40
therefore interfere with normal regulation of the comple-
ment system.
Those individuals, who are homozygous for the CFHR1/
CFHR3 deletions and, therefore do not express the
respective proteins, are highly protected from developing
AMD
(20)
.
2.2 Complement factor B (BF), complement compo-
nent 2 (C2)
Complement factor B (BF) is involved in the activation
of the complement alternative pathway and complement
component 2 (C2) is involved in the activation of the
classical pathway of the complement and both have adja-
cent genes located 500 base pair apart on chromosome
6p21.3 within the major histocompatibility complex
class III region
(21)
. Haplotypes in BF and C2 have been
linked to AMD. In particular, the L9H in BF and the
E318D in C2 and also the R32Q in BF and a variant in
intron 10 of C2 have been showed to be protective for
AMD by Gold et al.
(21)
. They hypothesized that the sig-
nificance of the haplotypes is due largely to the BF vari-
ants, which are in strong linkage disequilibrium with C2.
BF is a complement activating factor and studies have
demonstrated that at least one of the two variants associ-
ated with AMD (R32Q BF) leads to an impairment in
the complement activation function of BF. This means
that the absence of these variants C2/BF can predispose
patients to AMD
(21)
.
Thus, much like impaired CFH-mediated complement
inhibition confers AMD risk, decreased complement
activation by BF might serve to protect against AMD
risk.
2.3 Complement component 3 (C3)
C3 is the central element of the complement cascade and
a candidate gene to be involved in AMD, since its cleav-
age product, C3a, not only was found in drusen but also
was proved to induce vascular endothelial growth factor
expression and promote choroidal neovascularization in
both in vitro and in vivo
(22-24)
. The variants R102G and
P314L of the C3 gene significantly increase the risk of
early and all subtypes of AMD and this risk seems to be
independent of CFH Y402H, LOC387715 A69S and
smoking
(25)
.
In 2003 Majewski et al. suggested that chromosome
that alter CFH function might contribute to the devel-
opment of AMD. Their importance varies among the
race of the population.
In the variant (polymorphism) CFH Y402H of the CFH
gene, there is a substitution on the nucleotide in exon 9
(1277) where thymine
(T)
is changed for cytosine
(C)
(rs1061170) which is the allele risk. This change leads to
the substitution of the aminoacid in the position 402 in
the protein, from tyrosine
(Y)
to histidine
(H)
.
Homozygote CC or heterozygote TC can account for
50% of AMD cases. The risk attributable for a disease is
the rate of disease among individuals with a given char-
acteristic minus the rate of the disease among indivuals
without that characteristic. The population attributable
risk (PAR) in individuals with this polymorphism for
developing AMD is 43% to 50%
(11,12,18)
.
When compared with those with no risk allele TT, one
copy of the Tyr402His polimorphysm (heterozygous for
the risk allele TC), increases the risk of AMD by a factor
of 2.2 to 4.6 (these individuals are at least twice and half
more likely to develop AMD) and two copies of the risk
allele (homozygous for the risk allele CC) increases the
risk by a factor of 3.3 to 7.4 in Whites
(19)
.
In addition to the common risk haplotype carrying the
C allele of CFH Y402H, haplotype analysis of CFH has
revealed two common protective haplotypes: homozy-
gous deletions CFHR1 or CFHR3.
The gene cluster of CFH includes other “CFH-related
genes“: CFHR1, CFHR2, CFHR3, CFHR4 and
CFHR5. This means that the CFH gene resides within
the region of complement activation (RCA), which
includes also five “CFH–related” genes. While the func-
tion of the CFH related genes is largely unknown, the
high degree of sequence similarity between these genes
and the suggestion that they arose out of duplication
events with CFH, suggest an overlapping function of the
CFH-related genes in immune system function and /or
regulation.
There is a common and widespread (commonly found
in many different populations in the world) deletion
within the RCA locus that encompasses the CFHR1
and CFHR3 genes. However the frequency of homo-
zygous CFHR1 or CFHR3 deletion shows considerable
variation between ethnic groups and occurs in 17.3%
of African populations, 15.9% of African-American,
6.8% of Hispanic, 4.7% of Caucasian and 2.2% of
Chinese cohorts
(20)
. This is in agreement with AMD less
frequency among African-Americans compared with
Caucasians and Chinese populations. CFH1 and CFH3
protein may compete with CFH for C3 binding and
3. LOC387715/ARMS2 and HTRA1
