Most previous studies including a meta-analysis of 10 studies,
27 have found a reduced risk of advanced AMD for subjects carrying one or two ε4 alleles and nonsignificant increased risk for ε2 carriers.
41–45 The largest pooled analysis of 15 studies
26 confirmed ε4 alleles to be strongly protective against and showed that ε2 homozygote carriers were at a moderately elevated risk of advanced AMD (OR = 1.83,
P = 0.04; the latter being consistent with a recessive genetic model). The role of
ApoE variants in the risk of earlier stage AMD and nonexudative AMD is not well understood. Our finding is consistent with the results from the largest pooled analysis of 15 studies. The increased risk of CNV for subjects with the ε2ε2 genotype (OR = 1.4,;
P = 0.11) in our study supports a recessive model. In addition, we showed that ε4 alleles reduced the risk of AMD of all subtypes and the ε2 allele increased risk in overall AMD in an additive manner. Protein ApoE is a lipid transport protein for low density lipoprotein (LDL). The isoforms of ApoE differ in binding affinity to the LDL-receptor, which affects total cholesterol levels. Variants in the
LIPC, ABCA1, and
CETP genes also have been shown to be associated with AMD and cholesterol levels,
6,19,38 suggesting that variation in genes that modulate retinal cholesterol levels may influence AMD risk. Recently, a number of studies pointed to the involvement of
ApoE in T cell proliferation, macrophage function regulation, and modulation of inflammation.
46,47 The association of
ApoE with AMD also could support the role of immunoregulation and cell signaling in AMD pathogenesis.
48 Moreover, while the ε4 allele is protective against AMD, it is associated with an increased risk of cardiovascular disease (CVD), atherosclerosis, and Alzheimer's disease (AD).
49 Amyloid, a major inflammatory component commonly seen in the plaques of Alzheimer patients, also is observed in drusen.
50 Further investigations are needed to understand the mechanisms by which
ApoE mediates the risks of AMD.