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.

Keywords: alleles; cholesterol; genotype; hepatocytes; prevalence.

Figure 1

Relationship of APOE genotypes (prevalence shown in panel A) to Lp(a) mass (B), Lp(a)-C (C), LDL-C (D), LDL-C corr (E), apoB (F), LDL-particle number (LDL-P) (G), triglycerides (H) and small dense LDL (J).

Figure 2

Relationship of Lp(a) mass to Lp(a)-C and LDL-C.

Figure 3

Conceptual rendition of the potential role of apoE, LDLR, LRP1 in the catabolsim of Lp(a). ApoE on triglyceride-rich lipoproteins (TRLs) compete with Lp(a) for binding to LDLR and LRP1 on hepatocytes. (A) ApoE2 is the lower affinity isoform for LDLR and LRP1, which allow LDL and Lp(a) particles to clear faster. (B-C) Relatively high affinity isoforms, such as apoE4 and apoE3 favor hepatic clearance of TRLs via LDLR and LRP1 over LDL and Lp(a). This results in elevated LDL-C, apoB and Lp(a) levels. (C) ApoE4 partitions preferentially on TRLs and thus generates a bigger mass of lipoproteins to outcompete Lp(a) binding.