Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype An Analysis of 431 239 Patients

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 epsilon 2 having the weakest binding to LDL receptor at <2% relative to epsilon 3 and epsilon 4. Approach and Results-APOE genotypes (epsilon 2/epsilon 2, epsilon 2/epsilon 3, epsilon 2/epsilon 4, epsilon 3/epsilon 3, epsilon 3/epsilon 4, and epsilon 4/epsilon 4), 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 e2: 7.35%, epsilon 3: 77.56%, and e4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in epsilon 4/epsilon 4 compared with epsilon 2/epsilon 2 genotypes and increased significantly according to APOE genotype: epsilon 2/epsilon 2: 23.4 (29.2), epsilon 2/epsilon 3: 31.3 (38.0), epsilon 2/epsilon 4: 32.8 (38.5), epsilon 3/epsilon 3: 33.2 (39.1), epsilon 3/epsilon 4: 35.5 (41.6), and epsilon 4/epsilon 4: 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 e2 alleles, compared with LDL < 250 mg/dL. The lowest Lp(a) mass levels were present in patients with epsilon 2 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.