The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration

Invest Ophthalmol Vis Sci. 2004 May;45(5):1311-5. doi: 10.1167/iovs.03-1121.


Purpose: To date, of all the genes studied in relation to age-related macular degeneration (AMD), the alleles of the apolipoprotein (apoE) gene have been the most consistently associated with disease. However, not all apoE studies have found an association, and among these the associations differ. The current study was conducted to investigate further the association of this gene in AMD.

Methods: Three hundred twenty-two unrelated individuals with diagnosed AMD and 123 unrelated but ethnically matched control subjects were analyzed. All subjects completed a standard questionnaire and were given a fundus examination. A blood sample was collected for DNA extraction. The common allelic variants of apoE were screened through the use of polymerase chain reaction (PCR) and restriction enzyme digestion followed by statistical analysis.

Results: Individuals with the epsilon3 epsilon4 genotype of apoE had an approximate halving of disease risk for late (end-stage) AMD (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.34-0.98) relative to the epsilon3 epsilon3 genotype at age of ascertainment. Stratification of late AMD into atrophic and neovascular disease revealed that the greatest protective effect for the epsilon3 epsilon4 genotype was in individuals with atrophic disease (OR 0.35, 95% CI 0.13-0.92). Men with the epsilon3 epsilon4 genotype also showed almost a threefold reduction in risk of disease in late AMD (OR 0.36, 95% CI 0.16-0.82). However, individuals with late AMD and the epsilon2 epsilon3 genotype had a significantly earlier mean age of diagnosis of disease (3.4 years, P = 0.015) compared with those with the epsilon3 epsilon3 genotype, and this was most evident in women (3.9 years, P = 0.011) and in individuals with neovascular disease (4.7 years, P = 0.003).

Conclusions: The alleles of apoE appear to have a role in the etiology of AMD, with the epsilon4 allele being protective, or at the very least, delaying the age of diagnosis of disease, whereas the epsilon2 allele appears to have a modifier effect by bringing forward the mean age of disease diagnosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Apolipoprotein E2
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • DNA / analysis
  • Female
  • Genotype
  • Humans
  • Macular Degeneration / genetics*
  • Male
  • Polymerase Chain Reaction
  • Risk Factors


  • Apolipoprotein E2
  • Apolipoprotein E4
  • Apolipoproteins E
  • DNA