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Editors Selection IGR 16-4

Clinical glaucoma: Pseudoexfoliation

Robert Ritch

Comment by Robert Ritch on:

12356 Effects of apolipoprotein E genotypes on the development of exfoliation syndrome, Yilmaz A; Tamer L; Ates NA et al., Experimental Eye Research, 2005; 80: 871-875


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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.

References

  1. Eichner JE, Dun ST, Perveen G, et al. Apolipoprotein E Polymorphism and Cardiovascular Disease: A HuGE Review. Am J Epidemiol 2002; 155: 487-495
  2. Stengard JH, Weiss KM, Sing CF. An ecological study of association between coronary heart disease mortality rates in men and the relative frequencies of common allelic variations in the gene coding for apolipoprotein E. Hum Genet 1998; 103: 234-241
  3. Seshadri S, Drachman DA, Lippa CF. Apolipoprotein E 4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know. Arch Neurol 1995; 52: 1074-1079
  4. Li YJ, Hauser MA, Scott WK, et al. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology 2004; 62: 2005-2009
  5. Zareparsi S, Reddick AC, Branham KE, et al. Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci 2004; 45: 1306-1310
  6. Baird PN, Guida E, Chu DT, et al. The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2004; 45: 1311-1315
  7. Mabuchi F, Tang S, Ando D, et al. The apolipoprotein E gene polymorphism is associated with open angle glaucoma in the Japanese. Mol Vis 2005; 11: 609-612
  8. Ressiniotis T, Griffiths PG, Birch M, et al. Apolipoprotein E promoter polymorphisms do not have a major influence on the risk of developing primary open angle glaucoma. Mol Vis 2004; 10: 805-807
  9. Vickers JC, Craig JE, Stankovich J, et al. The apolipoprotein epsilon4 gene is associated with elevated risk of normal tension glaucoma. Mol Vis 2002; 8: 389-393
  10. Lake S, Liverani E, Desai M, et al. Normal tension glaucoma is not associated with the common apolipoprotein E gene polymorphisms. Br J Ophthalmol 2004; 88: 491-493
  11. Reiter K, Bille JF, Dreher AW, et al. Retinal nerve fiber layer thickness measurement by Fourier-ellipsometry using the laser tomographic scanner. Biomet Opt ?????
  12. Copin B, Brezin AP, Valtot F, et al. Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene. Am J Hum Genet 2002; 70: 1575-1581
  13. Fan BJ, Wang DY, Fan DS, et al. SNPs and interaction analyses of myocilin, optineurin, and apolipoprotein E in primary open angle glaucoma patients. Mol Vis 2005; 11: 625-631
  14. Zenkel M, Pöschl E, von der Mark K, et al. Differential gene expression in pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci 2005; 46: 3742-3752
  15. Ritch R, Schlötzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol 2001; 45: 265-315
  16. Vessani RM, Liebmann JM, Jofe M, Ritch R. Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol 2003; 136: 41-46


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