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Apolipoproteins
Apolipoproteins, the protein component of lipoproteins, combine with free cholesterol, phospholipids, cholesterol esters, and triglycerides to form lipoproteins. Human plasma contains five main types of apolipoproteins (A-E). ApoE has 3 common alleles: E2, E3, and E4. Apo-E3 is the most frequent allele (>60%) in all populations studied. The apo gene polymorphism affects the level of its gene product; E2 is associated with higher concentrations of apo-E and E4 with lower concentrations.1 Allelic variation affects plasma concentrations of total cholesterol, LDL cholesterol, and apo B, the major protein of LDL, VLDL, and chylomicrons, and their metabolic regulation. The general ranking of allotypic phenotypes from most to least common is generally 3/3, 4/3, 3/2, 4/4, 4/2, and 2/2, although different populations have different allele frequencies. In general, E2 lowers total cholesterol levels and E4 raises them.
Apolipoproteins have been studied in disorders associated with abnormalities of cholesterol and lipids, such as coronary artery disease, stroke, peripheral arterial disease, and diabetes mellitus, and with Alzheimer's disease. The MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Project, a multinational study sponsored by the World Health Organization, suggests that an increase of 0.01 in the relative frequency of the E4 allele increases the death rate from coronary heart disease by 24.5 per 100,000.2 The lifetime risk of developing Alzheimer's disease is 15 percent for persons with no family history of the disease. The risk increases to 29 percent for carriers of one E4 allele and is 9 percent for those with no E4 allele.3 Apo-E4 is also associated with an increased risk and decreased age of onset of Parkinson's disease.4
ApoE polymorphisms have been investigated in eye diseases. ApoE-4 was associated with a significant reduced risk of developing age-related macular degeneration.5-6 In Japan, Mabuchi et al. found lower frequencies of E2 and E4 alleles and higher frequencies of E3 in open-angle glaucoma patients. Patients with E4 also had significantly lower maximum IOP.7 Others have not found positive results.8 APOE-4 has been associated with elevated risk for normal-tension glaucoma,9 but this has been disputed.10-11 APOE-promoter polymorphisms have been associated with phenotypic modification of POAG (increased damage and higher IOP) and to interact with a polymorphism in the myocilin promoter, suggesting that
APOE is a potent modifier for POAG.12 It has been suggested that common polymorphisms in MYOC, OPTN, and APOE might interactively contribute to POAG.13 In exfoliation syndrome (XFS), apolipoprotein D has been reported to be upregulated.14
Yilmaz et al. (579) evaluated the possible association between apo E polymorphism and the occurrence of XFS. The E2/E2, E2/E3 and E2/E4 genotypes and the in2 allele had an increased risk of developing XFS while the in3 allele was protective. This is an interesting observation which requires further investigation. All things considered, there are a number of loose ends which remain to be tied together. Similarities have been noted between exfoliation material and amyloid, which also has allelic apolipoprotein associations. Exfoliation syndrome has been associated with transient ischemic attacks, stroke, myocardial infarction, and Alzheimer's disease.15 These have also been associated with elevated serum homocysteine levels, which in turn have been associated with XFS, with or without glaucoma.16 A study assessing apolipoprotein isoforms with homocysteine levels in patients with XFS with and without glaucoma would be a useful next step.