Apolipoprotein E Genotyping, Cardiovascular Disease Risk

  • Determines APOE genotype in context of HLP III for evaluation of premature CHD
  • Use for cardiovascular risk assessment only
  • Not recommended for asymptomatic individuals <18 years
Related Test
  • Determines APOE genotype in context of evaluation for Alzheimer disease (AD)
  • Supports a clinical diagnosis of AD in symptomatic individuals
  • Not recommended for predictive testing in asymptomatic individuals

The APOE gene encodes the apolipoprotein E (apoE) protein, which combines with lipids to form lipoproteins that transport cholesterol and other fats through the bloodstream.

The three most common APOE variants are designated as the e2, e3, and e4 alleles. E3 is the wild type allele, while e2 is associated with an increased risk for early cardiovascular disease (CVD) and hyperlipoproteinemia type III (HLP III) and E4 is associated with Alzheimer disease.

Disease Overview

Incidence of Hyperlipoproteinemia Type III

  • 1/5,000
  • May account for up to 5% of premature coronary heart disease (CHD)

Clinical Presentation/Treatment of Hyperlipoproteinemia Type III

  • Elevated cholesterol, triglycerides, very low density lipoprotein (VLDL)
  • Premature CHD, vascular disease, peripheral artery disease
  • Xanthomas
  • Early identification allows treatment with lipid-lowering agents




Inheritance of Hyperlipoproteinemia Type III

Autosomal recessive


ApoE is a critical protein component of VLDL and chylomicrons


Three common alleles (e2, e3, e4) differ at amino acid positions 112 (130 legacy) and 158 (176 legacy)

  • Allele frequencies:
    • e2 (c.388T; p.130Cys and c.526C>T; p.Arg176Cys): 10%
    • e3 (c.388T; p.130Cys and c.526C; p.176Arg): 75%
    • e4 (c.388T>C; p.Cys130Arg and c.526C; p.176Arg): 15%
  • APOE e2: binds the lipoprotein receptors with only 2% of the affinity of e3 and e4 isoforms
    • Results in impaired clearance of chylomicron and VLDL remnants
    • Leads to increased plasma cholesterol and triglyceride levels
  • Homozygosity for e2 is present in 1% of White individuals
    • Only genotype associated with HLP III
    • 1-4% of homozygotes will develop HLP III
    • Found in >90% of individuals with HLP III
  • APOE e3: considered wild type
  • APOE e4: associated with increased plasma cholesterol

Test Interpretation


  • Clinical sensitivity: >90% for individuals with HLP III 
  • Analytical sensitivity/specificity: 99%


  • APOE e2/e2: provides additional evidence for a clinical diagnosis of HLP III; by itself, genotype is not diagnostic for HLP III
  • APOE e3/e3: most common genotype found in general population
  • APOE e4/e4: associated with increased plasma cholesterol levels that may contribute to CHD
  • APOE e2/e3, e2/e4, e3/e4: no significantly increased risk for HLP III
  • APOE e2/e4 and e3/e4: some association with increased plasma cholesterol levels and atherosclerosis


  • Diagnostic errors can occur due to rare sequence variations
  • Rare APOE variants and variants in other genes that cause HLP III are not detected
  • APOE e2 homozygosity is neither sufficient nor necessary to cause HPL III