title: Lipoprotein(a) Mass Levels Increase Significantly According toAPOEGenotype: 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.APOEgenotypes 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:APOEgenotypes (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 ofAPOEtraits 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 toAPOEgenotype: 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
  APOEgenotypes 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.
authors.affiliation: From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); Salveo Diagnostics, Inc, Richmond, VA (S.A.V., J.P.M.); Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center (P.L.S.M.G.), Department of Medicine, Division of Endocrinology and Metabolism (P.L.S.M.G.), and Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center (S.T.), University of California San Diego, La Jolla.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Moriarty
authors.affiliation: From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); Salveo Diagnostics, Inc, Richmond, VA (S.A.V., J.P.M.); Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center (P.L.S.M.G.), Department of Medicine, Division of Endocrinology and Metabolism (P.L.S.M.G.), and Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center (S.T.), University of California San Diego, La Jolla.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Varvel
authors.affiliation: From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); Salveo Diagnostics, Inc, Richmond, VA (S.A.V., J.P.M.); Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center (P.L.S.M.G.), Department of Medicine, Division of Endocrinology and Metabolism (P.L.S.M.G.), and Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center (S.T.), University of California San Diego, La Jolla.
authors.forename: Philip L S M
authors.initials: PL
authors.lastname: Gordts
authors.affiliation: From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); Salveo Diagnostics, Inc, Richmond, VA (S.A.V., J.P.M.); Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center (P.L.S.M.G.), Department of Medicine, Division of Endocrinology and Metabolism (P.L.S.M.G.), and Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center (S.T.), University of California San Diego, La Jolla.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McConnell
authors.affiliation: From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); Salveo Diagnostics, Inc, Richmond, VA (S.A.V., J.P.M.); Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center (P.L.S.M.G.), Department of Medicine, Division of Endocrinology and Metabolism (P.L.S.M.G.), and Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center (S.T.), University of California San Diego, La Jolla. stsimikas@ucsd.edu.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100 / Q000097:blood; D001057:Apolipoproteins E / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010641:Phenotype
chemical_list: C569471:APOB protein, human; C000612345:ApoE protein, human; D053299:Apolipoprotein B-100; D001057:Apolipoproteins E; D015415:Biomarkers; D008078:Cholesterol, LDL; D017270:Lipoprotein(a)
keywords: alleles; cholesterol; genotype; hepatocytes; prevalence