APOE genotype tests are most often done as part of research protocols to help understand the role of genetic factors in cardiovascular disease. However, the testing is sometimes used in clinical settings to help confirm a diagnosis of type III hyperlipoproteinemia (also known as familial dysbetalipoproteinemia).
APOE Genotyping, Cardiovascular Disease
A blood sample drawn from a vein in your arm
Apolipoprotein E (Apo E) is a protein that helps transport lipids (fats and cholesterol) in the blood. It is recognized by specific cell surface receptors that allow it to deliver lipids to cells for use or storage and to deliver excess lipids to the liver for excretion.
The ApoE protein has three genetic forms that have slightly different compositions. They are called ApoE2, ApoE3, and ApoE 4. ApoE3 is the most common form. Compared to ApoeE3, ApoE2 is poorly recognized by cell surface receptors whereas ApoE4 binds more tightly to those receptors. People with ApoE2 tend to have higher amounts of lipids in their blood since delivery from blood to cells is impaired by poor binding of ApoE2 to receptors.
Three different genes (termed alleles) are designated as e2, e3, and e4 and code respectively for ApoE2, ApoE3, and ApoE4. Each person inherits one allele from each parent. A person who has the same allele from each parent is termed homozygous: e2/e2 or e3/e3 or e4/e4. One who has different alleles is termed heterozygous: e2/e3 or e2/e4 or e3/e4.
The APOE genotype test evaluates a person's DNA to determine what APOE forms (alleles) are present. APOE e3/e3 is the most common genotype (seen in well over half of the population) and is considered "neutral." Risks of disease are made relative to the e3/e3 population. APOE e4 (as e4/e4 and e4/e3) is found in nearly a quarter of the population and is associated with an increased risk of atherosclerosis. People with these genotypes could be predisposed to a significantly elevated level of LDL-C ("bad cholesterol") and triglycerides when their diet is high in saturated fat. The various APOE allele frequencies differ between ethnic populations.
People with the APOE e2 allele tend to have lower LDL-C levels but elevated triglycerides. APOE e2 is also associated with type III hyperlipoproteinemia/hyperlipidemia (HPL III or familial dysbetalipoproteinemia), a rare inherited disorder that causes fatty yellowish deposits on the skin called xanthomas, increased triglycerides in the blood, and atherosclerosis that develops at an early age. Importantly, while a large majority of patients with type III hyperlipoproteinemia are homozygous for the e2 allele (e2/e2), less than 10% of people with the e2/e2 genotype develop type III hyperlipoproteinemia/hyperlipidemia.
How is it used?
While APOE genotyping is mostly done in research settings, it can be used clinically to help in diagnosis and treatment of elevated lipid levels.
APOE testing may be used to help diagnose type III hyperlipoproteinemia (HPL III or familial dysbetalipoproteinemia) in a person with symptoms that suggest the disorder and to evaluate the potential for the condition in other family members. This is a rare inherited disorder that causes fatty, yellowish deposits on the skin called xanthomas, a high level of triglycerides in the blood, and atherosclerosis that develops at an early age.
APOE genotyping has potential to help guide lipid treatment. In cases of high cholesterol and triglyceride levels, statins are usually considered the treatment of choice to decrease the risk of developing cardiovascular disease (CVD). However, there is a wide variability in the response to these lipid-lowering drugs that is in part influenced by the APOE genotype. At present, the clinical utility of this type of information is yet to be totally understood.
When is it ordered?
As a test to evaluate lipid metabolism or cardiovascular risk, APOE genotyping is ordered when someone has:
- Significantly elevated cholesterol and triglyceride levels that do not respond to dietary and exercise lifestyle changes
- Family members known to have abnormal APOE alleles and a healthcare practitioner wants to see if the person might be at a higher risk for early heart disease
- Yellowish skin lesions called xanthomas and the healthcare practitioner suspects type III hyperlipoproteinemia
What does the test result mean?
APOE e4 (genotype e4/e4 or e4/e3) is found in nearly a quarter of the population and is associated with an increased risk of atherosclerosis. People with these genotypes could be predisposed to significantly elevated levels of LDL-C ("bad cholesterol") and triglycerides when their diet is high in saturated fat.
People with the APOE e2/e2 alleles tend to have lower LDL-C levels but elevated triglycerides. APOE e2 is also associated with type III hyperlipoproteinemia/hyperlipidemia. People with APOE e2/e2 alleles are at a higher risk of premature vascular disease, but they may never develop disease. APOE genotyping adds additional information and, if symptoms are present, e2/e2 can help confirm type III hyperlipoproteinemia.
Most cases of apoE-influenced type III hyperlipoproteinemia occur in an autosomal recessive manner, meaning that individuals with an e2/e3 genotype may be carriers of disease but may not show signs of lipid dysfunction.
Is there anything else I should know?
APOE genotyping is not available in every laboratory. If a healthcare practitioner recommends this test, the specimen will likely be sent to a reference laboratory and results may take longer to return than they would from a local laboratory.
Alterations in lipid concentrations do not lead directly to vascular disease or atherosclerosis. Other factors, such as obesity, diabetes, and hypothyroidism, also play a role in whether a person actually develops disease. Additionally, APOE genetic tests cannot detect all mutations that may cause type III hyperlipoproteinemia or other lipid-related diseases. Therefore, the absence of a mutation cannot rule out the possibility of disease or carrier status.
Should everyone have their APOE genotype tested?
Is there a reason to test for APOE genotype more than once?