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Genetics of AMD
4
Age-related macular degeneration (AMD) is a complex
disease with demographic and environmental risk factors
(age, diet, and smoking) but also genetic risk factors. In
fact, instead of having a single contributory gene, there
are multiple genes of variable effects that seem to be
involved turning the issue of genetics of AMD a complex
one: AMD involves environmental factors and varying
susceptibilities to these external factors based upon dife-
rent genetic backgrounds
(1)
.
The genetic component of the disease has been suspected
from family, twin and sibling studies. According to
several family studies, patients with a family history of
AMD have an increased risk for developing AMD
(2,3)
.
The concordance for the presence of the disease is greater
among homozigous twins than among heterozygous
twins. In 2008, Luo et al.
(4)
estimated the magnitude of
familial risks in a population–based cross-sectional and
case–control study. Recurrence risk in relatives indicate
increased relative risks in siblings (2.95), first cous-
ins (1.29), second cousins (1.13) and parents (5.66) of
affected elements.
Many linkage and association studies have showed that
chromosomes 1q (1q25-31) and 10q (10q26) had genes
involved in this pathology
(5-7)
.
It was the completion of the Human Genoma Project,
5 years ago, resulting in the knowledge of the sequenc-
ing of the human genome that allowed improved DNA
sequencing and mapping technologies and consequently,
identification of Single Nucleotide Polymorphism
(SNPs).
There are several types of genetic sequences variations
(polymorphisms) in the human genome: repeated
polymorphisms, insertions and deletions. However the
majority of the DNA sequence variations in the human
genome is in the form of SNPs which are persistent sin-
gle changes, substitutions or variants of a single base in
at least a population and with a frequency of more than
1% referred as alleles and representing altered forms of
a gene: different alleles may produce variations in inher-
ited characteristics
(8,9)
. These variants are also important
because they serve as genetic markers and in this way they
can help in determining those which confer increased or
decreased risk of several diseases including AMD.
Dissection of the genetic background of AMD has
undergone tremendous progress in the last 2 years. We
know, now, some
polymorphisms which modulate
AMD risk.
2.1 Complement factor H (CFH)
CFH is a negative regulator of alternative pathway of the
complement system which means that in normal con-
ditions, it inhibits the alternative pathway complement
system. It is encoded by a gene localized in 1q23-32 and
its dysfunction may lead to excessive inflammation and
tissue damage
(10)
. Complement activity is very important
for the imune responses against pathogens and dying cells
but, over-activation can result in complement-mediated
damage to nearby healthy tissue cells. It is now accepted
that CFH gene is an important susceptibility gene, har-
bouring variants and haplotypes (short DNA sequences
containing alleles) associated with increased and reduced
risk of AMD. Six CFH gene variants have been reported
in AMD association studies as major genetic factors for
developing AMD in Caucasians
(11-15)
: rs1061170, (CFH
Y402H); rs3753394; rs800292; rs1061147; rs380390;
rs1329428. However in the Chinese and Japanese pop-
ulations only three of these CFH SNPs (rs1329498,
rs800292 and rs3753394) were associated with risk of
AMD
(16,17)
. So it is possible that CFH could play a cen-
tral role in AMD pathogenesis and that multiple SNPs
1. Introduction
2. Complement system factors and AMD
Author:
Elisete Brandão, MD
Hospital S. João, Porto, Portugal
