Besides senescence and lifestyle, genetic predisposition is recognized to be a risk factor for AMD. Classic genetic studies
6 7 8 and whole-genome scans have led to the identification of chromosomal loci on 1q, 9q, 10q, 16q, and 22q by linkage analysis, but most underlying genes have yet to be characterized.
9 10 11 12 13 14 15 16 17 18 Based on common pathogenic features in AMD, atherosclerosis, and cardiovascular disease, a common biochemical mechanism was proposed for these diseases, and variants in genes involved in inflammation, oxidative stress, and cholesterol metabolism were suggested to be the potential candidates.
19 20 Recent studies have indicated that single-nucleotide polymorphisms (SNPs) in genes regulating innate immunity, such as complement factor-H (
CFH)
21 22 23 24 25 26 toll-like receptor-4 (
TLR4),
27 and
APOE 28 29 30 31 , contribute significant susceptibility to AMD. The Tyr402His (T>C) variant in
CFH, increased the relative risk (RR) of having AMD by four- to fivefold, with an odds ratio (OR) ranging from 2.4 to 4.6 for the carrier C allele and 3.3 to 7.4 for the homozygous CC genotype in several independent studies.
22 23 24 25 It was further demonstrated that an early age at diagnosis and family history of AMD was associated with the high-risk allele.
24 A risk haplotype was also identified at the
CFH locus along with the flanking SNPs.
26 The Asp299Gly SNP in
TLR4 also exhibited a 2.65-fold increased risk of AMD and exhibited an additive risk (OR = 4.13,
P = 0.002) with allelic variants of
APOE and ATP-binding cassette transporter-1 (
ABCA1) involved in cholesterol efflux, suggesting that altered
TLR4 signaling by this variant may influence phagocytic function of RPE, thereby contributing to damage of the RPE.
27 Most of the studies on
APOE gene polymorphism have indicated an elevated risk of AMD with
APOE-ε2 allele and a reduced risk with the
APOE-ε4 allele.
28 29 30 31