54
common variants in the gene encoding CFH confer
major susceptibility to AMD
(14,15,16,17)
. A year later, at-
risk and protective haplotypes were identified in two
other genes encoding complement proteins, BF and
C2
(18)
.
These markers include:
• Complement factor H (Chromosome 1q32, Entrez
Gene ID 3075) Polymorphisms in the complement fac-
tor H gene (CFH) are associated with a significantly
increased risk for the development of age-related macular
degeneration (AMD). The most documented risk-con-
ferring single-nucleotide polymorphism results in a tyro-
sine-to-histidine substitution at position 402 (Y402H)
of the CFH protein.
• Complement factor B (chromosome 6p21.3, Entrez
Gene ID 629)
• Complement Component 2 (chromosome 6p21.3,
Entrez Gene ID 717)
• PLEKHA1/ARMS2/HtrA1 (chromosome 10q26,
Entrez Gene ID 387715/5654/59338)
• Excision repair cross-complementing rodent repair
deficiency, complementation group 6 (chromosome
10q11.23, Entrez Gene ID 2074)
• VEGF (chromosome 6p12, Entrez Gene ID 7422)
3. Inflammatory biomarkers
Various immunological molecules and inflammatory
mediators have been identified at the site of AMD
lesions
(19)
. Pro inflammatory cytokines are released from
immune cells during an inflammatory response. These
cytokines mediate inflammatory effects. Elevated levels
of AMD biomarkers, e.g., markers of systemic inflam-
mation: C-Reactive Protein (CRP), Interleukin 6 (IL-6),
Tumor Necrosis Factor alpha-Receptor II (TNF
α
-RII),
Intercellular Adhesion Molecule (IcAM), Vascular
Cell Adhesion Molecule (VCAM ); lipid biomarkers:
Apolipoprotein B (ApLP B) or Lipoprotein (a) (Lp-a);
homocysteine (Hc); and fibrinogen (Fbg), are predictive
of development and progression of AMD.
4. C-reactive protein
CRP may be involved in the pathogenesis of AMD
through chronic inflammation leading to oxidative
damage, endothelial dysfunction, drusen development
or the degeneration of Bruch’s membrane
(20)
. CRP may
also have a direct role in AMD development through its
To identify morphological and/or functional early mark-
ers of CNV development in fellow eyes of patients with
exudative AMD in the other eye, our group performed
a single center, prospective, observational, longitudinal
two year study, enrolling patients with neovascular AMD
in one eye (the non-study eye) and early ARM in the fel-
low eye (study eye) at risk for the development of CNV.
It was possible to identify a sequence of alterations at the
chorioretinal interface during the development of CNV
and progression of early ARM to neovascular AMD
using different imaging methods simultaneously and at
regular intervals to characterize markers or predictors of
conversion to CNV. It was also possible to correlate the
evolution of the identified alterations with the develop-
ment of CNV and to demonstrate the reliability and
relative value of different clinical methodologies used to
identify AMD disease progression.
2. Genetic biomarkers
AMD is a complex disease caused by the combination
of genetic predisposition and environmental factors.
The prevalence of AMD increases with age. The adverse
effect of smoking is well established. Genetic predispo-
sition has been demonstrated by familial aggregation
studies and twin studies. Using genome linkage scan
and association studies, multiple potentially causative
genes have been identified. The chromosomes most
commonly implicated are 1q25-31 and 10q26. In par-
ticular, variants in the gene for the complement fac-
tor H (CFH) and the genes PLEKHA1/LOC387715/
HTRA1, Factor B (BF) and complement component
2 (C2) have been implicated as major risk or protec-
tive factors for the development of AMD. There have
been some advances in the treatment of this condition;
however, a complete cure remains remote but hope-
ful. Understanding the causative environmental and
genetic interactions will facilitate the development of
future preventive methods and treatments.
AMD-associated SNPs may eventually serve to iden-
tify at-risk individuals and separate AMD patients into
homogenous groups for preventive and therapeutic
studies. These genetic biomarkers also serve as power-
ful tools in the elucidation of the underlying etiology
of AMD. We limit our discussion predominantly to
those SNPs that are consistently associated with AMD
in multiple case–control studies and, thus, have the
strongest potential to serve as genetic biomarkers. In
early 2005, four groups reported independently that
