though dysbetalipoproteinaemia itself does not significantly affect Lp(a). Mechanistically, apoE appears to impair Lp(a) production rather than its clearance. The findings deepen understanding of the genetic and mechanistic pathways governing Lp(a) synthesis and secretion, beyond the dominant LPA locus.

Original abstract

Purpose Of Review: Lipoprotein (a) [Lp(a)] is a highly atherogenic lipoprotein species. A unique feature of Lp(a) is the strong genetic determination of its concentration. The LPA gene is responsible for up to 90% of the variance in Lp(a), but other genes also have an impact.

Recent Findings: Genome-wide associations studies indicate that the APOE gene, encoding apolipoprotein E (apoE), is the second most important locus modulating Lp(a) concentrations. Population studies clearly show that carriers of the apoE2 variant (ε2) display reduced Lp(a) levels, the lowest concentrations being observed in ε2/ε2 homozygotes. This genotype can lead predisposed adults to develop dysbetalipoproteinemia, a lipid disorder characterized by sharp elevations in cholesterol and triglycerides. However, dysbetalipoproteinemia does not significantly modulate circulating Lp(a). Mechanistically, apoE appears to impair the production but not the catabolism of Lp(a). These observations underline the complexity of Lp(a) metabolism and provide key insights into the pathways governing Lp(a) synthesis and secretion.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.