Cardiovascular Disease Risk Factor (Apolipoprotein E) Genetic Test

When an individual has too much LDL-cholesterol (“bad” cholesterol) in the bloodstream, it accumulates as fatty deposits, and stimulates extra cell growth within the blood vessels, leading to atherosclerotic plaques. There are many genetic and environmental factors that can contribute to elevated LDL-cholesterol levels. Genetic variants of the APOE, LDLR, APOB and PCSK9 genes are all linked to an increased risk of elevated LDL-cholesterol and cardiovascular disease. Other factors that can affect LDL-cholesterol levels include gender (males generally have higher levels), age (older people have higher levels), excess alcohol consumption, high fat diet, low physical activity and obesity. Variations in the APOE gene are also linked to an increased risk of hyperlipoproteinemia type III. This disorder results in the diminished metabolism of cholesterol and triglycerides in the blood, leading to cardiovascular problems.

The APOE gene encodes Apolipoprotein E, a protein involved in the production, delivery and utlization of cholesterol in the body. The APOE gene is located on chromosome 19. There are three common forms or alleles of APOE – e2, e3 and e4. One allele is inherited from each parent, resulting in six possible combinations: e2/e2, e3/e3, e4/e4, e2/e3, e2/e4 or e3/e4. The e3 allele is the most common allele worldwide and is viewed as the neutral allele, with no increased or decreased risk of cardiovascular disease. The e4 allele is associated with an increased risk of elevated LDL-cholesterol and cardiovascular disease. The e2 allele does not increase the risk of elevated LDL-cholesterol. However, there is an increased risk of hyperlipoproteinemia type III in individuals with the e2/e2 genotype.

Different versions of the APOE gene also affect how a person responds to diet and statins (cholesterol-lowering drugs). Individuals with the e3/e3 and e2/e3 genotypes are likely to respond well to statins. The e2/e2 genotype is also associated with a good reponse to statins, and a low sugar/low carbohydrate diet is also recommended. Individuals at a higher risk of elevated LDL-cholesterol (genotypes e3/e4 and e4/e4) do not responsd efficiently to statins. Instead a low-fat diet is recommended for these individuals to effectively lower LDL-cholesterol levels before cardiovascular problems occur.

A simple DNA test can be completed to determine which alleles of APOE a person has inherited. The three alleles are e2, e3 and e4. Each person can inherit two identical alleles or two different alleles of APOE.

• e2/e2 – This genotype is associated with lower LDL-cholesterol levels but an increased risk for hyperlipoproteinemia type III. A person with this genotype will respond well to statins.
• e2/e3 – This genotype is not associated with an increased risk of elevated LDL-cholesterol. A person with this genotype will respond well to statins.
• e3/e3 – This genotype is not associated with an increased risk of elevated LDL-cholesterol. A person with this genotype will respond well to statins.
• e3/e4 or e4/e4 – These genotypes are associated with an increased risk of cardiovascular disease, due to elevated LDL-cholesterol levels. People with these genotypes do not respond well to statins but will benefit from a low fat diet.
• e2/e4 – This rare genotype has been the least well studied and results have been conflicting. Some studies indicate that it is associated with an increased risk of elevated LDL-cholesterol levels (due to the presence of the e4 allele). However, other studies indicate that it is associated with a similar neutral phenotype to the e3/e3 genotype.

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