42
increased risk in homozigous individuals. Their work, also
revealed that in homozygous for the deletion-insertion
variant, expression of ARMS2 is absent. They localized the
ARMS2 protein within the photoreceptor layer namely, to
the mitochondria–enriched ellipsoid region of the inner
segments and in accordance; they proposed a functional
role of ARMS2 in mitochondrial homeostasis. According
to Fritsche et al., this suggests, that this polimorphysm is
the sought-after functional variant with relevance in AMD
etiology in 10q26 locus.
However, as Fritsche et al. recognize, it is ultimately
required formal exclusion of functional consequences
for the remaining polymorphisms on the risk haplotype
namely, A69S in ARMS2 gene and HTRA1 promoter
variant. The A69S and the InDel are in 100% LD and on
the same haplotype and so the effects are not independent
to each other
(46)
. The work of Fritsche and colleagues does
not eliminate all other possibilities
(28)
, nobody disputes
the role of complement genes in AMD in spite of the
functional consequences of the disease associated variants
being not known for CFH, CFB/C2 and/or C3.
The ApoE gene, located on chromosome 19q13.2, is poly-
morphic and has three isoforms wich are common, E2, E3
and E4, coded by different alleles: the ancestral E3 and the
SNPs, E2 and E4
(47)
.
Most studies favour a protective role for the ApoE4 SNP
and a slight risk-conferring role for ApoE2
(47-51)
. However
other studies do not
(52-55)
.
5.1 Genotype and response to antioxidative/zinc
therapeutics
One of the first works in this area was that of Michael
Klein et al.
(56)
. These authors correlated the CFH and
LOC387715 A69S genotypes with the therapeutic
responses to supplementation with antioxidants and
zinc. They concluded that, in homozygous individu-
als for the non-risk phenotype (Y402Y/Y402Y), 34% of
those treated with placebo progressed to advanced AMD,
compared to 11% of those treated with antioxidants and
zinc: a reduction of approximately 68%. In homozygous
individuals for the risk allele (Y402H/Y402H), 44% of
those treated with placebo progressed to advanced AMD,
compared with 39% of those treated with antioxidants
plus zinc: a reduction of only 11%. A similar interac-
tion was observed in the groups taking zinc versus those
not taking zinc: intake had a more protective effect in
patients with non-risk alleles compared to patients with
risk alleles. These results suggest that the zinc plus anti-
oxidative treatment seems to have less impact on those
with the high-risk CFH variant. These authors found no
association between LOC387715/ARMS2 A69S and the
response to AREDS treatment.
5.2 Genotype and response to intravitreous
bevacizumab
Brantley et al
(57)
investigated 86 wet AMD patients for
the association between CFH and LOC387715/ARMS2
genotypes and the response to treatment with bevaci-
zumab. For the CFH genotypes results show that only
10.5% of patients homozigous for the risk - conferring
allele Y402H/Y402H genotype demonstrated improved
vision with treatment compared with 53.7% of patients
homozigous for the non-risk allele Y402Y/Y402Y and the
heterozigous for the non-risk allele Y402Y/Y402H vari-
ants. They found that the CFH variants are associated
to the responses to bevacizumab but that LOC387715/
ARMS2 are not.
5.3 Genotype and response to photodynamic therapy
Goverdhan et al
(58)
and Brantley et al
(59)
studied the asso-
ciation of the CFH and LOC387715 genotypes with the
response to PDT. They found no statistical association
with the LOC387715 genotype but a statistical associa-
tion with CFH genotype: risk allele genotypes have better
results than non-risk allele genotypes. However more stud-
ies are warranted before any definitive conclusions.
1. Genetics variants at two chromosomal loci, 1q31 and
10q26, confer major disease risks, together accounting for
more than 50% of AMD pathology
(11-14, 27,30)
.
At present SNPs are the best available markers of AMD
risk: SNPs in complementt factor H and ARMS2/
HTRA1 capture a substancial fraction of AMD risk and
permit the identification of individuals at high risk of
developing AMD. Genetic markers can successefully iden-
tify individuals whose lifetime risk of age-related macular
4. Apolipoprotein E gene (ApoE)
6. Conclusions
5. SNP genotype and therapeutic
responses
