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

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.