Current knowledge and trends in age-related macular degeneration: Genetics, epidemiology, and prevention

Abstract

To address the most dynamic and current issues concerning human genetics, risk factors, pharmacoeconomics, and prevention regarding age-related macular degeneration.
An online review of the database Pubmed and Ovid was performed, searching for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk factors, VEGF, prevention, genetics and their compound phrases. The search was limited to articles published since 1985 to date. All returned articles were carefully screened and their references were manually reviewed for additional relevant data. The webpage www.clinicaltrials.gov was also accessed in search of relevant research trials.
A total of 366 articles were reviewed, including 64 additional articles extracted from the references and 25 webpages and online databases from different institutions. At the end, only 244 references were included in this review.
Age-related macular degeneration is a complex multifactorial disease that has an uneven manifestation around the world but with one common denominator, it is increasing and spreading. The economic burden that this disease poses in developed nations will increase in the coming years. Effective preventive therapies need to be developed in the near future.

Full text

Review
CURRENT KNOWLEDGE AND TRENDS IN
AGE-RELATED MACULAR DEGENERATION
Genetics, Epidemiology, and Prevention
RAUL VELEZ-MONTOYA, MD,* SCOTT C. N. OLIVER, MD,* JEFFREY L. OLSON, MD,*
STUART L. FINE, MD,* HUGO QUIROZ-MERCADO, MD,†NARESH MANDAVA, MD*
Purpose: To address the most dynamic and current issues concerning human
genetics, risk factors, pharmacoeconomics, and prevention regarding age-related
macular degeneration.
Methods: An online review of the database Pubmed and Ovid was performed, searching
for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk
factors, VEGF, prevention, genetics and their compound phrases. The search was
limited to articles published since 1985 to date. All returned articles were carefully
screened and their references were manually reviewed for additional relevant data. The
webpage www.clinicaltrials.gov was also accessed in search of relevant research trials.
Results: A total of 366 articles were reviewed, including 64 additional articles extracted
from the references and 25 webpages and online databases from different institutions.
At the end, only 244 references were included in this review.
Conclusion: Age-related macular degeneration is a complex multifactorial disease that
has an uneven manifestation around the world but with one common denominator, it is
increasing and spreading. The economic burden that this disease poses in developed
nations will increase in the coming years. Effective preventive therapies need to be
developed in the near future.
RETINA 34:423–441, 2014
Age-related macular degeneration (AMD) is a com-
plex disease and remains very difficult to define.
First described by Holloway & Verhoeff in 1929, the
disease has remained a clinical and therapeutic challenge
for the western medicine and has become an important
public health problem.
1–3
As the global population ages,
more and more resources are being designated to uncover
and understand the fine molecular mechanisms related
to the disease and the role of human genetics and
environmental risk factors. In addition, new therapeutics
options throughout the course of the disease are evolving
rapidly.
4
The office visit of patients with AMD has evolved
from a scenario in which “there is nothing more to
offer you”with the almost certain chance of severe visual
loss in 2 years or immediately after treatment, to the
current office visit which includes a comprehensive
review of the patient’s lifestyle, genetic heritage, insur-
ance coverage, patient ability to return frequently for
treatment or ancillary tests, choosing between admin-
istering a Food and Drug Administration-approved or
From the *Department of Ophthalmology, University of Colorado
School of Medicine, Rocky Mountain Lions Eye Institute, Anschutz
Medical Campus, Aurora, Colorado; and †Department of Ophthal-
mology, Denver Health Medical Center, University of Colorado
School of Medicine, Denver, Colorado.
Supported by Genetech, Ophthotech, and Thrombogenics
(S.C.N.O., J.L.O., and N.M.) and the National Eye Institute, NIH
(S.L.F.).
R. Velez-Montoya and H. Quiroz-Mercado have no financial/
conflicting interests to disclose.
Reprint requests: Raul Velez-Montoya, MD, Department of
Ophthalmology, University of Colorado School of Medicine, Rocky
Mountain Lions Eye Institute, Anschutz Medical Campus, 1675
Aurora Court, Aurora, CO 80045; e-mail: raul.velez-montoya@
ucdenver.edu
423

an off-label drug, and possible clinical trial enrollment.
Fortunately, these issues are background to interventions
that confer up to a 94% chance of stabilizing or increas-
ing vision till 2 years after treatment.
5,6
The amount of information that comes to the surface
every year regarding this topic is overwhelming, and it
is a daunting task trying to track every detail. A com-
prehensive consideration of the pathogenesis, diagnostic
methods, clinical presentation, and treatment is beyond
the scope of this article. Instead, we will focus our
efforts in reviewing important pending aspects from a
previous review.
7
Therefore in the following text, we
will summarize the latest randomized clinical trials,
reviews and meta-analyses that address specific aspects
of the disease including epidemiology, pharmacoeco-
nomics, risk factors, the role of human genetics, and
disease prevention. This will help the reader to rethink
about the role of AMD in the global perspective and
correctly position the impact it will have in the twenty-
first century global economy.
General Concepts About Age-related
Macular Degeneration
Age-related macular degeneration is the leading
cause of irreversible vision loss in people aged 50
and older in the developed world.
4,8,9
The international
consensus classifies the disease in two well-defined
clinical forms: the “wet”form is the least prevalent
but perhaps the most studied of the two.
10,11
Although
it is responsible of 90% of the cases of acute vision
loss associated with AMD, it accounts only for 20% of
the reported cases of AMD.
12–15
The hallmark of wet
AMD is the development of choroidal neovascularization
(CNV) along with the leakage of fluid, retina pigment
epithelium (RPE) detachment, hemorrhage, exudation,
scarring, and severe visual loss if not treated
promptly.
6,16–20
The “dry”form is characterized by a
slow and progressive degeneration of the RPE leading
to the death of photoreceptor cells in the same area.
The most severe manifestation of dry AMD is geographic
atrophy (GA).
6,17,19–21
Despite its slow progression,
the combination of an ever growing population, the rate
of aging and its high prevalence (80% of the cases of
AMD), has made dry AMD currently responsible for
21% of all cases of legal blindness in North America.
17
Whatever the clinical presentation, one of the
earliest signs of AMD is the formation of subretinal
or sub-RPE deposits called drusen.
19,22–24
Postmortem
studies in eyes with AMD revealed a mixed composi-
tion featuring the various types of cellular debris (from
degenerated RPE), lipids, proteins from the immune
system, and markers of complement activation, sug-
gesting that drusenlike atherosclerosis and other
aging phenomena have a significant inflammatory
component which includes a dysregulation of the
complement pathways.
23–26
The interplay between
the aging of the RPE and Bruch membrane and
the formation of drusen is not completely clear.
The coalescence of these deposits to form large soft
drusen seems to predispose to late-stage AMD;
however, despite the fact that laser photocoagulation
seems to promote their disappearances, this does not
translate to reduce the risk in developing late-stage
disease or vision loss.
27
Thus it remains unclear
whether drusen lead to AMD or are just symptoms
of an underlying pathology.
12,27,28
The neovascular component of wet AMD has been
the focus of rigorous research that has helped us to
understand a small part of the complex process of
angiogenesis in a wide range of diseases.
29
Those studies
have led to the identification of various molecules that
serve as proangiogenic factors including vascular
endothelial growth factor (VEGF), basic fibroblast
growth factor, placentallike growth factor (PLGF),
transforming growth factor-b, platelet-derived growth
factor, interleukin-8, nitric oxide synthetase, angiopoietin,
pleiotrophin among others.
29–33
Vascular endothelial
growth factor is a dimeric glycoprotein that belongs to
the superfamily of platelet-derived growth factors.
29,33,34
There are five members of this family identified so
far (A, B, C, D, and placentallike growth factor).
The VEGF-A is most relevant for intraocular angio-
genesis.
34–37
It has at least 6 isoforms (121, 121b,
145, 165, 189, and 206) with the isoform 165 being
the most abundant in eyes with wet AMD.
29,34–36
There are three identified receptors for VEGF-A:
VEGFR-1 (fetal liver tyrosine kinase-1 or FLT1),
VEGFR-2 (Kinase insert domain receptor or FLK1),
and VEGFR-3.
34,38
The VEGFR-2 has higher affinity
for VEGF among the three and is the receptor implicated
in the potentiation of angiogenesis.
38,39
The function of
the other two receptors is not entirely clear but it seems
to be related to the recruitment of monocytes and lym-
phangiogenesis.
34,39
The activation of endothelial cells by
VEGF and other proangiogenic factors causes the release
of proteases that degrade the basement membrane. The
endothelial cell, now an active cell, starts to proliferate
and migrate toward the angiogenic stimulus using integ-
rins to mediate cell adhesion and form new vessels.
40–42
Angiogenesis is also understood as an imbalance
between proangiogenic and angiogenic inhibitory
factors.
29,43
Whenever the production of those
inhibitors is impaired, the delicate balance can favor
angiogenesis. Angiogenesis inhibitors identified thus
far include endostatin, various heparinases, interferon
(-a, -b, -g), angiostatin, thrombospondin, pigment
epithelium-derived factor, and others.
29,31,43
424 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 3

Although the classification of the disease into dry
and wet forms has provided a simple nomenclature to
describe its clinical characteristics, this classification
does not correlate with the risk of visual loss nor does
it serve in a particular way to assess the risk of AMD
progression according to the presence or absence of
certain risk factors.
12,44
Therefore the amount of infor-
mation that we can draw from this particular classifi-
cation is limited. Perhaps a more useful classification
in this regard is the one proposed by the Age-Related
Eye Disease Study (AREDS), a trial sponsored by the
National Institutes of Health.
12,44,45
Originally, this
system consisted of a nine-level classification, which
like the original Early Treatment Diabetic Retinopathy
Study (ETDRS) classification was a bit impractical to
implement in a busy retinal practice.
46,47
However, a
simplified version may be applied easily to clinical
practice. This consists of 3 levels of severity: “Early
AMD”is defined by the presence of a few (.5 and
,20) medium-sized drusen (63–124 mm) or retinal
pigmentary abnormalities
47
;“Intermediate AMD”is
characterized by at least 1 large drusen ($125 mm),
various medium-sized drusen, or GA that does not
extend to the center of the macula
48
;“Advanced (late)
AMD”can be either nonneovascular (dry) or neovascular
(wet) and is characterized by the presence of GA and
drusen extending to the center of the macula or by CNV
and its sequelae.
19,48
In the early stages, the risk of visual loss at 5 years
is usually low and the disease may be asymptomatic.
However, some symptoms may occur including blurred
vision, scotomas, decreased contrast sensitivity, and
abnormal dark adaptation.
15,49
The identification of the
intermediate stage is critical, not just because the risk of
progression to late-stage ranges between 12% and 50%
in 5 years (if the fellow eye also has the late stage of
AMD), but also because it is the stage that most benefits
from lifestyle modifications (e.g., smoking cessation)
and antioxidant therapy (see below risk factors and
genetics).
12,48,50
Patients suffering from the advanced
nonneovascular stage develop a gradual and insidious
visual loss with central or pericentral scotomata which
typically develop over the course of months or
years.
15,49
Conversely, patients with the neovascular
form develop a sudden and profound visual loss within
days or weeks as a result of hemorrhage or fluid accu-
mulation secondary to CNV.
15,51
Global Perspective and Economics of Age-related
Macular Degeneration
Currently, there are 6.9 billion human beings in
the world. However, according to the patterns of
demographic explosion, this figure is expected to grow
to around 9.5 billion by 2050, more or less a 1.4-fold
increase in 40 years.
52–54
Interestingly, the segment of
the population aged 60 and older will experience an
unparallel demographic growth, particularly among
high-income economies. For example, in 2000, there
were around 606 million people over 60 years in the
world, but it is estimated that this number will rise to
up to 2.4 billion by 2050, a nearly 4-fold increase.
52–55
As age is the strongest predictive factor for AMD, we
can expect a sharp rise in the cases of late AMD in the
next 40 years. This may represent an increase from
23.47 million cases in 2010 to up to 80.44 million
by 2050.
52
In 2009, the United States Census Bureau
projected that the older population aged 65 or older
will expand considerably between 2010 and 2050,
reaching 88.5 million by 2050 (more than double that
projected for 2010).
56
The same source projected that
the oldest population (meaning the population aged
85 years or older) will increase from 5.1 million in
2010 to 19 million by 2050.
56
In Europe, it is projected
that 3 of every 10 people will be over age 65 by
the same date.
57
According to the definition of visual
impairment, low vision and blindness given by the
International Statistical Classification of Disease Inju-
ries and Causes of Death (10th revision, ICD-10) and
data from the World Health Organization
58,59
;AMDis
currently considered the third leading cause of blindness
worldwide (only behind cataract and glaucoma) and it
accounts for 8.7% of blind persons globally.
59,60
Even though the numbers will reach epidemic
proportions; AMD will not manifest equally in all
regions of the world. The more developed economies,
with a longer life span, will suffer a heavier economic
burden.
52,61
There might be also a difference in
prevalence among races. For example, an analysis
of the participants in the Multi-Ethnic Study of
Atherosclerosis (MESA, the US population) showed
a prevalence of AMD in persons aged 45 years to
85 years to be 2.4% in African Americans, 4.2% in
Hispanics, and 4.6% in Chinese-decent individuals.
62
Although there are some confounders like different
lifestyle, dietary, and socioeconomic environment that
need to be considered, incidence of AMD among these
ethnic groups was generally lower (though not
statistically significant) than in the white, which
had prevalence of 5.4%.
62
Although, the National
Health and Nutrition Examination Survey III
(NHANES III) did not find any significant differences
between the nonHispanic white and nonHispanic black
(odds ratio [OR], 0.34; 95% confidence interval [CI],
0.10–1.18) and Mexican Americans (OR, 0.25; 95% CI,
0.07–0.90).
63
In the Los Angeles Latino Eye Study
(LALES), a study sponsored by the National Eye
Institute and the National Institutes of Health,
UPDATE IN AMD: GENETICS, EPIDEMIOLOGY, AND PREVENTION VELEZ-MONTOYA ET AL 425

individuals of Native American ancestry were nearly
15 times more likely to have GA (95% CI, 1.8–12.6)
than Latinos.
64
Although the prevalence of AMD is relatively higher
in western populations (the white), it is increasingly
becoming a public health issue among Asian countries
because of the rapidly changing demographics and
westernization of the diet and lifestyle.
60,65,66
In India,
the prevalence of AMD ranged between 1.4% and 1.8%
in different epidemiologic studies.
67
The INDEYE study
reported an increased prevalence of advanced AMD
among patients aged 70 years or older (4.6%).
66
It is
estimated that by 2050, 244 million people (14.9% of
the population in India) will reach 65 years or more,
which means that the incidence of age-related diseases
will likely increase in the future.
67
Similar observations
have been made in the Malayan population in
Singapore.
68,69
In China, a study reported a prevalence
of 4.7% for early AMD among patients aged 50 years
or older in a rural environment and 0.2% for advanced
AMD with a significant higher risk of early AMD in
male smokers.
70
In Australia, the Blue Mountain Eye Study (BMES)
demonstrated that over 23,000 older Australians have
severely impaired vision because of AMD-related
complications (best-corrected visual acuity of
6/60 or worse [20/200]), and .90,000 have some
degree of bilateral visual impairment because of
AMD (best-corrected visual acuity of 6/12 to 6/60
or worse [20/40to20/200]).
71,72
In Canada, there
are currently 4 million people affected to some
degree with AMD.
73
The National Coalition on
Vision Health in Canada estimated a 111% increase
in the incidence of AMD by 2030. It has also
pointed out that visual impairment can lead to several
other problems including an increased fall risk in the
elderly population, increased dependence on care givers,
and decreased quality of life.
73,74
In the United States, 11.5% of the population is
affected to some degree with AMD.
8,75
The estimated
overall prevalence of any form of AMD is 9%
among Americans 40 years or older (8.5 million
affected people).
15,76
The prevalence of late-stage
AMD in Americans aged 40 or older is 1.5%, however
it increases up to 7.1% in people aged 75 or older and
it is estimated to double by 2020.
15
Epidemiologic
studies of Europeans and Japanese subjects have
shown similar prevalence rates.
15,77,78
Calculation of the annual cost that AMD represents
for the global economy is a difficult task. It is important
to note that traditional cost-effectiveness studies typi-
cally measure only the cost and health effects associated
with a particular aspect and do not generally include the
overall cost of probable systemic adverse effects and
sequelae.
61
This is of particular relevance because the
current standard of care for advanced neovascular AMD
includes three drugs whose systemic adverse effects (in
the short-term and long-term) may not be fully known.
The fact that most of the published studies that address
the subject do not seem to explicitly use sensitivity
analysis for ascertaining that assumptions and biases
were adequately addressed, plus the fact that up to
70% of the studies are lacking details regarding the
component of the economic model used makes it diffi-
cult to base a clinical decision on purely economic data
and therefore they should be taken with caution.
61
In 2009, in Australia, socioeconomic data indicated
that the annual total cost of the disease (treatment and
related disabilities) reached A$2.6 billion.
79,80
As the
trend of increased life expectancy continues over the
next 20 years, it is expected to reach A$6.5 billion per
annum by 2025.
80
In the United Kingdom in 2000,
a country with a similar prevalence of AMD, the cost
of support services (namely visual aids and rehabilitation,
social security benefits, tax allowance and community,
and residential care) for patients with AMD had been
estimated at £6,455 ($10,350) during the first year of
diagnosis of blindness and £6,295 ($10,092) for each
year thereafter.
61,81
In 2004, the direct medical cost of
AMD treatment in the United States was estimated at
$575 million excluding related expenses like nursing
homes, care takers, home health care costs, and produc-
tivity losses.
82
The figure is expected to continue to rise
as the population ages and as the expenses of therapies
for neovascular AMD increase.
55,82
Recent data released
by the Comparison of Age-Related Macular Degeneration
Treatments Trials (CATT) research group has sparked
controversy about the economic implications for the
United States government opting for a cheaper drug
(Avastin [bevacizumab; Genentech, San Francisco,
CA]), instead of a drug several times more expensive
(Lucentis [ranibizumab; Novartis, Basel, Switzerland])
($595 vs. $23,400 per year of treatment).
83
In the
United Kingdom, it has been calculated that with
25,000 new cases of neovascular AMD annually,
the cost of treating these patients with ranibizumab
would amount to £300 million ($481.78 million). How-
ever, if bevacizumab is used instead, then the cost
would be £8 million ($12.85 million). This represents
a considerable annual savings to the National Health
Service of the United Kingdom.
52,84
The randomized
controlled trial of alternative treatments to inhibit VEGF
in age-related choroidal neovascularisation (IVAN) is an
ongoing study in the United Kingdom aimed to com-
pare head-to-head both drugs (Lucentis vs. Avastin).
The study is designed in a similar fashion to the CATT
study and will probably add more evidence about the
strong economic implications of selecting one or another
426 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 3

treatment.
85
Because of a wide variety of important
details that need to be addressed when referring to
the last two clinical trials regarding treatment outcomes,
treatment modalities, regimens, and the important impli-
cations that they might have in the long-term, a more
detailed description and a point-by-point discussion of
2 years of results from CATT and 1 year of result from
IVA is done with a great detail elsewhere.
7
Risk Factors for Age-related
Macular Degeneration
With the introduction of anti-VEGF drugs, the treat-
ment of advanced neovascular AMD changed drasti-
cally. This was a game-changing therapy that redefined
completely the treatment and prognosis for wet AMD.
The evidence that timely treatment given at the onset of
CNV secondary to AMD will lead to better visual
outcomes pushed for an early identification of persons
at the highest risk of progression to the late stages.
86,87
A number of risk factors for progression have been
identified in several studies including genetic, demo-
graphic, nutritional, lifestyle, medical, environmental,
and ocular factors.
14,19
Nevertheless, their respective as-
sociation with AMD, measured as OR, on these studies
were very often small and underpowered. A meta-analysis
by Chakravarthy et al analyzed 18 prospective cross-
sectional studies and 8 case–control studies, which
included 94,058 patients (261–22,071) of whom
3,178 had late AMD stages (8–776). From 73 possible
risk factors, they identified 16 that can be screened in
a nonspecialist setting. Table 1 summarizes the most
relevant findings.
14
In their meta-analysis, only age,
current smoking status, cataract surgery, and family
history of late AMD were strongly and consistently
associated with the advanced AMD stages. It is impor-
tant to note that the AREDS 1 study, after analyzing the
results from 4,577 patients (8,050 eyes) on their Report
25, the authors were not able to conclude any clear
association between cataract extraction and the risk of
progression to advanced AMD.
88
Other risk factors
with a positive association but with lower strength
(OR estimates 1.5 or less) were increased body mass
index, hypertension, history of cardiovascular disease,
and increased levels of plasma fibrinogen.
14
Although
vascular diseases (e.g., myocardial infarction, stroke,
and angina) OR findings across different studies are
inconsistent, the pooled estimates for case–control
studies were statistical significant (OR, 2.20; 95%
CI, 1.49–3.26). The same is true for hypertensive
status (OR, 1.48; 95% CI, 1.22–1.75). The association
between diabetes and advanced AMD was less consistent
with prospective studies reporting a significant associa-
tion while cross-sectional and case–control studies did
not.
14
Additional environmental factors that may influence
AMD pathogenesis but have not been proven conclu-
sively are sunlight exposure, alcohol use, and infection
(particularly Chlamydia pneumoniae).
89–92
Smoking is by far the strongest environmental risk
factor associated with AMD progression.
93
Its associ-
ation with the genetic variants of the complement fac-
tor H (CFH) poses a higher risk than the one by
the genetic alteration alone (see genetic section).
94,95
A dose effect of the enhanced risk of AMD with
Table 1. Risk Factors for Advanced Stages of AMD
Strong and consistent association with risk of progression to advanced AMD (OR 1.5 or higher)
Age (.60 years or older)
Smoking status
Previous cataract surgery
Positive family history of advanced AMD
Lower strength association with risk of progression to advanced AMD (OR between 1.1 and 1.5)
Increased body mass index
Hypertensive status
Positive history of cardiovascular diseases
Increased plasma levels of fibrinogen
Diabetic status
No association or not conclusive
Gender (female: OR, 1.0–1.06; 95% CI, 0.78–1.44)
Positive history of cerebrovascular diseases
Serum triglycerides
Serum C-reactive protein
Protective factor
Darker iris pigmentation (brown vs. blue eyes)
Based on the published data by Chakravarthy et al.
14
The AREDS 1 Study did not find any clear association between cataract surgery
and the risk of progression of AMD (Neovascular AMD: right eye 1.2 [95% CI, 0.64–1.18], left eye 1.07 [95% CI, 0.72–1.58]; GA: right eye
0.80 [95% CI, 0.61–1.06], left eye 0.86 [95% CI, 0.63–1.19]).
UPDATE IN AMD: GENETICS, EPIDEMIOLOGY, AND PREVENTION VELEZ-MONTOYA ET AL 427

increasing number of cigarettes smoked (pack per
year) has also been reported.
96,97
The mechanism by
which smoking damages the retina is unknown, how-
ever, it has been linked to increased oxidative stress,
platelet aggregation, higher fibrinogen level, and
reduced plasma high-density lipoproteins and antioxi-
dant levels (ascorbic acid and protein sulfhydryl
groups).
98–102
Cigarette smoke is comprised of gas
and tar phases. Each phase contains free radicals in-
cluding reactive oxygen species, epoxides, peroxides,
nitric oxide, nitrogen dioxide, peroxynitrite, and per-
oxynitrates among others.
103
It is said that each puff of
a cigarette contains an average of 1,015 free radicals,
capable of causing the oxidation of DNA, lipids, and
proteins.
100,103,104
In the AREDS Report 19, the OR
for developing advanced AMD with 10 pack-years or
higher was 1.55.
96
The result of the US Twin Study
(USTS) showed that the current smokers had a 1.9-fold
increased risk for having late AMD.
105
Smoking also
increases the risk for GA (OR, 2.83).
97,100
Although
smoking cessation reduces the risk for progression of
AMD, exsmokers still have a higher risk for advanced
AMD than nonsmoker control subjects (CNV: OR,
1.82; GA: OR, 2.80).
97,100
And last but not the least,
if smokers take antioxidant supplements containing
beta-carotene, the risk of lung cancer is potentially
increased.
106,107
Aging is the single strongest risk factor for AMD.
19,108
Data from different population-based studies show a clear
association between the increasing age and late forms
of AMD. The LALES study reported an OR of 0.3 (CI,
0.0–0.6) among a Latin population aged 60 years or
more. However, the risk increases to 8.5 (CI, 3.5–13.5)
among participants aged 80 years or more. Similar
results are observed in the BMES where the OR for
late AMD rises from 0.5 (CI, 0.1–0.8) among people
aged 60 years or older to up to 12.0 (CI, 8.7–15.4) in
people of 80 years or older. The Beaver Dam Eye
Study (BDES), a study also sponsored by the NEI,
reported an OR of 0.8 (CI, 0.3–1.3) in 60-year-old
whites, which increased to 9.5 (CI, 6.2–12.8) among
participants aged 80 or more.
14,68,109–111
Age-related Macular Degeneration Prevention
The socioeconomic benefits of primary and secondary
prevention of AMD are enormous.
55
Because the
predominant hypothesis about AMD pathophysiology
involves a complex interaction between many path-
ologic events, measures targeting a single risk factor
may not prevent the progression of the disease.
Therefore, strong efforts have been aimed to try
to detect multiple possible targets to decrease the
progression of the disease.
Because of the fact that oxidative damage from
different sources (light exposure, inflammation, local
production of reactive oxygen species) to the retina
has been strongly implicated with AMD, the use of
antioxidant nutrients is thought to be protective.
74
The
AREDS study has provided strong evidence on this
regard. The study demonstrated that daily dose of
b-carotene (15 mg), vitamin C (500 mg), vitamin E
(400 IU), zinc oxide (80 mg), and cupric oxide (2 mg)
may help slow the progression of late AMD by 25% in
all comers, with a 19% reduction in severe vision loss
in individuals with high-risk characteristics.
12
It has
been reported that the projected increase of visual
impairment and blindness from AMD by 2050 may
be reduced by 17.6% if vitamin prophylaxis is given
in addition to the standard treatment for neovascular
AMD (anti-VEGF drugs) when compared with the
standard treatment for neovascular AMD alone.
112
With an approximate cost of $200 per annum, anti-
oxidant supplementation seems to be a cost-effective
method of prevention disability.
112
However, there are
special issues to consider before giving supplements.
First the AREDS formula is a type of active treatment
with a dosage of ingredients far higher than the dietary
reference intake, which is a system of nutrition recom-
mendations from the Institute of Medicine of the US
National Academy of Sciences. Attaining antioxidant
doses from AREDS through diet alone would be
extremely difficult.
75
Second, the intake of the AREDS
nutrients carries secondary risk including kidney stones
formation from vitamin C; Fatigue, muscle weakness,
decreased thyroid function, increased hemorrhagic stroke
risk from vitamin E; increased lung cancer risk in smok-
ers, yellow discoloration of the skin from B-carotene;
anemia, decreased serum high-density lipoprotein choles-
terol, and stomach upset from zinc intake.
113,114
Finally,
the benefits of the AREDS supplementation were
observed only among participants with the higher natural
risk of progression (AREDS Categories 3 and 4). In the
United States, 80% of the people over age 70 fall into
Categories 1 and 2 making it less likely that most people
benefit from the formula.
12
Currently, the AREDS 2 (NCT00345176) is a multi-
center randomized trial intended to assess the effective-
ness of decreasing the original pharmacologic dose of
zinc to a level closer to the dietary intake (25 mg). The
study will also assess the role of oral supplementation
with high doses of lutein, zeaxanthin, omega-3 fatty
acids, and the omission of b-carotene from the original
AREDS formula.
115,116
The ongoing study has finished
the enrollment phase (4,203 participants) and the study
group is preparing to report their first preliminary report
somewhere during this year. One important difference
with the original AREDS (beside the supplementation
428 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 3

formulas) is that the AREDS 2 is aimed to assess the
effectiveness among patients with high risk for devel-
oping advance AMD. Therefore the population demo-
graphics is remarkably different since they tend to be
older (media age, 74 years) and possibly with more
potential to confounders (statin drugs intake, aspirin,
cardiovascular diseases).
116
Other studies have evaluated the role of antioxidant
supplementation in the prevention of AMD. Parisi
et al
117
evaluated the influence of short-term carote-
noids and antioxidants on retinal function on nonad-
vanced AMD. In this randomized control trial, patients
in the study group were supplemented with vitamin C
(180 mg), vitamin E (30 mg), zinc (22.5 mg), copper
(1 mg), lutein (10 mg), zeaxanthin (1 mg), and astax-
anthin (4 mg) daily for 1 year. At the end of the study,
the authors concluded that the function of the central
retina in patients with nonadvanced AMD could be
improved by supplementation with carotenoids and
antioxidants.
117
The Physicians Health Study II, a dou-
ble-masked placebo-controlled trial, randomized
14,642 subjects into 16 possible combinations of vitamin
C (500 mg), vitamin E (400 IU), and b-carotene
(50 mg).
118
The aim was to assess the role of primary
prevention with antioxidants in the incidence of
cardiovascular disease, cancer, cataract, and AMD.
After a follow-up time of 8 years (11,545 subjects),
the study concluded that antioxidants had no notable
beneficial or harmful effect on the risk of cataract.
The analysis regarding AMD is still in progress.
118
The Rotterdam study investigated also the effect that
a vitamin-rich and mineral-rich diet has on the inci-
dence of AMD. Although an active intervention was
not done during the study, they still found a striking
35% decrease in the incidence of AMD. They con-
cluded that a vitamin-rich and mineral-rich diet should
be recommended to those with the early signs of AMD
and strong family history.
119,120
Lutein and zeaxanthin. Macula pigment is composed
primarily of the xanthophylls lutein and zeaxanthin,
members of the carotenoid family.
55
Their antioxidant
properties and their ability to filter short-wavelength
light makes them a logical candidate for AMD preven-
tion because they may help to protect the outer retina
and the retinal pigment epithelium from oxidative stress
and aid in cell membrane stability.
117,121
Nevertheless,
the benefits of dietary supplementation have been
inconsistent in many studies. In 2006, the Carotenoids
in Age-Related Eye Disease Study (CAREDS) in-
vestigated the protective factor of a diet rich in
lutein/zeaxanthin in women for AMD.
122
They found
that the prevalence of intermediate AMD was not sta-
tistically different between the high and low intake
groups. However, when the analysis was limited to pre-
viously healthy women younger than 75 years with
a stable intake of lutein/zeaxanthin, they found substan-
tially lower ORs (0.57; 95% CI, 0.34–0.95) for inter-
mediate forms of AMD.
122
The Cohort Pathologies
Oculaires Liées à l’Age (POLA) was a prospective
study concluded in 1997.
91,123
The study was aimed
to determine the effects of plasma carotenoids in the
incidence of cataract and AMD. This study analyzed
899 subjects for plasma levels of lutein, zeaxanthin,
39-dehydrolutein, tocopherols, total cholesterol, and tri-
glycerides. They concluded that there was a reduction
in the risk of AMD in those with the highest quintile of
plasma carotenes, especially for plasma zeaxanthin
(OR, 0.07; 95% CI, 0.01–0.58).
123
Conversely, a pro-
spective study by Cho et al,
124
in which 71,494 women
and 41,546 men aged 50 years or more were followed
for 18 years, the lutein/zeaxanthin intake was not asso-
ciated with the risk of self-reported AMD, although
there was a statistically nonsignificant and nonlinear
inverse association between carotenoid intake and
advanced neovascular AMD. As we previously men-
tioned, the AREDS 2 study is designed to evaluate
the effects of nutrient supplements on the progression
of AMD and age-related cataracts.
115,116
One of the
primary objectives of the study is to evaluate the effect
of dietary xanthophylls supplements with and without
omega-3 fatty acids. Since 2006, participants are being
randomized to take 1 of the following formulas: pla-
cebo, lutein plus zeaxanthin (10 mg/2 mg), docosahex-
aenoic acid (DHA) plus eicosapentaenoic acid (EPA)
(350 mg/650 mg), or lutein plus zeaxanthin (10 mg/2
mg) plus DHA plus EPA (350 mg/650 mg). Results
will be available by the end of this year.
115,116
Omega-3 fatty acids. These include the a-linolenic
acid (short-chain), DHA, and EPA. These essential
fatty acids must come from dietary intake because
they cannot be synthesized by the human body.
55,125
a-Linolenic acid and EPA are the biologic precursors
of DHA.
125,126
Docosahexaenoic acid is found in great
concentration in the retina, especially in the outer seg-
ment disk of photoreceptor.
127,128
Studies have shown
that DHA has a protagonic role in influencing the cell
membranes’biophysical properties, as a regulator of
the visual cycle, controller of transmembrane trans-
port system, and precursor of other biologically
active molecules (resolvins and protectins).
127,129,130
Eicosapentaenoic acid regulates lipoprotein metabolism
and suppresses the expression of various compounds of
the inflammatory response.
131
There are also several
studies indicating that long-chain omega-3 fatty acids
may protect against oxidative stress which, in addition
to their antiinflammatory and physiologic roles, makes
them promising candidates for AMD prevention.
127,132
UPDATE IN AMD: GENETICS, EPIDEMIOLOGY, AND PREVENTION VELEZ-MONTOYA ET AL 429

In the BMES, one serving of fish per week was
associated with a reduced 10-year risk of early AMD
(RR, 0.69; 95% CI, 0.49–0.98).
133
In the AREDS,
participants with a higher intake of omega-3 fatty acids
were approximately half as likely to have advanced
neovascular AMD at baseline (OR, 0.61; 95% CI,
0.41–0.90) or to progress form intermediate to advanced
nonneovascular AMD (GA) after 6 years of follow-up
(OR, 0.42; 95% CI, 0.23–0.87).
134
Furthermore, a meta-
analysis by Chong et al
131
with a pooled data from
88,974 people from 3 prospective cohorts, 3 case–
control, and 3 cross-sectional studies (no randomized
controlled trials were included), which included
3,203 cases of AMD, compared the highest and low-
est omega-3 fatty acid intake groups and noted a 38%
reduction of the likelihood of late AMD. Fish intake
of twice or more per week compared with an intake of
less than once per month was also associated with
a 37% reduction in the risk of early AMD. Fish intake
was also associated with a protective effect for
advanced AMD development (OR, 0.67; 95% CI,
0.53–0.85).
131
The USTS of AMD found that fish
consumption and omega-3 fatty acid intake reduced
the risk of AMD by an estimated 22%. However, the
study was not randomized and hence its impact is
limited.
105
Although fish oils are a good source of omega-3
fatty acids, there are several considerations to weigh
before recommending it to our patients. First, an
antithrombotic effect has been described with fish oil
intake. Even though concomitant administration of fish
oil with warfarin or heparin has shown no additional
risk for bleeding, its administration to patients with high
hemorrhagic risk should be done with caution.
135–137
And second, the risk of fish contamination with
environmental contaminants such as mercury should
be reviewed with the patient, especially if she is
pregnant or breast-feeding. In this regard, fish oil
supplements are generally considered safe because
most industrial purification processes eliminate this
and other toxins.
138
Statins as protective agents. Epidemiologic, genetic,
and pathologic studies have shown a number of risk
factors shared by AMD and atherosclerosis, leading to
the idea that HMG Co-A reductase inhibitors, also
known as statins which are beneficial in the prevention
of atherosclerosis, may also exert protective effects in
AMD.
139,140
There are several properties of the drug
group that may be beneficial in preventing AMD, low-
ering serum lipids may improve Bruch membrane func-
tion (by cleaning lipids deposits) and increasing retina
perfusion (reduction of atherosclerosis plaques).
139,141
The statins downregulate the expression of several mol-
ecules, including transcriptional factors for inflammation
and proliferation (NF-B, HIF-1), metalloproteinases, and
reducetheplasmalevelofVEGF.
140,142
Because of the
fact that statins decrease the plasma levels of oxidized
lipids and low-density lipoproteins, they may also exert
an antioxidant effect on the Bruch membrane choroid and
outer retina.
139,142,143
Although most of the studies to date have not proved
aclearbenefit of statin therapy for the prevention of
AMD, those are mostly composed of retrospective,
case–control or small prospective and short followed-up
studies. The lack of a randomized, controlled prospec-
tive study precludes a more definite conclusion.
144–146
Age-related Macular Degeneration Genetics
The notion that early recognition and prompt treat-
ment may have a profound effect on vision recovery in
patients with AMD has fueled efforts to try to identify
individuals whose condition is more likely to progress
to advanced stages.
86,147
The previous studies indicate
that inherited genetic features extend conventional pa-
rameters, such as smoking, family history, age, and
stage of the disease, and improve the ability to predict
progression to visual impairment among those with
early or asymptomatic stages of the disease.
148
Several
attempts to assess multiple genetic and environmental
risk factors as indicators of progression have been
made. The main goal is that at some point in the near
future we will be able to provide patients and clini-
cians with enough diagnostic information related to
AMD risk, that they can make decisions efficiently
about changing lifestyles and personalized treatment,
with improved outcomes and a more prudent use of the
health-care budget.
79
To have a tool (test) that can
discriminate between those patients who will develop
a vision-threatening disease and those who will not, or
that can predict the rate of disease progression or
define patient’s likely response to a specific treatment
will be a powerful asset in the daily clinical practice.
79
The contribution of genetics to AMD was carefully
documented in the 1990s with multiple studies. Twin
studies revealed that monozygotic twins have a high
level of concordance for AMD compared with dizy-
gotic twins. Some estimates suggested that as much as
71% of the variation in the overall severity of AMD
was genetically determined.
149–151
Familial aggregation
and a higher risk of disease in first-degree relatives of
affected individuals are also proof of a genetic predispo-
sition of the disease.
151–153
Linkage studies have revealed
multiple loci, which harbor genes for AMD across the
human genome. However, it was not until the develop-
ment of more advanced genotyping technologies that
gene identification in complex disease was feasible.
154,155
430 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 3

The genome-wide association studies (GWAS) is a pow-
erful laboratory technique that enables the examination of
many common genetic variants (like single nucleotide
polymorphism [SNPs]) in different individuals; looking
for an association with traits like major diseases. Using
this technique in large cohorts of patients has revealed
several susceptible loci in complex diseases like diabetes,
rheumatoid arthritis, systemic lupus erythematosus,
and AMD.
156,157
This technology, backed up by
robust statistical methodologies, has helped identify
precise disease intervals on chromosomes facilitating
a better understanding of the molecular genetic basis
of AMD.
158
Susceptibility genes have been found in complement-
mediated inflammation and oxidative stress pathways
(consistent with the current hypothesis about the
pathophysiology of the disease and the importance of
inflammatory pathways, reactive oxygen species, and
local oxidative damage).
74
Complement Pathway
Despite the many efforts since the 1990s, the major
breakthrough came until 2005 with the identification
of a strong association between AMD and variants in
and around the CFH.
159–161
The complement pathway
is a primitive enzymatic cascade, composed of various
proteins, that is an important amplifier of innate and
adaptive immunity and serves as mediators of the
immune response.
93,162,163
Complement factor H is
a serum glycoprotein, mainly produced in the liver,
which is a natural inhibitor of complement factor 3
(C3) convertase and impedes the activation of the
alternate complement pathway.
74,159,164
It has been
found in large quantities in the RPE and within drusen,
and its gene is located on Chromosome 1q31.
159
It acts
as a cofactor for the factor I-mediated proteolytic inac-
tivation of C3b to iC3b.
93,149
The protein is composed
of 20 repetitive units of 60 amino acids known as com-
ponent compound modules (CCP) or short consensus
repeats.
105
The most highly investigated genetic
variant or SNPs to date are rs1061170 at nucleotide
position 1,277 within exon 9 of the CHF gene (MIM
1134370).
159–161,165
The T-to-C change on this
SNP results in an amino acid change from tyrosine
at Position 402 to that of a histidine (Y402H) which
lies within CCP7, that has binding sites for heparin,
C-reactive protein, necrotic cells, and M protein
(some of them are drusen constituents).
166–169
This
polymorphism shows an ethnic variability. It is
found in 35% of individuals of European descent
but is not observed in patients with Japanese,
Korean, or Chinese ancestry.
170–172
Several major
studies have linked Y402H polymorphism with an
elevated risk for AMD development, a significant
earlier age of exudative disease onset (7 years earlier),
and increased risk of progression of the disease (OR,
2.43; 95% CI, 1.07–5.49), and was supposed to repre-
sent the major genetic risk factor for AMD.
79,173
Afine
mapping of the region found that .20 variants in and
around CFH were even more strongly associated with
AMD than was Y402H, potentially suggesting that reg-
ulation of the expression of CFH and neighboring genes
rather than structural alterations of the protein mediates
AMD susceptibility.
174,175
Li et al grouped CFH poly-
morphism into two common risk haplotypes: H1 and
H3, several rare risk haplotypes: H5 to H8, and two
protective haplotypes: H2 and H4. The OR of having
AMD in individuals with a high-risk haplotype com-
pared with low-risk haplotype was 18 (assuming a
prevalence of 20%. Note that the estimated probabilities
of developing disease for each genotype configuration
will depend on the overall disease prevalence, which
varies with age).
174
The Y402H polymorphism has also been linked to
the other diseases like dense deposit disease, myocardial
infarction, and more inconsistently with Alzheimer
disease.
176–178
Interestingly, patients with dense deposit
disease also develop ocular drusen indistinguishable
from those observed in AMD.
164
The Y402H polymorphism has also been used as
a predictor of patient’s outcome after treatment. After
a large study that included 273 patients treated with
photodynamic therapy, there was no significant differ-
ence in the genotype distribution among patients who
responded to treatment and those that did not.
179–181
Mixed results on this regard were reported in smaller
and underpowered studies. Some small studies have
indicated that homozygous individuals showed a greater
loss of visual acuity after treatment with intravitreal
bevacizumab whereas individuals undergoing intra-
vitreal ranibizumab had a significant higher risk of
requiring further intravitreal injections compared
with heterozygous patients.
182,183
Other genes involved in the complement cascade
has also been explored, some of which has exhibited
a very strong association with AMD. Gene polymor-
phism of complement factor B (CFB) and complement
component 2 (C2) on Chromosome 6, within the major
histocompatibility complex III region, were found to be
associated with AMD.
184,185
However, individual SNPs
for C2 (E318D) and CFB (R32Q) showed a protective
effect, even after controlling for mutation in CFH.
186
The C3 is a plasma protein that serves as a convergence
point of all complement pathways. Its gene is located on
Chromosome 19p11.
79
The SNP rs2230199 (which re-
sults in a substitution of arginine to glycine in Position
102) results in a 2.6-fold increased risk for AMD in
UPDATE IN AMD: GENETICS, EPIDEMIOLOGY, AND PREVENTION VELEZ-MONTOYA ET AL 431

homozygous white patients.
187,188
However, in the
other study, the mutation showed no gene–gene inter-
actions and its effect is considered to be an additive
effect to C2, CFB, and CFH variants.
189,190
Gene poly-
morphism of the complement component 1 (C1) has
also been associated to AMD and polymorphism within
the Serping1 gene, a naturally occurring C1 inhibitor,
nevertheless this association has not been fully con-
firmed yet.
191,192
Oxidative Damage and Age-related
Macular Degeneration
Oxidative damage from different sources is thought
to be one of the multiple components of the complex
molecular mechanism of AMD. The predisposition to
oxidative cell injury, from inherited mutations of
molecules that participate in the initiation or repair
of oxidative stress, is believed that may be a key factor
in AMD predisposition and progression. The mito-
chondria are organelles that help to control oxidative
stress through their role in oxidative phosphorylation
in the retina.
60,74
The AMD-associated locus on
Chromosome 10q26, contain the age-related maculop-
athy susceptibility 2 (ARMS2, formerly known as
LOC387715)/HtrA serine peptidase 1 (HTRA1, also
known as PRSS11) region.
193–195
At least three potential
candidate genes reside in this region of association.
19
Although the precise function of ARMS2 is unknown,
the protein was originally localized to the outer mem-
brane of the mitochondria.
193,196
Therefore, it was
thought that the rs10490924 polymorphism might
affect the conformational/interaction of the protein,
affecting the function of the mitochondria.
196
In addition,
the ARMS2 polymorphism affects the polyadenylation
signal of the ARMS2 gene, which results in instabil-
ity of its mRNA and reduces the production of its
gene product.
196
An early report of 1,166 cases and
945 control subjects identified an OR for developing
AMD of 8.2 among homozygous participants and 2.7
in heterozygous participants.
194
Acase–control study
in a Japanese cohort replicates this association.
197
Genetic studies also suggest the modification of the
susceptibility effect on ARMS2 by smoking,
198
consis-
tent with its involvement in mitochondrial function;
nevertheless, a recent study based on cell cultures, indi-
cated that the ARMS2 protein was distributed in the
cytosol and not in the mitochondrial outer membrane.
Hence the risk conferred by ARMS2 may involve addi-
tional pathways other that oxidative damage.
199
Studies using GWAS techniques pointed HTRA1 as
one of the potential AMD susceptible gene on 10q26.
60
HTRA1 is a heat shock serine protease that plays a role
in degradation of extracellular membrane proteins.
200
Immunohistochemistry assays have shown elevated
expression of HTRA1 mRNA and protein localization
within drusen.
195
A meta-analysis comprised of 14
case–control studies about the HTRA1 promoter
polymorphism (rs11200638) found a strong associ-
ation with AMD (OR in homozygous, 7.46; 95% CI,
6.16–9.04).
201
Nonetheless, it is possible that sus-
ceptibility variants within ARMS2 gene affect the
activity of HRTA1 promoter, which is only a few
kilobases from ARMS2 so that both genes influence
AMD susceptibility.
19
Mutations in HTRA1 promoter
have been consistently found in American, Australian,
Asian, and European populations, conferring a twofold
to tenfold increase in the risk for AMD.
200,202–204
Several studies have analyzed the combined inter-
action of CFH and ARMS2/HTRA1 polymorphism in
terms of susceptibility for AMD. The two-locus ORs
based on the combined genotype for the risk alleles
of CFH and ARMS2 ranged from 27 to 227 and
from 8 to 193 for the combined risk of CFH and
HTRA1.
202,205–208
Globally, 75% of all AMD could
be explained by the combined effect of CFH and
ARMS2/HTRA1 based on population-attributable risk
percent for the homozygous risk alleles.
60
Other Candidate Genes for Age-related
Macular Degeneration
The Apolipoprotein E (ApoE) gene, located on
Chromosome 19, was an early target of candidate
gene studies because of its presence in drusen, its key
role in the transport of lipids, cholesterol, and
established association with the other degenerative
diseases like Alzheimer disease.
209–212
There are three
isoforms of ApoE: Epsilon 2 (E2), Epsilon 3 (E3), and
Epsilon 4 (E4).
213,214
The latter was found to have
a protective effect over the other isoforms with a two-
fold to threefold decrease in the development of
AMD.
211,212,215
In contrast, The E2 isoform conferred
a 1.5-fold increase risk of AMD in the Rotterdam
Study.
209,216
In 2006, Baird et al
210
documented a sig-
nificantly increased risk of progression of AMD in
a female population with the E2 genotype, relative to
the E4 genotype of the ApoE gene (OR, 4.8; 95% CI,
1.19–19.09), suggesting a potential gender involvement
in the risk of disease. Several studies have disputed the
significance of ApoE isoforms contributing to AMD,
especially in Asian population.
217–219
A meta-analysis
by Thakkinstian et al
220
concluded that there is a 20%
risk attributed to E2 and a 40% protective effect for E4
in autosomal recessive and autosomal dominant roles,
respectively.
Because of the role of the Toll-like receptor 4
(TLR4) in innate immunity, its potential function in
432 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 3

photoreceptor shedding/phagocytosis, cholesterol
transport, proinflammatory signaling, and transmem-
brane signaling and its location within an AMD
susceptibility locus (9q32-33) made it an attractive
target for candidate gene studies.
221–223
The D229G
polymorphism was reported to confer a threefold
increased risk for AMD and seems to have an additive
effect to ApoE and ABCA4; however, this association
has not been replicated by others.
224–226
More recently,
an association between AMD and another Toll-like
receptor 3 (TLR3) has been reported but the association
still has to be replicated in larger cohorts.
227,228
Other candidate gene studies focused on genes in-
volved in macular dystrophies with clinical similarities
with AMD have been made. One of the first genes,
which appeared to exhibit an association with AMD,
was ABCA4 (autosomal recessive Stargardt disease).
19
This gene is a member of the ATP-binding cassette
proteins, subfamily A, which plays a key role in the
visual cycle.
229–231
Mutations in the tissue inhibitor of
metalloproteinases-3 (TIMP3) gene, responsible for
autosomal dominant Sorsby fundus dystrophy; in the
epidermal growth factor-containing fibulinlike ECM
protein 1 (EFEMP17Fibulin-3) gene, responsible for
Malattia Leventinese/Doyne honeycomb retinal dystro-
phy (which has hallmark drusenlike lesions arranged in
a radial pattern); in the elongation of very long-chain
fatty acid-like 4 (EOVL4) gene, responsible for auto-
somal dominant Stargardtlike macular dystrophy and
mutation in the VMD2 gene (Best disease, RDS gene
[butterfly dystrophy/bull’s eye maculopathy] and
C1QTNF5 [autosomal dominant late-onset retinal/
macular degeneration]) have also been examined.
Nonetheless, most of the studies have yielded mixed
findings with marginal or negative association with
AMD.
222,232–234
Polymorphism in the matrix metalloproteinase 9
gene (MMP9) may confer a threefold risk of having
AMD; beside, the increased inactive forms of MMP9
have been found in aging patients.
235,236
Fibulin-5 is
an extracellular matrix protein that participates in the
polymerization of elastin into mature fibrils. It is
believed that a decreased production or a defective
interaction between Fibulin-5 and proteins within
Bruch membrane may predispose to AMD.
237
Although several missense mutations have been found
in all five Fibulin genes in patients with AMD, its
association with AMD as a predictive target still needs
to be proved.
238
Mutations within genes related with
DNA repair and microglialike ERCC6 and CX3CR1
were examined for association with AMD; some of
them have even showed to have an epistatic interaction
with CFH variants. Multiple associations between
AMD and HLA and cytokine genes have also been
reported.
239,240
Conclusion
Age-related macular degeneration is a complex
disease that only recently we have begun to unravel
the complicated mechanism of its physiopathology.
Benefits of modern life like an increased human
longevity have made this disease one of the biggest
risks for disability in late adulthood, and an impending
challenge for public health programs around the world.
From the two main types of AMD, the neovascular
form has been the focus of extensive research.
7
Although the current available treatments are far from
perfect, much has improved in terms of visual acuity
and slowing the progression.
7
Unfortunately, we still
cannot say the same about the most prevalent form of
the disease, the nonneovascular or dry form, which
still lacks proper approved treatment.
7
The discovery
of the role of VEGF-A in the physiopathogenesis of
AMD has been a major breakthrough indeed.
10,13,37
However, the complexity of the neovascularization
phenomenon extends far beyond a single growth
factor.
43
The recently approved aflibercept (Eylea;
Bayer/Regeneron Pharmaceuticals Inc, Tarrytown,
NY) is the first antiangiogenic inhibitor, aimed
specifically to treat advanced forms of neovascular
AMD, that beside blocking VEGF-A, also blocks
the other isoforms of VEGF and placental growth
factor 1 and 2.
7,241
This property (in addition to
the fact that can be dosed every 8 weeks instead of
every 4 weeks) gives a small advantage (at least
theoretically) over the other two most frequently
used drugs (ranibizumab, Lucentis; Novartis, Duluth,
GA and Bevacizumab, Avastin; Genetech/Roche, Inc,
San Francisco, CA). Whether this will translate into
longer lasting effects or better visual acuities in the
future is still uncertain. In a previous revision, the
authors did an in deep review about multiple aspects
regarding new research efforts for the treatment of the
dry form of the disease.
7
These efforts include immu-
nosuppressant agents, intravitreal implants of steroid
drugs, complement inhibitors, neurotrophic factors,
5-HT1a agonists, retinoids, and choroidal blood per-
fusion enhancers. Some of them have reached the
clinical trial phase and have received fast track des-
ignation from Food and Drug Administration for
further development.
7
It is only a matter of time
until we can offer more to these patients than the
current AREDS multivitamin regimen.
The continuing growth of the population, especially
the segment that encompass elderly people (60 years
UPDATE IN AMD: GENETICS, EPIDEMIOLOGY, AND PREVENTION VELEZ-MONTOYA ET AL 433

or older) will certainly affect the incidence and pre-
valence of the disease in the near future,
52,54
specially
among emergent economies in Asia and Latin America
whose life expectancies and the quality of life have
been rising.
67,68,70
Among the several risk factors associated with the
disease, special attention should be placed on those
that can be actively modified by the physicians. All
active smokers of 50 years or older should be encouraged
to stop smoking because this is the most important
modifiable risk factor associated with AMD.
14
Ahealthy
lifestyle should also be advised because a balanced diet
and regular exercise has been linked to lower body mass
indexes, lower serum triglycerides, and better control of
systemic disease like diabetes mellitus and systemic
hypertension.
14,134
Dietary supplementation with
antioxidants should be recommended to those with
moderate-to-high risk of progression.
44
In this
regard, the physician should take extra caution and
ensure regular monitoring of patients with a medical
history of kidney stones, hypothyroidism, stroke,
gastritis, and anemia.
75,113
Furthermore, the physi-
cian should be aware at all time about the content of
such supplements and ensure that the supplements
do not contain b-carotene or derivates if the patient
has antecedents of being smoker.
106,107
Although
dietary supplementation of fish oils (omega-3 fatty
acids), lutein, and zeaxanthin is also desirable, the
association between these supplements and the
reduction of cataract and AMD progression is not
completely proven.
116,125
In this regard, the results
of the AREDS 2 trial soon to be published are of
special relevance. Some of the key differences
between the AREDS 1 and 2 are that the latter
included a more elderly population because they
recruited only the patients with the highest risk
of natural progression of the disease.
116
Therefore
results should be taken with caution because the
results might not be applicable to all the patients
in general on a regular practice. Another important
factor to consider is that 96% of the enrolled
population is of white ancestry.
116
This will make
difficult to translate the results to other ethnicities
with different incidence and prevalence of the dis-
ease. An unexpected advantage is that 44% of the
enrolled patients are taking statin-class, cholesterol-
lowering drugs.
116,139,140,144,146
Subgroup analysis in
the future will help clarify the role of this drug class
as protective factors for AMD progression.
To try to calculate the annual cost of AMD to health
programs is a daunting task. Especially because there
is no clear model that allows us to correctly picture the
entire proportion of the problem. What is true is that
the current model will not endure the heavy economic
burden that current treatments represent for the
governments. Drastic changes in terms of prevention
and cheaper treatment options must be made if we
want to avoid a major collapse of the health care
systems.
Genetic testing and counseling seems to be the new
frontier in modern medicine. Ideally, being able to
accurately predict the disease’s behavior, rhythm of
progression, and its response to certain types of treat-
ments, even before it manifests on the patients’retina,
should be an invaluable asset in the daily clinical care.
52
Detection of susceptibility genes will allow us to better
plan the surveillance in patients with high susceptibility
for the disease, and avoid excessive visits and tests to
patients with natural protection or low susceptibility to
AMD.
242
Early recognition and prompt treatment has
been related to better prognosis, the additional data
from genetic testing will allow us to tailor more person-
alized treatments, minimizing the cost (less recurrences
and less need of repeated treatment) while maximizing
the outcomes (better visual acuities, slower progression
of the disease).
242
Nevertheless, putting aside the
limited understanding about the genetics of the disease
at this time and the ever-growing number of candidate
genes, we have to consider also how these types of
tests will impact the already expensive treatment of
AMD (at least at the beginning).
242
Sometimes,
genetic tests are not covered entirely (or not at all)
or reimbursement is justly denied by the insurance
company, meaning a heavier out-of-pocket burden
for the patients.
243
As if that were not enough, genetic
testing is by far one of the most expensive tests out
there.
243,244
They are also complicate techniques that
require special laboratory setting that may not be avail-
able everywhere, forcing the clinicians to send the test
elsewhere to be processed. This will indirectly increase
the costs because this will probably involve additional
fees like special shipping of biologic materials, patient’s
additional visits, and the need of repeating the test
because of wrong ordering of the test, misinterpretation
of the results, among others.
243
Therefore, we must first
demonstrate an absolute benefit for the patient and
accessibility to the test before we start asking for
genetic counseling to all our patients.
242,244
In summary, AMD is a disease with global epidemic
proportions, which we can only expect to continue
rising. Public health models have proven to be insuf-
ficient to adequately address the complete array of
economic factors associated with the disease in the
future; major changes are needed to secure that all
treatment options are accessible to all, without col-
lapsing the health care system in the process. Clini-
cians should destine more efforts during office visits
into trying to modify conducts that can potentially
434 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 3

decrease the risk of developing or delay the pro-
gression of the disease and detect patients that can be
beneficed with antioxidant supplementation. Genetic
testing and counseling can potentially be of use as an
aid in decision-making process, allowing us to design
personalized treatment and surveillance schedules.
Although this can positively impact the cost of the
treatments, for now, the technology is not easily
available and difficult to fund with the current
economic model.
Key words: genetic, epidemiology, risk factors,
age-related macular degeneration, pharmacoeconom-
ics, VEGF, prevention.
Acknowledgments
The authors thank Jacqui Trujillo for her aid in the
editorial process.
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