Update on the role of genetics in AMD
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conclusion that AMD, like many other chronic age-related diseases,
results from the interplay of multiple environmental and genetic
factors, which in combination account for development of the
phenotype. The condition is strongly age-related, and tobacco smoking
is the most consistent and modifiable significant risk factor. Other
environmental risk factors that have been reported include
cardiovascular disease, hypertension, high body mass index, and low
education level.
GENETIC SUSCEPTIBILITY AND AMD
It is now beyond question that genes play a significant etiological
role in AMD. Studies to identify genetic AMD-susceptibility variants
have utilized all available techniques such as genome-wide linkage
approaches (twins, sib pairs, and families) and case-control
association studies. For the most part, studies have been limited to
the study of the phenotypic extremes; that is, advanced cases or those
with no signs of the condition, and case-control populations of
extreme phenotypes. This is because it is reasonably achievable to
ascertain these phenotypes.
Early studies
Early studies concentrated on genome-wide linkage and familial
association analyses (twins, sib pairs, and families). The first
genetic locus for AMD was localized in a single large pedigree to
chromosome 1q. Later, a co-segregating variant in HMCN-1
(hemicentin-1) was identified. HMCN-1 lies in close proximity to the
CFH (complement factor H) gene, discussed below. Meta-analysis of a
number of linkage studies consistently identified this same locus and
several other genomic regions which were later shown to harbor
specific genetic variants. Others remain the subject of further
investigation.
Complement genes
The first well established specific genetic variant to be associated
with advanced AMD was the single nucleotide polymorphism (SNP)
rs1061170 (T1277C; Y402H) in the CFH gene. This finding has been
replicated by numerous studies. Additional analyses of the RCA locus
on chromosome 1q in which the gene resides have concluded that
haplotypes encompassing both CFH and neighboring genes, acting
independently or in concert with the Y402H change, confer increased
risk of drusen formation and advanced AMD. Subsequent analyses of the
complement pathway identified SNPs in other complement components:
complement factors C2, CFB, C3, and CFI. CFH is a regulator of
complement activation, dysfunction of which has been linked to retinal
pathology.
The challenges of 10q26
Early genome-wide linkage studies consistently identified an AMD
susceptibility locus on chromosome 10q26. A combination of genotyping
and direct sequencing of this region initially identified two SNPs, 6
kb apart, in high linkage disequilibrium in many Caucasian
populations, that are strongly associated with advanced AMD, as
follows.
The rs10490924 (A69S) variant lies within the putative gene,
LOC387715, now named ARMS2 (age-related maculopathy susceptibility 2).
ARMS2 has no known function, and the predicted protein shows little
homology with other proteins. ARMS2 is only present in higher
primates, and mRNA transcripts can be detected in the retina. Whether
the protein is translated is still debated. Immunohistochemical
analyses have provided conflicting evidence localizing protein within
the mitochondrion in the inner segment of the photoreceptor; the
cytoplasm, among other locations. Most recently, an indel in ARMS2 has
been reported that appears to affect translation of the protein and
has been postulated to be the functional variant at the 10q26 locus.
The rs11200638 SNP resides in the promoter of the gene, HTRA1, a
serine protease found in the retina (among other tissues).
Preliminary, functional analyses suggest that the polymorphism at this
position alters expression levels of the gene.
The era of genome-wide SNP-association studies (GWAS)
Modern advances in genotyping technology have facilitated the
high-throughput analysis of hundreds of thousands of single-nucleotide
polymorphisms on a single chip. In 2010, a consortium of researchers
published the results of two independent GWASs with subsequent
replication of positive findings. These studies identified several new
genes associated with advanced AMD status. Of interest, this study
implicated genes associated with lipid metabolism, specifically the
HDL pathway, ABCA1, LIPC, CETP, and LPL. Other replicated findings
included significantly associated SNPs near the gene encoding TIMP3
(tissue inhibitor of metalloproteinase 3), which is involved in
remodeling of the extracellular matrix in the retina.
Other genes
Associations in the genes APOE (apolipoprotein E), ABCA4 (ATP-binding
cassette A4), CX3CR1 (chemokine 3 receptor 1), PON1, TLR4 (toll-like
receptor 4), ERCC6, ELOVL4, VLDLR (very low density lipoprotein
receptor), fibulin-5, hemicentin-1, TLR3 (toll-like receptor 3), C1q
(complement factor C1q), VEGF (vascular endothelial growth factor),
SERPING1, and LRP6 have been reported in single populations.
PHARMACOGENETICS IN AMD
Pharmacogenetics attempts to define the genetic variants that
determine variable response to medication. The ultimate goal is to
identify those who respond best and avoid adverse reactions. Garrod
first recognized a familial or genetic tendency to variability in drug
response and hypothesized that drugs were metabolized by specific
pathways of genes in which defects would result in differences in drug
concentrations and therefore drug effect. A large number of studies
have now defined pharmacogenetic interactions in many biomedical
fields. These include therapies for neurological and psychiatric
disorders, asthma, cardiovascular disease, and cancer.
Initial studies in AMD have focused on three different treatments:
Age-Related Eye Disease Study (AREDS) supplementation, photodynamic
therapy (PDT), and anti-VEGF therapy. In all instances, studies to
date have been limited to retrospective analyses.
Anti-VEGF agents
In one retrospective study, 86 patients being treated with bevacizumab
(Avastin™) alone were evaluated for associations between treatment
response and common polymorphisms in the genes CFH and ARMS2. Patients
homozygous for both CFH risk alleles (CC) had worse visual outcomes
than those with the CFH TC and TT genotypes. In a similar
retrospective analysis, but involving 156 patients who were receiving
ranibizumab, the same authors were able to replicate this finding.
These studies were well conducted; however, the associations do not
necessarily imply causality and there may have been additional
confounders.
AREDS supplements
The AREDS was an 11-center National Institutes of Health-funded study
initiated in 1992 with 4757 participants. It included an 8-year
randomized control trial which established that a combination of zinc
and antioxidants (beta-carotene, vitamin C, and vitamin E) produced a
25% reduction in development of advanced AMD and a 19% reduction in
severe vision loss in individuals determined to be at high risk of
developing the advanced forms of the disease. Conversely, 22% of
participants receiving antioxidants and zinc had a 15-letter decrease
in visual acuity despite treatment. Use of these oral supplements is
now current standard of practice in the United States. Indeed, they
remain the only therapy for early, intermediate, and dry AMD.
A recent evaluation of the AREDS cohort found evidence of an
interaction between the CFH genotype and treatment with antioxidants
plus zinc when compared with placebo. This interaction appears to have
arisen because supplementation was associated with a greater reduction
in AMD progression (68%) in those with the low risk TT genotype
compared with those with the high risk CC genotype (11%).
These results may imply that the strong genetic predisposition to AMD
conferred by the CC genotype limits the benefits available from zinc
and antioxidants (beta-carotene, vitamin C, and vitamin E). In this
pharmacogenetics study, the authors evaluated whether known
AMD-susceptibility genotypes in those who at entry into the study had
early to intermediate AMD and progressed to advanced disease were
associated with treatment assignment. Previously, these same genes had
been reported to be independently associated with progression to
advanced AMD. There is good biological plausibility to support a
possible role for CFH. Evidence supports the assertion that CFH
protein dysfunction results in excessive inflammation and tissue
damage of the type involved in the pathogenesis of AMD. Inflammation
is known to intensify oxidative stress, and since AREDS supplements
are thought to have an antioxidant effect, it seems reasonable to
assume that CFH polymorphisms could play a role in treatment response.
PDT
PDT was until recently the most widely used therapy for neovascular
AMD and still retains a role for individuals in whom anti-VEGF agents
are contraindicated. PDT to the macula induces thrombosis of
neovascular vessels (choroidal neovascularization) which have been
photosensitized by the administration of verteporfin. Efficacy was
originally established in a series of randomized control trials
including the TAP (Treatment of Age-Related Macular Degeneration with
Photodynamic Therapy), VIP (Visudyne in Photodynamic Therapy), and
Visudyne in Minimally Classic Choroidal Neovascularization studies.
Considerable variability in response is observed with PDT and may vary
by ethnicity. In an attempt to identify whether genetic influences are
involved, a set of variants in genes associated with thrombosis were
retrospectively evaluated in two studies (84 and 90 subjects).
Patients were divided into those that were PDT “responders” and
those that were “nonresponders” (3-month follow-up). Patients were
genotyped for factor V G1691A, prothrombin G20210A, factor XIII-A
G185T, methylenetetrahydrofolate reductase C677T, methionine synthase
A2756G, and methionine synthase reductase A66G. “Nonresponse” was
more frequent in those with the hyperfibrinolytic G185T gene
polymorphism of factor XIII-A, and response was associated with those
with the thrombophilic factor V 1691A and prothrombin 20210A alleles.
PREDICTING THE RISK OF DEVELOPING ADVANCED AMD
The idea of employing a risk assessment algorithm to identify
individuals at risk of developing AMD is attractive. The fact that
drusen, the hallmark of the condition, appear prior to the development
of vision loss offers an unusually useful clinical feature that might
be combined with genetic and environmental risk factors to give an
accurate risk assessment. Several such models have been proposed.
Seddon et al described a model derived from the AREDS study population
that included all these factors using the AREDS clinical AMD grading
scale. In the model, points are assigned for the risk factors in their
model to determine an individual’s risk score. Zanke et al described
a model that gives a lifetime risk estimate based on genetics and
environmental factors, and recently Chen et al proposed a model that
examined risk of bilateral involvement. There is no conclusive
evidence that genetic variants assist in predicting progression of
disease once advanced AMD is established. One study found no
association of progression of geographic atrophy with variants in the
CFH, C3, and ARMS2 genes. A second study found no association of
progression with variants in CFH, C2, C3, and CFI, but did note a
nominal association with ARMS2.
CONCLUDING REMARKS
AMD is a major health burden and one that is rapidly growing as the
population of the Western world ages, en masse. Although the
introduction of anti-VEGF agents has revolutionized outcomes for those
with the less common neovascular form of AMD, there is limitation to
the effectiveness of these regimens. There is currently neither
effective treatment for geographic atrophy nor for earlier stages of
disease. Dissecting the genetic etiology of the condition holds
substantial promise for the identification of new avenues for
therapeutic development. It is likely that conventional genome-wide
and candidate gene approaches may have reached their limit to resolve
new variants. Genome-wide strategies are not themselves redundant but
will be superseded by next-generation technology such as whole Exmore
and full genome sequencing. Furthermore, the analysis of individuals
with intermediate AMD phenotypes and the use of extended pedigrees
with carefully quantified endophenotypes offer the opportunity to
investigate less common, rarer, and private mutations, otherwise
largely unidentifiable using case-control populations.
Clin Ophthalmol. 2011;5:1127-33
http://www.ncbi.nlm.nih.gov/pubmed/21887094
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