Apolipoprotein E (ApoE)

Clinical Usage

  • Evaluate individuals with elevated cholesterol and triglycerides to aid in the diagnosis of hyperlipoproteinemia
  • Identify a cause for type III hyperlipoproteinemia (HLP III) or premature coronary heart disease (CHD)
  • Screen individuals with a family history of HLP III or premature CHD 
  • Distinguishing an Apo E variant from other causes of elevated cholesterol is important because effective treatment of type III hyperlipoproteinemia to prevent atherosclerosis often requires a different approach than treatment of other dyslipidemias.

Background Information

Apolipolipoprotein E, coded by the ApoE gene, is a major component of very low-density lipoproteins (VLDLs) and binds to a specific receptor on liver and peripheral cells. VLDLs transport cholesterol and other lipids through blood between the liver and other tissues to maintain normal levels.  Maintaining normal levels of cholesterol and triglycerides is essential for prevention of cardiovascular diseases that affect the heart and blood vessels.

Three major alleles of ApoE are detected: E3, E4, and E2.

E3 is the normal form and codes for apolipoprotein E3 which has normal function.  The  E3 isoform of apolipoprotein E is distinguished by cysteine at position 112 (112 CYS) and argenine at position 158 (158 ARG) in the receptor-binding region of the protein.

The E2 allele is associated with an increased risk of type III hyperlipidemia, which is characterized by increased blood levels of cholesterol, triglycerides and beta-very low-density lipoproteins (beta-VLDLs).  The E2 variant has a cysteine at position 158 of the protein.  E2 has a reduced ability to bind cell receptors.  Ninety-five percent of patients with type III hyperlipoproteinemia are homozygous for E2, and this is a familial dyslipidemia associated with a high risk of coronary heart disease, atherosclerosis and peripheral vascular disease. Symptoms include angina, heart attack, claudication, and leg pain. 

The E4 isoform has an argenine at position 112 of the protein.  E4 is associated with increased levels of total cholesterol and beta-lipoprotein, which is a causative factor in the development of atherosclerosis.  The risk of heart attack and stroke is also increased in these individuals.  The E4 allele is also associated with an increased risk of Alzheimer’s Disease.  Not all people with Alzheimer disease have the APOE E4 allele, and not all people who have this allele will develop the disease.

Gene Information

The human Apo E gene spans 3.7 kb including four exons and is located on chromosome 19. The ApoE gene is located on the long (q) arm of chromosome 19 at position 13.2.  More precisely, the ApoE gene is located from base pair 45,409,038 to base pair 45,412,649 on chromosome 19.   Three common alleles of ApoE encoding isoforms, E2, E3 and E4 are identified by single nucleotide polymorphisms in this test.

Population Information

Adapted from Eichner et al, Am J Epidemiol 155:487-495.  (2002)

Test Method

These assays were developed using CLSI guidelines.  Control DNA samples of known genotype are tested together with each patient sample to ensure correct results.  Genomic DNA is extracted from the submitted buccal swab  or blood sample and subjected to polymerase chain reaction (PCR).  The E3, E4 and E2 alleles of ApoE were detected.  



• Buccal swab
• Whole blood,  2-5 mL, into:
i. EDTA-containing tube (purple or lavender top), or
ii. ACD-containing tube (yellow top), or
iii. Citrate-containing tube (blue top).
• Store at 2-8°C.  Ship by overnight carrier at ambient temperature.

Rejection Criteria

• Buccal swab:
i. Physical damage
ii. Specimen appears to have microbial contamination or other visible contamination
iii. The name on the tube does not match the name on the paperwork.
iv. It is older than 10 days.
• blood specimen:
i. It is collected in a heparin-containing tube because heparin can inhibit the PCR reaction.
ii. It leaked in the shipping container.
iii. The name on the tube does not match the name on the paperwork.
iv. It is older than 10 days.


APOE E3/E3 – normal genotype
APOE E2/E2 – strong association with type III hyperlipidemia (HLP III) 
APOE E4/E4 – associated with increased plasma cholesterol levels and associated with an increased risk for atherosclerosis 
APOE E2/E3 or E2/E4 – some association with HLP III with an increased risk for atherosclerosis
APOE E3/E4 – some association with increased plasma cholesterol levels that may contribute to Coronary Heart Disease 

CPT code


Test Limitations

Other rare mutations for the ApoE genes will not be detected in this test.  The detection of genetic variants does not replace the need for appropriate clinical monitoring by the health care provider.  These tests were developed and the performance characteristics were determined by MDL.  This cardiac panel has not been cleared or approved by the US Food and Drug Administration.  The FDA has determined that such approval is not necessary.


1. Anoop S, Anoop M, Meena K, Luthra K.  Apolipoprotein E polymorphism in cerebrovascular & coronary heart diseases.  Indian J Med Res 132: 363-378.  2010
2. Ballantyne CM, Herd JA, Stein EA, Ferlic LL, Dunn JK, Gotto AM, Marian AJ.  Apolipoprotein E Genotypes and Response of Plasma Lipids and Progression-Regression of Coronary Atherosclerosis to Lipid-Lowering Drug Therapy.  Journal of the American College of Cardiology.  36(5):  1572-1578.   2000