Clinical Spotlight

Apolipoprotein E genotype (ApoE) testing for cardiovascular risk assessment

By Thomas Dayspring MD, FACP, FNLA, NCMP, Director, North Jersey Institute of Menopausal Lipidology

Lipoproteins are apoprotein enwrapped collections of lipids (cholesterol, cholesteryl ester, triglycerides, phospholipids) that traffic lipids between tissues. Apolipoprotein E (ApoE) is found in the TG-rich lipoproteins — i.e., very low-density lipoprotein (VLDL) particles, chylomicrons, VLDL and chylomicron remnant lipoproteins, intermediate density lipoproteins (IDL), and some very large high-density lipoproteins (HDL). It is not present on LDL particles. ApoE is a ligand, along with ApoB, for the LDL receptor, and mediates aspects of lipoprotein clearance, lipidation, and delipidation. ApoE also modulates activity of enzymes involved in lipoprotein trafficking and metabolism (lipolysis)1.

The polymorphic ApoE gene (with alleles ε2, ε3, and ε4) codes for three protein isoforms (E2, E3, and E4) and a patient’s genotype (alleles) can be determined by gene amplification techniques. Genotype frequencies (USA) are E3/E3; ~55%, E3/E4; ~25%, E2/E3; ~15%, E2/E4; ~1-2%, E4/E4; ~1-2% and E2/E2; ~1-2%, but ethnic differences exist2. Differences in ApoE isoform receptor-binding affect TG-rich particle lipolysis and clearance, thus plasma lipid and lipoprotein levels. ApoE genotyping can thus indicate risk for coronary artery disease. The phenotypic expression of the different isoforms varies according to diverse environmental stimuli (e.g., smoking, obesity, diet) and genetic background3,4.

The extensive literature regarding specific ApoE genotypes and cardiovascular (CV) risk is confusing, as data are conflicting, despite known differences in lipid metabolism according to ApoE genotype5. However, most studies measure lipoprotein response via lipoprotein cholesterol, when it is now well-established that apolipoproteins (e.g., ApoB and A-I) and lipoprotein particle numbers are superior indicators of CV risk. Judging effects of ApoE genotype solely on changes in lipoprotein cholesterol is tenuous. The studies are summarized in the HDL, Inc. test guide. The points below summarize how the practicing clinician can effectively utilize the ApoE genotype information in patient care. ApoE genotyping is a one-time test that can help clinicians rapidly assess the level of CV risk, what additional testing is needed, what therapies might be needed, and what patient response to those therapies is likely to be.

1 Most E2 carriers have the lowest CV risk, patients with E4 the highest. Susceptible to Type III dyslipoproteinemia, E2 carriers should be periodically monitored for signs of insulin resistance (insulin levels, free fatty acids, lipoprotein insulin resistance score, albuminuria, adiponectin, c-peptide), diabetes (glucose, average glucose, HbA1c), weight gain, polycystic ovarian syndrome, lipodystrophy (HIV), hypothyroidism, and should avoid triglyceride-raising drugs.

2 The presence of an E4 or E2 allele, especially E4/E4, should prompt baseline evaluation, continual monitoring, and therapeutic adjustment of omega-3 and omega-6 fatty acid profile, and cholesterol homeostasis (via sterol markers of absorption and synthesis). Patients should have their fatty acid profile optimized regardless of their ApoE status, and treatment with prescription or supplemental omega-3, even for triglyceride lowering, should not be withheld because of their ApoE status (Bill Harris PhD, personal communication).

3 Testing also helps physicians when prescribing lipid-lowering drugs, the effects of which are influenced by the ApoE genotype. Treatment responses in E4 carriers may not be robust, and achieving goals in such patients will likely require serious lifestyle advice, early statin-combination prescriptions and non-prescription medications. Such patients can really benefit from regular contact with their HDL, Inc. Health Coaches.

4 All patients are told that smoking cessation is critical to reduce CV risk but the deleterious effects of smoking are the greatest for E4 carriers6. Motivational counseling can help patients quit smoking.

  1. Mahley RW, Rall SC, Jr. Annu Rev Genomics Hum Genet 2000; 1:507-37.
  2. Eichner JE et al. Am J Epidemiol 2002;155:487-95.
  3. Nieminen T et al. Pharmacogenomics 2008;9(10):1475-1486.
  4. Talmud PJ. NutrMetabCardiovasc Dis 2007;17:148-52.
  5. Minihane AM et al. Proc Nutr Soc. 2007;66(2):183-197.
  6. Jofre-Monseny L et al. Mol Nutr Food Res 2008;52:131-145.