The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.
ABSTRACT To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye.
Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Related Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients.
There were no statistically significant relationships between clinical findings and genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovascularization (P = 9.0 × 10(-8)), and unilateral late AMD versus bilateral late AMD (P = 5.9 × 10(-8)).
In this series, in patients with geographic atrophy or choroidal neovascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S substitution may serve as a marker for bilateral advanced AMD.
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ABSTRACT: In the decade that has passed since the initial release of the Human Genome, numerous advancements in science and technology within and beyond genetics and genomics have been encouraged and enhanced by the availability of this vast and remarkable data resource. Progress in understanding three common, complex diseases: age-related macular degeneration (AMD), Alzheimer's disease (AD), and multiple sclerosis (MS), are three exemplars of the incredible impact on the elucidation of the genetic architecture of disease. The approaches used in these diseases have been successfully applied to numerous other complex diseases. For example, the heritability of AMD was confirmed upon the release of the first genome-wide association study (GWAS) along with confirmatory reports that supported the findings of that state-of-the art method, thus setting the foundation for future GWAS in other heritable diseases. Following this seminal discovery and applying it to other diseases including AD and MS, the genetic knowledge of AD expanded far beyond the well-known APOE locus and now includes more than 20 loci. MS genetics saw a similar increase beyond the HLA loci and now has more than 100 known risk loci. Ongoing and future efforts will seek to define the remaining heritability of these diseases; the next decade could very well hold the key to attaining this goal.Genes. 01/2014; 5(3):518-535.
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ABSTRACT: To evaluate the relationships between plasma malondialdehyde (MDA) level and ARMS2 variants and phenotypes in patients with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD). This study is a retrospective case-control study. Plasma MDA was measured in 84 controls, 62 patients with PCV, and 42 patients with nAMD. Participants were genotyped for ARMS2 polymorphism. Phenotypes including bilaterality and greatest linear dimension based on fluorescein angiography (FA-GLD) and indocyanine green angiography (ICGA-GLD), were evaluated. Plasma MDA in the PCV and nAMD groups was higher than in the control group (P < 0.001, respectively). For ARMS2 variants, plasma MDA of homozygous high-risk genotype (TT) was higher than that of homozygous low-risk genotype (GG) in all groups (P < 0.001, respectively). Plasma MDA was higher in homozygous high-risk genotype than in heterozygous genotype in the control, PCV, and nAMD groups (P = 0.021, 0.002, and 0.004, respectively). In the nAMD group, there was a correlation between plasma MDA and both FA-GLD (r = 0.418, P = 0.006) and ICGA-GLD (r = 0.329, P = 0.033). There was a difference in plasma MDA between patients with unilateral and bilateral lesions in both PCV and nAMD (P = 0.017 and 0.019, respectively). This study revealed significant relationships between the plasma MDA level and ARMS2 variants and phenotypes in PCV and nAMD.Retina (Philadelphia, Pa.) 11/2013; · 2.93 Impact Factor
THE ARMS2 A69S VARIANT AND
BILATERAL ADVANCED AGE-RELATED
STEPHEN G. SCHWARTZ, MD, MBA,* ANITA AGARWAL, MD,† JACLYN L. KOVACH, MD,*
PAUL J. GALLINS, MS,‡ WILLIAM CADE, MS,‡ ERIC A. POSTEL, MD,§ GAOFENG WANG, PHD,‡
JUAN AYALA-HAEDO, MD,‡ KYLEE M. SPENCER, PHD,¶ JONATHAN L. HAINES, PHD,¶
MARGARET A. PERICAK-VANCE, PHD,‡ WILLIAM K. SCOTT, PHD‡
Purpose: To identify genetic associations between specific risk genes and bilateral
advanced age-related macular degeneration (AMD) in a retrospective, observational case
series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830
patients with choroidal neovascularization in at least 1 eye.
Methods: Patients underwent clinical examination and fundus photography. The images
were subsequently graded using a modified grading system adapted from the Age-Related
Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-
associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients.
Results: There were no statistically significant relationships between clinical findings and
genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced
AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic
atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovas-
cularization (P = 9.0 · 10−8), and unilateral late AMD versus bilateral late AMD (P = 5.9 · 10−8).
Conclusion: In this series, in patients with geographic atrophy or choroidal neo-
vascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with
geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S
substitution may serve as a marker for bilateral advanced AMD.
RETINA 32:1486–1491, 2012
the leading cause of irreversible visual loss among
espite continued advances in retinal care, age-
related macular degeneration (AMD) remains
the elderly in developed countries.1Advanced AMD
is characterized by geographic atrophy (GA) and/or
choroidal neovascularization (CNV), with associated
potential severe visual loss.2
AMD is associated with worse functional outcomes
and increased health resource usage and societal
costs.3Recent studies have established AMD suscep-
tibility loci at or near the genes CFH,4–7ARMS2,8
C3,9,10CFB,11and others. However, less is known
about the influence of these genes on disease severity
or bilaterality. We performed a retrospective study in
an observational case series in an attempt to identify
genetic associations between genotype in these major
AMD risk genes and bilateral advanced AMD.
This clinic-based data set contained 1,401 unrelated
non-Hispanic white patients with AMD, 1,003 of
whom had advanced AMD (GA or CNV) in at least
From the *Bascom Palmer Eye Institute, University of Miami
Miller School of Medicine, Miami, Florida; †Vanderbilt Eye Insti-
tute, Vanderbilt University, Nashville, Tennessee; ‡John P. Hussman
Institute for Human Genomics, University of Miami Miller School of
Medicine, Miami, Florida; §Duke University Eye Center, Durham,
North Carolina; and ¶Center for Human Genetics Research, Vander-
bilt University, Nashville, Tennessee.
Partially supported by the National Institutes of Health grant
7R01EY012118, National Institutes of Health Center Grant P30-
EY014801, and by an unrestricted grant to the University of Miami
from Research to Prevent Blindness, New York, NY.
Stephen G. Schwartz, MD, MBA, is a consultant for Alimera Sci-
ences and Bausch & Lomb and is listed as inventor on a patent relating
to the use of genetic data in the diagnosis of steroid-induced glaucoma.
Anita Agarwal, MD, Eric A. Postel, MD, Jonathan L. Haines, PhD,
Margaret A. Pericak-Vance, PhD, and William K. Scott, PhD, are
listed as inventors on patents relating to the use of genetic data in
the diagnosis of age-related macular degeneration.
Reprint requests: Stephen G. Schwartz, MD, MBA, 311 9th
Street North, #100, Naples, FL 34102; e-mail: sschwartz2@med.
1 eye. Patients were recruited from the Duke Univer-
sity Eye Center, the Vanderbilt Eye Institute, and the
Bascom Palmer Eye Institute. Patients were recruited
without considering severity or bilaterality of disease.
Written informed consent was obtained from all
patients. This study was approved by the Institutional
Review Boards of all participating institutions, was
compliant with the Health Insurance Portability and
Accountability Act of 1996, and adhered to the tenets
of the Declaration of Helsinki.
All patients were examined by a fellowship-trained
retina specialist. Examination techniques included slit-
lamp biomicroscopy and dilated fundus examination,
including indirect ophthalmoscopy. Fundus photogra-
phy was obtained, and the images were subsequently
graded using a modified grading system adapted from
the Age-Related Eye Disease Study (Table 1).12History
of cigarette smoking was obtained from participants via
a self-administered questionnaire, and individuals were
classified as “ever” smokers if they reported smoking at
least 100 cigarettes over their lifetimes.
Whole blood was obtained and processed for DNA
extraction using a standard protocol (Puregene; Gentra
Systems, Minneapolis, MN). Patient genotypes were
determined using previously described assays for CFH
Y402H (CC, CT, or TT),5ARMS2 A69S (GG, GT, or
TT),13C3 R102G (GG, GC, or CC),14and CFB R32Q
(GG, GA, or AA).15Briefly, regardless of assay, gen-
otypes were obtained by using sample sets randomized
regarding clinical status and center of origin, with
DNA samples from Foundation Jean Dausset-Centre
d’Etude du Polymorphisme Humain families dupli-
cated between and across plates for use as a quality
control. All markers included in this analysis had
.95% reproducibility and efficiency. Genotypes for
each marker were in Hardy–Weinberg equilibrium in
controls. All laboratory personnel were masked to the
affection status of the individuals being genotyped.
Association of AMD grade with sex was assessed
by chi-square test of association, and association with
age was assessed by one-way analysis of variance.
Univariate association of AMD severity with genotype
at each polymorphism was assessed with Fisher exact
test. Association of genotype at each polymorphism
(coded in additive fashion—0, 1, 2—as the number
of minor alleles) with highest AMD grade and occur-
rence of late AMD in the fellow eye was examined
using unconditional logistic regression, adjusting for
age at examination and sex. Modification of associa-
tions by cigarette smoking was examined by incorpo-
rating the main effect of smoking (coded 1 if ever
smoked 100 cigarettes and 0 otherwise) and an inter-
action term between genotype and smoking and testing
the significance of these terms in the model. All anal-
yses were conducted using the SAS system Version
9.1 (SAS Institute, Cary, NC).
The mean age at examination and sex distribution
of the case series is described by grade in the more
severely affected eye in Table 2. We enrolled 1,401
unrelated patients with AMD (Grade 3 or above). Of
these, 1,003 patients had advanced AMD (Grade 4 or
above): 173 had GA (Grade 4) in at least 1 eye and
830 had CNV (Grade 5) in at least 1 eye. All patient
groups were ?60% women. Patients with Grade 3 dis-
ease (i.e., no GA or CNV) were significantly younger
than patients with GA or CNV (P , 0.0001).
The distribution of genotypes at CFH, C3, CFB, and
ARMS2 by grade is described in Table 3. There were no
significant differences among the patients with Grade 3,
4, or 5 disease regarding genotypes at CFH, C3, and
CFB, adjusting for age and sex. There was a statistically
significant relationship between the ARMS2 genotype and
the grade of AMD. With advancing grades of disease,
there was an increasing allele frequency of the ARMS2
A69S TT genotype (Fisher exact P = 8.20 · 10−11).
Of the 173 patients with GA, 167 patients had
clinical data recorded for both eyes. Of these
167 patients, 121 (72%) had GA in the fellow
eye and 46 (28%) had milder disease (Grades 1–3)
in the fellow eye. Of the 830 patients with CNV,
808 patients had clinical data recorded for both eyes.
Of these 808 patients, 496 (61%) had GA or CNV in
Table 1. Fundus Photograph Grading System
No drusen or small nonextensive drusen, without pigment abnormalities
Extensive small drusen or nonextensive intermediate drusen or pigment abnormalities associated with AMD
Extensive intermediate drusen or any large drusen
GA, with or without involvement of the center of the macula
Exudative AMD, including nondrusenoid pigment epithelial detachments, serous or hemorrhagic retinal
detachments, subretinal or sub–retinal pigment epithelium hemorrhage or fibrosis, or photocoagulation scars
consistent with treatment of AMD
ARMS2 AND BILATERAL ADVANCED AMD?SCHWARTZ ET AL
the fellow eye and 312 (39%) had milder disease
(Grades 1–3) in the fellow eye.
The associations of the risk alleles at CFH, C3, CFB,
and ARMS2 with the presence of bilateral advanced
AMD, adjusted for age and sex, are described in
Table 4. Three comparisons were performed: unilateral
GA versus bilateral GA, unilateral CNV versus bilateral
CNV, and unilateral late AMD (GA and CNV
combined) versus bilateral late AMD (GA and CNV
combined). There were no significant differences in
genotypes at CFH, C3, and CFB in any of these 3 com-
parisons. There was a statistically significant relation-
ship between the ARMS2 genotype and bilateral
advanced AMD. In patients with GA in at least 1 eye,
the presence of GA in the fellow eye was weakly asso-
ciated with increasing numbers of T alleles (test for
trend odds ratio = 1.57; P = 0.08). In patients with
CNV in at least 1 eye, the presence of CNV in the
fellow eye was more strongly associated with the T
allele (odds ratio = 1.82; P = 9.0 · 10−8). Similarly,
in individuals with either GA or CNV in 1 eye, the T
allele was strongly associated with bilateral AMD (odds
ratio = 1.73, P = 5.9 · 10−8). No effect modification or
confounding by cigarette smoking was detected for any
genotype or comparison tested (data not shown).
The age of onset of symptoms or age at first diagnosis
of AMD was not available for the majority of these
participants; only the age of enrollment in the study was
available. Therefore, the duration of disease could not
be considered in the analysis. Age at enrollment,
however, was available and considered as a covariate,
and mean ages for each group are described in Table 4.
There is a complex relationship between various
genetic markers and the risk of AMD.16,17A growing
body of literature suggests that certain features of
bilateral AMD may be associated with specific genetic
variants. The Blue Mountains Eye Study reported that
the CFH Y402H CC genotype associates with bilateral
involvement of any soft drusen, distinct soft drusen,
and pigmentary abnormalities, but not with bilateral
late AMD (GA or CNV).18Conversely, a study in
U.S. Hispanic/Latino cases found that the CFH
Y402H CT and TT genotypes associated with bilateral
intermediate-to-large soft drusen.19Finally, a study by
Chen et al20reported that the A allele for HTRA1
polymorphism rs11200638, which is in strong linkage
disequilibrium (r2. 0.9) with ARMS2 A69S, associ-
ates with bilateral CNV and GA.
In this series, an allele at ARMS2, but not at CFH,
C3, or CFB, is strongly associated with the presence of
bilateral advanced AMD. The relationship appears to
exist with both CNV and GA, although the subset of
Table 3. Association of Clinical Severity in 1,401 AMD Cases with Genotypes at CFH, ARMS2, C3,
and CFB Polymorphisms
Grade 3, N = 398 Grade 4, N = 173 Grade 5, N = 830
Frequency Frequency Frequency
8.2 · 10−11
Table 2. Description of 1,401 AMD Cases by AMD
Grade, Sex, and Age
GradeN Women (%)P
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES?2012?VOLUME 32?NUMBER 8
Table 4. Association of Genotype Frequencies in CFH, ARMS2, C3, and CFB With Bilateral AMD
Comparison 1 Comparison 2Comparison 3
N = 46,
Age = 76.3 years
N = 121,
Age = 80.4 years
N = 312,
Age = 75.9 years
N = 496,
Age = 79.0 years
N = 358,
Age = 75.9 years
N = 617,
Age = 79.3 years
Test for trend
Test for trend
Test for trend
Test for trend
OR = 0.94; 95% CI, 0.56–1.59; P = 0.83OR = 0.89; 95% CI, 0.71–1.10; P = 0.28 OR = 0.89; 95% CI, 0.73–1.09; P = 0.26
OR = 1.57; 95% CI, 0.94–2.61; P = 0.08 OR = 1.82; 95% CI, 1.46–2.27; P = 9.0 · 10−8
OR = 1.73; 95% CI, 1.42–2.12; P = 5.9 · 10−8
OR = 1.14; 95% CI, 0.66–1.96; P = 0.64OR = 0.87; 95% CI, 0.69–1.10; P = 0.23 OR = 0.91; 95% CI, 0.74–1.13; P = 0.39
OR = 1.10; 95% CI, 0.33–3.71; P = 0.87OR = 0.81; 95% CI, 0.49–1.33; P = 0.41 OR = 0.86; 95% CI, 0.54–1.36; P = 0.52
Unilateral late, Grade 4 or 5 in 1 eye and Grade 1, 2, or 3 in the fellow eye; unilateral GA, Grade 4 in 1 eye and Grade 1, 2, or 3 in the fellow eye; unilateral CNV, Grade 5 in 1 eye and
Grade 1, 2, or 3 in the fellow eye; bilateral GA, Grade 4/4; bilateral late, Grade 4/4, 4/5, 5/5; bilateral CNV, Grade 5/5; OR, odds ratio; CI, confidence interval.
ARMS2 AND BILATERAL ADVANCED AMD?SCHWARTZ ET AL
GA patients is smaller than the subset of CNV
patients. This is an observational, nonconsecutive
series of non-Hispanic white patients that represents
only a small fraction of the patients seen at three clin-
ical sites in the southeastern United States. These
patients may not be representative of all AMD patients
or of the elderly population as a whole. There is no
documented longitudinal follow-up, which may be
important because at least some of the patients with
unilateral advanced AMD will develop bilateral dis-
ease with time. However, this result is consistent with
and extends previous studies that have demonstrated a
advanced AMD. For example, ARMS2 A69S has been
reported to be an independent risk factor for CNV.21
There is a reported association between various fea-
tures of advanced AMD and ARMS2, but not CFH.22
This study confirms and extends the results reported
by Chen et al, who demonstrated that the A allele in
HTRA1 promoter polymorphism rs11200638 was more
frequent in bilateral late AMD.20The ARMS2 A69S
substitution and HTRA1 polymorphisms are in very
strong linkage disequilibrium, and their effects are
indistinguishable statistically. Although studies have
suggested a functional effect of each single nucleotide
polymorphism underlying the association with AMD,
evidence that the HTRA1 polymorphism is functional
and influences gene expression is inconsistent.23–31
This inconsistency, coupled with the observation that
the ARMS2 A69S variant changes the amino acid se-
quence of this protein, has suggested that ARMS2 is the
more likely AMD gene in this region. Although this
continues to be debated in the literature, the lack of
certainty on which gene is the AMD locus does not
change the interpretation of the present findings: Our
results are consistent with those reported by Chen et al,
and both studies demonstrate that the AMD susceptibility
locus in this region is associated with bilateral late AMD.
These findings build on those from Chen et al, demon-
strating that A69S is associated with several combina-
tions of bilateral late AMD (including mixed GA and
CNV), rather than simply bilateral GA (relative to uni-
lateral GA) or bilateral CNV (relative to unilateral CNV).
The relationship between ARMS2 and CNV appears
stronger than the relationship between ARMS2 and
GA. A recent study reported that ARMS2 is associated
with classic CNV, fibrovascular lesions, and poor
visual acuity.32One series reported that ARMS2, but
not CFH, C2, C3, APOE, or TLR3, was associated
with progression of GA calculated from serial fundus
photographs, but not with secondary measures of GA
progression.33Another series reported that ARMS2,
CFH, and C3 are associated with the presence, but
not the progression, of GA.34
The function of the ARMS2 gene product is unknown,
as is its role in the pathogenesis of AMD.35,36These
data suggest that the ARMS2 gene product may act at
a different step in the pathogenesis of AMD—perhaps
a more advanced stage—than do the complement fac-
tors and other studied genes.
This report offers confirmation that the T allele at
the ARMS2 A69S substitution associates with bilateral
advanced AMD and that most of this association is
because of a very strong association between this allele
and bilateral CNV. If these data can be validated, there
may be prognostic and therapeutic implications.
Key words: age-related macular degeneration,
ARMS2, choroidal neovascularization, genotypes, geo-
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ARMS2 AND BILATERAL ADVANCED AMD?SCHWARTZ ET AL