|MP 2.04.25||Apolipoprotein E Genotype or Phenotype in the Management of Cardiovascular Disease|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/4:2009
|Return to Medical Policy Index|
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Apolipoprotein E (apo E) is the primary apolipoprotein found in very-low-density lipoproteins and chylomicrons. Apo E is the primary binding protein for LDL receptors in the liver and is thought to play an important role in lipid metabolism. The apo E gene is polymorphic, consisting of 3 alleles (e2, e3, and e4) that code for 3 protein isoforms, known as E2, E3, and E4, which differ from one another by one amino acid. These molecules mediate lipid metabolism through their different interactions with the LDL receptors. The genotype of apo E alleles can be assessed by gene amplification techniques, or the apo E phenotype can be assessed by measuring plasma levels of apolipoprotein E.
There has been much research interest in investigating lipid metabolism and lipoprotein levels in patients with different apo E genotypes and phenotypes. It has been proposed that various genotypes are more atherogenic than others, and that apo E measurement may provide information on risk of coronary artery disease above traditional risk factor measurement. It has also been proposed that the apo E genotype may be useful in selection of specific components of lipid-lowering therapy, such as drug selection. In the major lipid-lowering intervention trials, including trials of statin therapy, there is considerable variability in response to therapy that cannot be explained by factors such as compliance. Apo E genotype may be one factor that determines an individual’s degree of response to interventions such as statin therapy.
Apolipoprotein E isoforms have also been investigated as a risk factor for Alzheimer’s disease. This topic is discussed separately in policy No. 2.04.13.
Determination of the apo E genotype or phenotype is considered investigational as a cardiovascular risk factor.
There is no specific code for apo E phenotyping or genotyping. For phenotyping, CPT code 84181 (Protein; Western blot) may be used.
BlueCard/National Account Issues
Determination of apo E may be included as a component of a comprehensive cardiovascular risk assessment offered by reference laboratories. Comprehensive risk assessment may include evaluation of small low-density lipoproteins, subclassification of high-density lipoproteins, high- sensitivity C-reactive protein, total plasma homocysteine, apolipoproteins A and B, lipoprotein a, small low-density LDL, and homocysteine levels. (These components are addressed separately in policies 2.04.12 and 2.04.20–2.04.25.) The lack of a specific CPT code may make identification of claims for apo E difficult. However, apo E phenotyping as part of cardiovascular risk assessment is likely when CPT code 84181 is submitted from a reference laboratory in conjunction with CPT codes 82172 (used to code for apolipoprotein B and lipoprotein a), CPT code 82664 (used to code for HDL subclasses), and CPT code 86141 (used to code for high-sensitivity C-reactive protein), CPT code 83090 (homocysteine), and CPT code 83716 (used to code for small, low-density LDL.)
Apo E as a Predictor of Cardiovascular Disease
A large body of research has focused on the correlation between lipid levels and the underlying apo E genotype. For example, in population studies the presence of an apo e2 allele is associated with the lowest cholesterol levels and the apo e4 allele is associated with the highest levels.(1, 2)
Numerous studies have focused on the relationship between genotype and physiologic markers of atherosclerotic disease. A number of small- to medium-sized cross-sectional and case-control studies have correlated apo E with surrogate outcomes such as carotid intima-media thickness. (3-6) These studies have generally shown a relationship between apo E and these surrogate outcomes. Other studies have suggested that carriers of apo e4 are more likely to develop signs of atherosclerosis independent of total and low-density lipoprotein (LDL) cholesterol levels. (7-9)
Some larger observational studies have correlated apo E genotype with clinical disease. The Copenhagen City Heart Study was a large case-control study of 940 adults with known ischemic heart disease and 9,241 adults in the general population. (10) In men with a genotype of e4/e4 compared to those with a genotype of e3/e3, the odds ratio of ischemic disease was 1.58. Among women, the odds ratio of those with a genotype of e3/2 compared to those with a genotype of 3/3 was 0.57. The attributable risk of apo E to coronary artery disease (CAD) was relatively small for all genotypes. The Atherosclerosis Risk in Communities (ARIC) study followed up 12,000 middle-aged individuals free of CAD at baseline for 10 years. (11) This study reported that the e3/2 genotype was associated with carotid artery atherosclerosis after controlling for other atherosclerotic risk factors. Volcik et al. reported that apo E polymorphisms were associated with LDL levels and carotid intima-media thickness, but were not predictive of incident CAD. (12)
- Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 1988; 8(1):1-21.
- Hallman DM, Boerwinkle E, Saha N et al. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet 1991; 49(2):338-49.
- Vaisi-Raygani A, Rahimi Z, Nomani H et al. The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. Clin Biochem 2007; 40(15):1150-6.
- Schmitz F, Mevissen V, Krantz C et al. Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolemia. Eur J Clin Invest 2007; 37(2):106-8.
- Koch W, Hoppmann P, Schomig A et al. Apolipoprotein E gene epsilon2/epsilon3/epsilon4 polymorphism and myocardial infarction: case-control study in a large population sample. Int J Cardiol 2008; 125(1):116-7
- Kulminski AM, Ukraintseva SV, Arbeev KG et al. Health-protective and adverse effects of the apolipoprotein E epsilon2 allele in older men. J Am Geriatr Soc 2008; 56(3):478-83.
- Wilson PW, Myers RH, Larson MG et al. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study. JAMA 1994; 272(21):1666-71.
- Wilson PW, Schaefer EJ, Larson MG et al. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 1996; 16(10):1250-5.
- Eichner JE, Kuller LH, Orchard TJ et al. Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol 1993; 71(2):160-5.
- Frikke-Schmidt R, Tybjaerg-Hansen A, Steffensen R et al. Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study. J Am Coll Cardiol 2000; 35(5):1192-9.
- de Andrade M, Thandi I, Brown S et al. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet 1995; 56(6):1379-90.
- Volcik KA, Barkley RA, Hutchinson RG et al. Apolipoprotein E polymorphisms predict low density lipoprotein levels and carotid artery wall thickness but not incident coronary heart disease in 1,491 ARIC study participants. Am J Epidemiol 2006; 164(4):342-8.
- Bennet AM, Di Angelantonio E, Ye Z et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298(11):1300-11.
- Eichner JE, Dunn ST, Perveen G et al. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002; 155(6):487-95.
- Hixson JE. Apolipoprotein E polymorphisms affect atherosclerosis in young males. Arterioscler Thromb 1991; 11(5):1237-44.
- Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285(19):2486-97.
- Sarkkinen E, Korhonen M, Erkkila A et al. Effect of apolipoprotein E polymorphism on serum lipid response to the separate modification of dietary fat and dietary cholesterol. Am J Clin Nutr 1998; 68(6):1215-22.
- Ordovas JM, Mooser V. The APOE locus and the pharmacogenetics of lipid response. Curr Opin Lipidol 2002; 13(2):113-7.
- Carmena R, Roederer G, Mailloux H et al. The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism. Metabolism 1993; 42(7):895-901.
- Chiodini BD, Franzosi MG, Barlera S et al. Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population. Eur Heart J 2007; 28(16):1977-83.
- Donnelly LA, Palmer CN, Whitley AL et al. Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study. Pharmacogenet Genomics 2008; 18(4):279-87.
- Vossen CY, Hoffmann MM, Hahmann H et al. Effect of Apo E genotype on lipid levels in patients with coronary heart disease during a 3-week inpatient rehabilitation program. Clin Pharmacol Ther 2008; 84(2):222-7.
|CPT||84181||Protein, Western blot|
|84999||No specific code for genotyping|
|ICD-9 Diagnosis||250||Diabetes, code range|
|272||Disorders of lipid metabolism, code range|
|410–414||Ischemic heart disease code range|
|440||Atherosclerosis, code range|
|443||Peripheral vascular disease, code range|
|V12.5||Personal history of disease of the circulatory system|
|V17.3-17.4||Family history of ischemic heart disease or other cardiovascular disease, respectively|
|Type of Service||Pathology/Laboratory|
|Place of Service||Outpatient|
Apolipoprotein E, Management of Cardiovascular Disease
Cardiovascular Risk Assessment, Apolipoprotein E
|05/31/01||Add to Medicine section||New policy|
|04/29/03||Replace policy||Policy updated with literature search; no change in policy statement; references added|
|11/9/04||Replace policy||Policy updated with literature search; no change in policy statement|
|08/17/05||Replace policy||Policy updated with literature search; no change in policy statement|
|04/09/08||Replace policy||Policy updated with literature search; no change in policy statement. Reference numbers 18 through 23 added|
|04/24/09||Replace policy||Policy extensively revised with literature search; previous updates condensed. References condensed and reordered; reference numbers 21 and 22 added. No change to policy statement|