41
Genetics of AMD
10q26 might contain an AMD gene
(7)
. Later this finding
has been replicated by other genome-wide linkage stud-
ies
(26)
and supported by a genome–scan meta-analysis
(5)
.
This locus contains three tightly linked genes: PLEKHA1,
LOC387715/ARMS2 (age related maculopathy sucepti-
bility gene 2) and HTRA1, a secreted heat shock serine
protease. In 2005 Jakobsdottir et al.
(27)
found that the
strongest association was over LOC387715/ARMS2 and
HTRA1, which share an extensive linkage disequilibrium
(LD) block harbouring the high risk haplotype.
There has been more dispute than agreement between the
studies in what concerns this locus. All initial genetic stud-
ies, about ten years ago, lacked statistical power (because
small samples were used), used cumbersome genotyping
technologies and poorly defined cohort. In recent years,
there are some publications of preliminary and uncon-
firmed genetic associations of the genes in this locus to
AMD
(28)
.
3.1 ARMS2 (LOC387715) SNP and AMD
The association of ARMS2 gene and AMD has been now
replicated in various independent studies especially the
advanced form of the disease, that means to say, the “wet”
or with choroidal neovascularization and the “dry” or geo-
graphic atrophy form of the disease
(29-32)
.
The risk confering polymorphism consists in a change in
the 69 position aminoacid alanine (
A
) to serine (
S
).
According to Ross
(31)
, heterozygosis at the ARMS2/
LOC387715 ( A69A/A69S) is associated with odds ratio
(OR) of 1.69-3.0 for advanced AMD while homozygozity
for the risk conferring allele (A69S/A69S) results in a OR
of 2.20-12.1. The frequency of the risk allele is higher in
patients with advanced AMD than in those with early or
intermediate AMD
(27,33)
.
Later two studies, based on semiquantitavive expression
data of allele associated differences in HTRA1 mRNA or
protein levels, suggested a diferent variant (rs11200638)
in the same LD block, in the promoter of HTRA1 gene as
the functional variant
(34,35)
.
3.2 HTRA1 (high temperature required factor A-1)
SNP and AMD
HTRA1 gene is located on chromosome 10q26.3,
extremely close to the locus of the ARMS2 gene
(10q26.13) and because of its role in extracellular matrix
homeostasis (its extracellular protease activity may favour
neovascularization) and in cellular growth or survival (it is
an inhibitor of TGF-ß family member
(36)
and it could play
a critical role in controlling TGF-ß dependent neuronal
survival
(37)
it seems a possible functional candidate gene.
Four significant SNPs have been reported in the promoter
and the first exon of HTRA1: G625A (rs11200638);
T487C (rs2672598); C102T, A34A (rs1049331);
G108T, G36G (rs2293870). However the most well doc-
umented, statistically significant AMD associated SNP is
rs11200638 (G625A) in the promotor region.
Caucasians, Chinese and Japanese heterozygous for
the risk allele (G/A) have a high OR of 1.60-2.61 and
Caucasians, Chinese and Japanese homozygous for the
risk allele (A/A), 6.56-10.0
(34,35,38-40)
.
According to Tam et al.
(40)
, there is an increase in popula-
tion attributable risk (about 5.5 fold increase) by the joint
effect of smoking and HTRA1 allele. This means that
smokers homozygous for the risk allele had a substantially
higher risk of developing wet AMD than non smokers
with the risk allele. However Deangelis et al
(41)
, in 2008
reported no interaction between this SNP and smoking.
In what concerns the studies which relate HRTA1 pro-
moter polymorphisms to risk factors for developing AMD,
three problems arise according to Allikmets and Dean
(28)
.
The variant encoding the A69S (rs10490924) in ARMS2
and the rs11200638 variant in HTRA1 are almost in
complete LD, so it is impossible to assign causality on the
basis of allele frequency alone.
10q26 locus doesn’t harbour a wet AMD gene as the
authors claimed but a late AMD gene as showned by
Weber and colleagues in 2005
(30)
.
All subsequent studies have failed to replicate the func-
tional data
(32,42)
.
This basically means that, as there is strong linkage dis-
equilibrium (LD) across ARMS2-HTRA1 region, genetic
association studies alone are insufficient to distinguish
between the two candidates. It is also necessary not only
the characterization of the extent of the variants associ-
ated to the disease but also the analysis of their possible
functional relevance in the disease process
(42)
. Doing this,
Fritsche et al.
(42)
claimed that the functional variant in
this locus is the deletion-insertion polymorphism vari-
ant 372-815delins54 in the ARMS2 gene. The deletion
removes the polyadenilation signal sequence at position
395-400 exclusively used for the addition of a poly A
tract 19 bp downstream. The insertion introduces a 64
bp AU-rich element, known for its properties to control
mRNA decay in many transcripts that encode a wide
variety of proteins
(43,45)
. They demonstrated that it is a
major risk factor for AMD: individuals carrying a single
copy of the risk allele deletion-insertion in ARMS2 gene
have a 2.8–fold increased risk compared with an 8.1–fold
