Genetics
APOE genotype e4/e4 carriers have 65% higher Lp(a) than e2/e2 carriers, an analysis of 431 239 patients (Arterioscler Thromb Vasc Biol 2017)
Original title: Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431 239 Patients
This analysis measured APOE genotype, Lp(a) mass, Lp(a)-cholesterol and related apoB lipoproteins in 431 239 patients to test whether APOE genotype, which affects LDL receptor binding affinity, influences Lp(a) levels. APOE allele prevalence was 7.35% for epsilon2, 77.56% for epsilon3, and 15.09% for epsilon4. Mean Lp(a) levels were 65% higher in epsilon4/epsilon4 than epsilon2/epsilon2 carriers, rising stepwise across genotypes from 23.4 mg/dL (epsilon2/epsilon2) to 38.5 mg/dL (epsilon4/epsilon4) (P<0.0001), with LDL cholesterol, apoB, and related lipoprotein measures showing similar patterns. Patients with LDL cholesterol at or above 250 mg/dL had higher Lp(a) across all APOE genotypes, especially those carrying epsilon2 alleles, compared with those below 250 mg/dL, while the lowest Lp(a) levels occurred in patients with epsilon2 isoforms and the lowest LDL cholesterol. The findings show APOE genotype strongly influences Lp(a) levels, suggesting competition between Lp(a) and apoE for shared clearance receptors.
Original abstract
Objective: Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. APOE genotypes have different affinities for the low-density lipoprotein (LDL) receptor and LDL-related protein-1, with ε2 having the weakest binding to LDL receptor at <2% relative to ε3 and ε4. APPROACH AND RESULTS: APOE genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4), Lp(a) mass, directly measured Lp(a)-cholesterol levels, and a variety of apoB-related lipoproteins were measured in 431 239 patients. The prevalence of APOE traits were ε2: 7.35%, ε3: 77.56%, and ε4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in ε4/ε4 compared with ε2/ε2 genotypes and increased significantly according to APOE genotype: ε2/ε2: 23.4 (29.2), ε2/ε3: 31.3 (38.0), ε2/ε4: 32.8 (38.5), ε3/ε3: 33.2 (39.1), ε3/ε4: 35.5 (41.6), and ε4/ε4: 38.5 (44.1) mg/dL (P<0.0001). LDL-cholesterol, apoB, Lp(a)-cholesterol, LDL-cholesterol corrected for Lp(a)-cholesterol content, LDL-particle number, and small, dense LDL also had similar patterns. Patients with LDL-cholesterol ≥250 mg/dL, who are more likely to have LDL receptor mutations and reduced affinity for apoB, had higher Lp(a) levels across all apoE isoforms, but particularly in patients with ε2 alleles, compared with LDL <250 mg/dL. The lowest Lp(a) mass levels were present in patients with ε2 isoforms and lowest LDL-cholesterol.
Conclusions: APOE genotypes strongly influence Lp(a) and apoB-related lipoprotein levels. This suggests that differences in affinity of apoE proteins for lipoprotein clearance receptors may affect Lp(a) catabolism, suggesting a competition between Lp(a) and apoE protein for similar receptors.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.