Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis.

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries. Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to identify those risk factors with strong levels of evidence which could be easily assessed by physicians or ophthalmologists to implement preventive interventions or address current behaviours.
A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point estimates of each risk factor and associated 95% confidence intervals (CI) were calculated.
Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease, and serum total and HDL cholesterol and triglyceride levels.
Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons at risk of AMD.

Full text

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RESEARCH ARTICLEOpen Access
Clinical risk factors for age-related macular
degeneration: a systematic review and
meta-analysis
Usha Chakravarthy1*, Tien Y Wong2,3, Astrid Fletcher4, Elisabeth Piault5, Christopher Evans5, Gergana Zlateva6,
Ronald Buggage7, Andreas Pleil6, Paul Mitchell8
Abstract
Background: Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries.
Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to
identify those risk factors with strong levels of evidence which could be easily assessed by physicians or
ophthalmologists to implement preventive interventions or address current behaviours.
Methods: A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies
involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late
AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to
combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point
estimates of each risk factor and associated 95% confidence intervals (CI) were calculated.
Results: Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed
strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were
higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors
with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular
disease, and serum total and HDL cholesterol and triglyceride levels.
Conclusions: Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD.
Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily
assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons
at risk of AMD.
Background
Age-related macular degeneration (AMD) is the leading
cause of blindness among people aged 55 years and
older in the U.S and other Western countries [1-3]. Late
stage AMD includes two morphological sub-types: neo-
vascular AMD and geographic atrophy [4,5]. Population
studies indicate that neovascular AMD accounts for two
thirds of late AMD cases, and 90% of blindness from
AMD [6]. Left untreated, neovascular AMD results
in severe visual impairment with an average loss of
around 4 lines of visual acuity within 2 years of disease
onset [7]. Patients with geographic atrophy also develop
visual loss although this tends to be more gradual.
With the introduction of new and effective treatments
for neovascular AMD, there is a strong rationale for
early identification of persons at highest risk of progres-
sion to the late stages as timely treatment given at the
onset of neovascular AMD will lead to better visual out-
comes [8-11]. In this regard, a number of major risk fac-
tors for AMD have been identified, including genetic
(e.g., complement factor H polymorphisms), demo-
graphic (e.g., ethnicity), nutritional (e.g., antioxidant
vitamins, dietary fats or fish), lifestyle (e.g., smoking),
medical (e.g., cardiovascular risk factors), environmental
(e.g., sun exposure), and ocular factors [12-16].
* Correspondence: U.Chakravarthy@qub.ac.uk
1Centre for Vision Science, Queen’s University Belfast, Northern Ireland, UK
Full list of author information is available at the end of the article
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
http://www.biomedcentral.com/1471-2415/10/31
© 2010 Chakravarthy et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

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However, the evidence and strength of association
remain variable in the literature. Furthermore, a number
of these risk factors (e.g., diet and genetic factors) are
not easily measured in routine clinical practice [17-21].
While ocular clinical signs such as drusen and pigmen-
tary irregularities are important markers for progression
to late AMD [22], the skills required for an appropriate
retinal evaluation to be performed followed by the inter-
pretation of the severity of the signs to make a meaning-
ful judgement of risk observed are limited to those with
retinal specialist knowledge. The impending explosion
in immunomodulatory pharmacotherapies which are in
currently in early phase clinical trials constitute another
important reason for non-specialist clinicians and gen-
eral ophthalmologists to be able to refer persons at very
high risk of development of late AMD. Therefore it was
our view that more precise estimates of risk for factors
that could be assessed through routine history taking
would be of value for appropriate counselling and
referral.
Methods
Selection of Risk factors
We performed a systematic review and meta-analysis of
a selection of risk factors for late AMD (neovascular
AMD and geographic atrophy). Initially, we scrutinized
in detail the literature on late AMD to identify all possi-
ble risk factors. The initial search yielded 73 possible
risk factors (Table 1). Following review by an expert
panel (UC, AF, PM, TYW), 16 factors that were consid-
ered to be readily measured in nonspecialist settings
were selected for the full systematic review. We did not
address ocular or genetic risk factors as these require
either specialist skills to conduct the retinal examination
or access to laboratory resources and genetic expertise.
We also excluded nutrition as an estimation of the
nutrition status through dietary questionnaires is also a
specialised field [23].
Data Sources
Searches were conducted in Medline and Cochrane
databases using these terms: macular degeneration OR
age-related macular degeneration OR age-related macu-
lopathy AND gender OR age OR race OR ethnicity OR
iris colour OR diabetes OR cardiovascular OR cerebro-
vascular OR hypertension OR smoking OR cataract sur-
gery OR family history OR body mass index OR
cholesterol OR fibrinogen OR C-reactive protein OR
triglyceride.
Studies and Participants
Prospective cohort, case-control, or cross-sectional stu-
dies, were included if they incorporated an estimate of
Table 1 Potential 73 Risk Factors for Late Age-related
macular degeneration, Identified in the Initial Review
• Ocular factors (n = 15)
• Nuclear opacity
• Cortical opacity
• Pterygium
• Lens opacity
• Horizontal cup-to-disc ratio
• Fellow eye
• Iris color*†
• Eye disease*
• Cataract/Cataract surgery*†
• Arcus cornea
• Arterioar-to-venular ratio
• Frekling
• Spherical equivalents
• Eye glasses for distance vision
• Family history of AMD†
• Cardiovascular factors (n = 7)
• Atherosclerosis
• History of CVD and cerebrovascular disease*†
• Serum Total Cholesterol level†and Serum HDL Cholesterol level†
• Hypertension*†
• Plasma antioxidants
• Other medical conditions or marker (n = 8)
• Biochemical variables* including serum albumin, C-Reactive
Protein,*†plasma fibrinogen,†and serum triglyceride†)
• Bone mineral density
• Diabetes*†
• Arthritis
• Menopause
• Diet (n = 11)
• Dietary intake
• Fat*
• Animal fat*
• Vegetable fat*
• Linoleic acid
• ∞-3 fatty acids EPA/DHA
• Antioxidants*
• Saturated fat
• Monounsaturated fat
• Polyunsaturated fat
• Trans-unsaturated fat
• Medications (n = 9)
• Birth control use
• Diuretics use
• Antacid use
• Antihypertensive medication use
• Anti-inflammatory drug use
• Hydrochlorothiazide use
• Hormone replacement therapy
• Hormones (women)
• Hypnotics/sedative
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association [odds ratio (OR) or relative risk (RR)]
between late AMD and at least one of the 16 risk fac-
tors. Non-English language articles were not included
because, after a preliminary assessment, we did not
identify any that fitted our inclusion criteria. Abstracts
and unpublished studies were also not included.
For articles that passed initial screen, additional
criteria were applied for inclusion in the meta-analysis:
1) estimates for association with neovascular AMD and
geographic atrophy were excluded when concomitantly
presented as late AMD to avoid double counting; 2) for
three epidemiological studies that examined the risk of
late AMD (i.e., Beaver Dam [24-26], Blue Mountains
[24-26], and Rotterdam [25,26]) both the original esti-
mates and pooled estimates of the three studies exist.
Therefore, to avoid double counting of these studies,
only the pooled estimate was retained. We did not
include studies that reported only the unadjusted results
(i.e., crude ORs). All studies included adjusted for age;
when studies reported more than one adjusted estimate,
the multivariate adjusted estimate was selected (i.e., if a
study reported either age adjusted or age, gender and
smoking adjusted results, the latter was chosen).
Outcome Measures
The primary outcome measure was late AMD, or each
type of late AMD if the overall results for late AMD
were not presented.
Study Selection
Searches were completed by 28 February 2007 and
yielded 295 references. The abstracts of these articles
were independently reviewed by two researchers (LP
and CE) and relevant data (e.g., study design, risk factor,
type of AMD) was recorded on a study-specific abstrac-
tion form. Full-text articles were then obtained based on
the initial screening of abstracts and the data extraction
form was completed. Any disagreements between the
two reviewers in the abstract review or following selec-
tion of articles for full text review were resolved by dis-
cussion. The bibliographies of the full text articles that
were reviewed were searched for relevant references.
In all, 128 unduplicated references were initially iden-
tified as being of potential relevance (the search was
repeated in November 2008 and seven additional articles
published in 2008 were included [27-32]), with 12 addi-
tional articles retrieved from the reference lists. From
the total of 147 articles, 70 fulfilled all eligibility criteria
and were selected for meta-analysis. One study was
excluded since the outcome was determined by clinical
criteria rather than retinal photography. In addition, 24
articles were excluded since authors reported progression
for early AMD as well as late AMD. In the final pool, 45
articles were retained for the meta-analyses including arti-
cles with results from 18 prospective studies [24,26,33-49],
and cross-sectional studies [12,25,28,30,31,50-63], and 8
case control studies (Figure 1) [50,64-70].
Data Synthesis
We used Comprehensive Meta-Analysis software version
2 for all meta-analyses. An overall meta-analysis was per-
formed for each risk factor if there were two or more
risk estimates irrespective of study design. In addition,
since the study design could influence the risk estimate,
meta-analyses were performed for each major type of
study within each risk factor. We conducted fixed-effects
and random-effects meta-analyses to combine these out-
comes across included studies by study design, estimating
overall raw point estimates of each risk factor and their
associated 95% confidence intervals (CI). The selection of
fixed-effects vs. random-effects models was based on the
reported I-squared value and associated p-value. If the p-
value was < 0.10 then random-effects was chosen, other-
wise fixed-effects was selected, except when there was
clear heterogeneity based on individual study results and
Table 1 Potential 73 Risk Factors for Late Age-related
macular degeneration, Identified in the Initial Review
(Continued)
• Life style (n = 3)
• Smoking*†
• Alcohol consumption
• Physical activity level
• Light and other exposures (n = 3)
• Place of birth
• Solar radiation/outdoor exposure*
• Chemical exposure
• Genetics (n = 9)
• fibulin 5
• CST3
• CX3CR
• TLR4
• VEGF
• LRP6
• MMP9
• HLA family of genes
• CFH
• Demographics (n = 8)
• Gender*†
• Age*†
• Race/ethnicity*†
• Education*
• Weight/Body mass index*†
• Waist circumference
• Height
• Marital status
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in these instances the more conservative random-effects
was selected. Forest plots were used to graphically pre-
sent the significant findings. Funnel plots were produced
to explore the potential for publication bias.
Results
In total, data from 18 prospective, cross-sectional studies
and8 case controlstudies[12,24-26,28,30,31,
33-47,49-54,57-73] were included in the final analysis,
contributing a sample of some 94,058 patients (ranging
from 261 to 22,071) including 3,178 (ranging from 8 to
776) late AMD cases. Table 2 summarizes the characteris-
tics of the 18 prospective and cross-sectional studies from
which estimates were included in the meta-analysis. Fun-
nel plots were reviewed and no evidence of publication
bias was observed.

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Figure 1 Study selection process.
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The findings for each risk factor except age are sum-
marized in Table 3 and discussed separately in the fol-
lowing sections.
Age
All studies found a strong association with increasing
age (Table 4 and Figure 2) [31,74].
Gender
Two estimates from two case control studies [64,65],
two estimates from cross-sectional studies [25,30],
and two prospective studies [27,75] contributed to this
meta-analysis. Findings from this analysis suggest
that there is no significant association between female
gender and late AMD. In the case control studies,
the overall OR for female gender was 1.00 (95%
CI 0.83 - 1.21), in the cross-sectional studies, it
was 1.06 (95% CI 0.78 - 1.44) (Figure 3). In the
prospective studies, it was 1.01 (95% CI 0.89 - 1.16).
Since the authors had not provided the confidence
intervals, one study could not be included in the
model [49].
Table 2 Summary of characteristics of the 18 prospective and cross sectional studies
STUDY NAME LOCATION DATE
OF
STUDY
POPULATION NUMBER OF
LATE AMD
SUBJECTS
AGE
RANGE
%
MALE
METHOD OF
FUNDUS
CAPTURE
METHOD OF
CLASSIFICATION
AREDS [64]USA1992-
1998
4,519 77660-80 NARetinal photo WARMGS
Baltimore Eye Study*[91]USA1985-
1988
4,3964840+ NARetinal photo International AMD
Barbados Eye Study*[42]Barbados1988-
1992
2,374 1240-84 43 Retinal photo Described in paper
Beaver Dam Eye Study
[24-26,39,47,57,92]
USA1988-
1990
4,92672 43-8644 Retinal photoWARMGS
Blue Mountains Eye Study*
[24-26,35,43,46]
Australia 1992-
1994
3,6546549+43Retinal photoWARMGS
Cardiovascular Health Study
[40]
USA1989-
1990
5,2013565+60Retinal photoWARMGS
Copenhagen City Study*
[33,49]
Denmark1986-
1988,
2000-
2002
94611260-8049Retinal photoDescribed in paper
European Study of Eye
Disease (EUREYE)[12]
Europe2000-
2003
4,752158 Aged
65+
45Retinal photoInternational AMD
Funagata Study[30]Japan2000-
2002
3,676835+51Retinal photoWARMGS
Los Angeles Latino Eye
Study (LALES) *[53,54,61]
USA1997-
2002
5,8752540+42Retinal photoWARMGS
Multi-ethnic Study of
Atherosclerosis (MESA)[41,59]
USA2002-
2004
6,17627 45-85 48Retinal photoWARMGS
NHANES III*[58]USA1998-
1994
8,27054 40+47 Retinal photoWARMGS
PHS[34,44]USA1982-
1989
22,071 64 40+100Retinal photoWARMGS
Progression of Age-related
Macular Degeneration Study
(PARMDS)[45]
USA1989-
1998
261NA60+NARetinal photoModification of the Age-
Related Eye Disease Study
Grading system
Pathologie Occulaires Liees a
l’age (POLA) *[51,52]
France2002,
2006
2,1834160+43Retinal photoFundus photo
Proyecto VER*[93]USA1997-
1999
2,78015 50+ 39Retinal photoWARMGS
Rotterdam Study*
[25,26,36,62,94]
Netherlands 1990-
1993
6,25110455+40 Retinal photoWARMGS
Singapore Malay Eye Study
(SiMES)[28,31]
Singapore19923,28023 40-8052 Retinal photoWARMGS
WARMGS: Wisconsin Age-Related Maculopathy Grading System; * Studies included in the meta-analyses
* From article referenced
Note: Case control studies were not included in this table
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Race/ethnicity
One case control study (AREDS) [64], two cross sec-
tional studies (NHANES III and LALES) [53,58] and
two prospective studies (MESA, CHS) [41,76] contribu-
ted to this analysis. All studies were based in the US
population. In the MESA Study [41], there were no sig-
nificant differences between whites (European origin),
Asians (i.e. predominantly Chinese ancestry), Blacks
(African Americans) or Hispanics in late AMD preva-
lence. In the NHANES III [58], there were no significant
differences between Non-Hispanic White, Non-Hispanic
Black (OR 0.34, 95%CI 0.10 - 1.18) and Mexican Ameri-
cans (OR 0.25, 95% CI 0.07 - 0.90). In the LALES [53],
individuals of Native American ancestry were nearly 15
times more likely to have geographic atrophy (95% CI
1.8 - 12.6) than Latinos. The OR was 0.91 (0.49 - 1.69)
in prospective cohort studies and 1.09 (0.09 - 13.56) in
cross-sectional studies for whites versus other races/eth-
nicities (Figure 4). An additional study, the Baltimore
Eye Study [77], was identified; however, the use of
differing nomenclatures in the Baltimore Eye Study to
identify racial types (e.g., African American, Chinese,
Mexican American) prevented its inclusion in the meta-
analysis.
Family history
Two case control studies were included in the meta-
analysis [68,69]. Findings from the meta-analysis show
an insignificant association between family history and
late AMD (OR 6.18; 95% CI 1.94 - 6.61). This was sup-
ported by findings from a cross-sectional study (OR
3.95. 95% CI 1.35 - 11.54) (Figure 5) [60].
Cataract surgery
Estimates from three prospective cohort studies
(i.e., Copenhagen, Blue Mountains, and Beaver Dam)
[24,27,35,38] at five-years and ten-years, and from five
cross-sectional studies (Salisbury Eye Evaluation, Proyecto
VER, Baltimore Eye Survey, and Blue Mountains) [63,78],
were analyzed. Only two case control studies [50,66] were
Table 3 Summary Results from the Meta-analysis
RISK FACTORPROSPECTIVE CROSS-SECTIONALCASE CONTROL
n Overall estimatenOverall estimatenOverall estimate
Gender (female)2 1.01 (0.89 - 1.16)2 1.06 (0.78 - 1.44)21.00 (0.83 - 1.21)
Race (white vs. other)30.91 (0.49 - 1.69)3 1.09 (0.09 - 13.56)*14.2 (2.23 - 8.00)
Family History*01 3.95 (1.35 - 11.54)26.18 (0.98 - 38.90)*
Cataract surgery*43.05 (2.05 - 4.55)2 1.59 (1.08 - 2.34)3 1.54 (1.24 - 1.91)
Iris colour*50.98 (0.72 - 1.32)4 0.88 (0.65 - 1.17)20.60 (0.12 - 2.98)*
Body Mass Index*9 1.28 (0.98 - 1.67)*10 1.21 (0.97 - 1.53)21.52 (1.15 - 2.00)
Smoking*51.86 (1.27 - 2.73)73.58 (2.68 - 4.79)61.78 (1.52 - 2.09)
Hypertension*41.02 (0.77 - 1.35)61.15 (0.88 - 1.51)31.48 (1.22 - 1.78)
Diabetes*3 1.66 (1.05 - 2.63)3 1.09 (0.61 - 1.92)10.55 (0.06 - 4.87)
Cardiovascular Disease*71.22 (0.92 - 1.63) 9 1.12 (0.86 - 1.47)62.20 (1.49 - 3.26)*
Cerebrovascular Diseases21.54 (0.82 - 2.90)51.10 (0.69 - 1.75)0
Serum Cholesterol (Total)40.99 (0.95 - 1.03) 50.94 (0.84 - 1.04) 1 4.66 (1.35 - 16.11)
Serum Cholesterol (HDL)31.00 (0.97 - 1.02)51.06 (0.80 - 1.39) 13.35 (0.92 - 12.23)
Serum Triglycerides21.00 (0.77 - 1.30) 31.08 (0.89 - 1.30) 10.90 (0.25 - 3.24)
Plasma Fibrinogen* 11.03 (0.81 - 1.32)31.45 (1.22 - 1.73)0
n = number of estimates entered in the models; *Figure is displayed
* Estimates from random effects models. All other estimates are fixed effects.
Table 4 Prevalence of late AMD by age (Adapted from Varma et al68and Kawasaki et al29)
AgeLos Angeles Baltimore
GroupLatino White
(yrs) [% (CI)][% (CI)]
Blue Mountains
White
[% (CI)]
Beaver Dam
White
[% (CI)]
Baltimore
Black
[% (CI)]
Barbados
Black
[% (CI)]
SiMES
Asian
[%]
40 – 49
50 – 59
60 – 69
70 – 79
≥ 80
0.00.00.00.4 (0.0 – 0.8)
0.7 (0.2 – 1.2)
0.4 (0.0 – 0.8)
1.0 (0.0 – 2.0)
0.0
0
0.2 (0.0 – 0.4)
0.3 (0.0 – 0.6)
1.5 (0.5 – 2.5)
8.5 (3.5 – 13.5)
0.5 (0.0 – 1.1)
0.7 (0.1 – 1.3)
2.9 (1.5 – 4.4)
7.0 (2.0 – 12.0)
0.00.2 (0.0 – 0.4)
0.8 (0.3 – 1.3)
3.7 (2.5 – 4.9)
9.5 (6.2 – 12.8)
0.4 (0.0 – 0.8)
0.4 (0.0 – 1.0)
0.0
0.0
0.21
0.39
2.49
0.5 (0.1 – 0.8)
2.6 (1.6 – 3.6)
12.0 (8.7 – 15.4)
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found. Analysis of the prospective cohort studies showed
that previous cataract surgery is a strong risk factor for
neovascular AMD (RR 3.05; CI 2.05 - 4.55). This finding is
supported by the results of the meta-analysis of the cross-
sectional studies (OR = 1.59; CI 1.08 - 2.34) (Figure 6).
Smoking
Estimates were reported from six prospective cohort
studies [26,33,34,42,79], five case control studies
[64,65,67,68,70] and five cross-sectional studies
[12,25,28,30,51] contributed to the meta-analysis. Signifi-
cant increases in AMD risk were seen in all the meta-
analyses for current versus never smokers. The OR for
case control studies was 1.78 (95% CI 1.52 - 2.09), and
that from cross-sectional studies was 3.58 (95% CI 2.68
- 4.79). The RR obtained through analysis of prospective
cohort studies was 1.86 (95% CI 1.27 - 2.73) (Figure 7).
Iris colour
Data from three prospective cohort studies [26,27,47],
from two control studies [65,68] and a pooled estimate
from a cross sectional study [25] were used in the meta-
analysis. Two studies were not used because the authors
had not provided the confidence interval of the estimate
[37,64], or because the data had already been considered
within a pooled analysis [58]. The meta-analysis of the
prospective cohort and cross-sectional studies suggests
that darker iris pigmentation (brown vs. blue eyes) is
protective, but the overall results were not significant
(OR 0.88; 95% CI 0.65 - 1.17 cross-sectional studies and
RR 0.98; 95% CI: 0.72 - 1.32 for prospective studies).
The case control results support this finding (0.60; 95%
CI 0.12 - 2.98) (Figure 8).
Body Mass Index (BMI)
Seven prospective cohort studies (Copenhagen, CHS,
PHS, PARMDS, Beaver Dam, Rotterdam, Blue Moun-
tains) [26,33,44-46,80] and six cross-sectional studies
(POLA, Beaver Dam, Rotterdam, Blue Mountains,
LALES, SiMES) [25,28,52,54] contributed to the meta-
analysis. Analysis of the prospective studies showed an
adverse effect of being overweight/obese and the risk of
late AMD (RR 1.28; 95% CI 0.98 - 1.67). Cross-sectional
study findings were in the same direction but did not
reach statistical significance (OR 1.21; 95% CI 0.97 -
1.53). However, the two case control studies [64,67] did
achieve statistical significance (OR 1.52; 95% 1.15 - 2.00)
(Figure 9).
Hypertension
Estimates from five prospective cohort studies
[26,27,42,46], three cases control studies [64,65,67], and
from seven cross-sectional studies [25,28,30,52,54]
0
2
4
6
8
10
12
14
40-4950-5960-6970-79
?80
KawasakiBaltimore (White) Beaver Dam (White)
Barbados (Black)Blue Mountains (White) Baltimore (Black)
LALES (Latino)
Figure 2 Prevalence of late AMD by age (adapted from Varma
et al [61] and Kawasaki et al [19]).
Group by
Subgroup within study
Study name Subgroup within studyComparisonPoint (raw) and 95% CI
Point Lower Upper
(raw)limitlimit
CCAREDS, GA-AMDCC Male1.3500.882 2.066
CCAREDS, NV-AMDCCMale0.9500.767 1.176
CCBlumenkranz 1986, NV-AMDCC Male0.4570.122 1.719
CC1.0030.830 1.212
CSSmith 2001, GA-AMD CSMale 1.4500.876 2.400
CS Smith 2001, NV-AMDCSMale0.9500.640 1.410
CSKawasaki 2008, Late AMDCSMale0.280 0.058 1.353
CS1.059 0.781 1.437
PC Buch 2005, Late AMDPCMale 1.2500.732 2.135
PCVan Leeuwen 2003, Late AMDPCMale1.0000.870 1.150
PC 1.0140.886 1.161
0.010.11 10100
Gender
Figure 3 Pooled odds ratio for late AMD by gender (female vs.
male).
Group by
Subgroup
within studywithin study
Study nameStudy name
Subgroup
within studywithin study
ComparisonComparison
Point (raw) and 95% CIPoint (raw) and 95% CI
Point Lower Upper
(raw)limit(raw)limitlimitlimit
CCCC
AREDS, NV-AMDAREDS, NV-AMDCC CCWhiteWhite
4.2204.2202.2292.2297.9887.988
CCCC4.220 4.2202.2292.2297.9887.988
PC PC
Klein 2006, Late AMD a Klein 2006, Late AMD aPCPCBlackBlack
0.520 0.5200.169 0.1691.595 1.595
PCPC
Klein 2006, Late AMD b Klein 2006, Late AMD b PCPC ChineseChinese
1.910 1.9100.750 0.7504.8674.867
PCPC
Klein 2006, Late AMD Klein 2006, Late AMDPC PCHispanics Hispanics
0.480 0.4800.138 0.1381.673 1.673
PC PC0.907 0.9070.487 0.4871.6901.690
Race/Ethnicity Race/Ethnicity
Fraser-Bell 2005, GA-AMDFraser-Bell 2005, GA-AMD CS CS
Native americanNative american
16.44016.4403.935 68.685 3.935 68.685
Klein 1999, Late AMD a Klein 1999, Late AMD aCS CS
Mexican Americans Mexican Americans
0.250 0.2500.070 0.0700.896 0.896
Klein 1999, Late AMD b Klein 1999, Late AMD bCS CS
Non-hispanic blacksNon-hispanic blacks
0.340 0.3400.099 0.0991.168 1.168
1.094 1.0940.088 13.560 0.088 13.560
0.01 0.01 0.10.11110 10100 100
CS CS
CS CS
CS CS
Group by
Subgroup
Subgroup
Point Lower Upper
Figure 4 Pooled odds ratio for late AMD and by race/ethnicity
(whites vs. other races/ethnicities).
Group by
Subgroup
within studywithin study
Study nameStudy name
Subgroup
within study within study
ComparisonComparison
Point (raw) and 95% CIPoint (raw) and 95% CI
Point
(raw)(raw)
Lower
limitlimit
Upper
limitlimit
0.01 0.010.1 0.111 1010 100100
Family HistoryFamily History
CC CCHyman 1983, Late AMDHyman 1983, Late AMD
CC CC
Family historyFamily history
CC CCKlaver 1998, Late AMD Klaver 1998, Late AMD
CCCC
Family historyFamily history
CCCC
CS CS Smith 1998, Late AMD Smith 1998, Late AMD
CSCS
Family historyFamily history3.950 3.950
1.3521.352
11.53911.539
CS CS3.9503.950
1.3521.352
11.53911.539
2.900 2.900
1.514 1.5145.5535.553
19.80019.800 3.1063.106126.232 126.232
6.1806.1800.9820.982
38.89638.896
Group by
Subgroup
Subgroup
Point Lower
Upper
Figure 5 Pooled odds ratio for late AMD by family history
(presence or absence).
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
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Page 8

contributed to this analysis. None of the analyses
showed statistically significant associations (prospective
cohort RR 1.02; 95% CI 0.77 - 1.35; cross-sectional stu-
dies OR 1.15; 95% CI: 0.88 - 1.51). The three case con-
trol studies did identify a significant association between
presence of hypertension and late AMD (OR 1.48; 95%
CI 1.22 - 1.78) (Figure 10).
Diabetes
Estimates from four prospective cohort studies
[24,42,46] and two cross-sectional estimates [52,54,60]
contributed to the meta-analysis. Based on the data
from the prospective cohort studies, the presence of
diabetes was associated with an increased risk of late
AMD (RR 1.66; 95% CI 1.05 - 2.63). In the cross-sec-
tional estimates that used data from two studies, asso-
ciations were nonsignificant (OR 1.09; 95% CI 0.61 -
1.92). Only one case control study [65] showed non-
significant association with diabetes (OR 0.55; 95% CI
0.06 - 4.87) (Figure 11).
History of Cardiovascular Disease
Five prospective cohort studies (including pooled esti-
mates) [26,33,42,46] four case control studies [65-68]
and seven cross-sectional studies [28,52,54,58] (including
pooled estimates [25]) contributed to the meta-analysis
of history of cardiovascular disease (self or medical
report) and late AMD. As previously mentioned, some
estimates [49,81] were not retained in the analysis. No
significant association was found in the prospective
cohort and the cross-sectional studies (RR 1.22, 95% CI
0.92 - 1.63 and OR 1.12; 95% CI 0.86 - 1.47). A signifi-
cant association was observed in the case control stu-
dies, with around double the odds of late AMD in
individuals with cardiovascular disease (OR 2.20; 95% CI
1.48 - 3.26) (Figure 12).
History of Cerebrovascular Diseases
Three prospective cohort studies [26,46] and six cross-
sectional studies [25,28,52,54] were included in the
meta-analysis of history of cerebrovascular diseases and
late AMD (Figure 13). No significant associations were
found (RR 1.54; 95% CI 0.82 - 2.90 and OR 1.10, 95%CI
0.69 - 1.75 for the prospective and the cross-sectional
studies, respectively).
Group by
Subgroup within study
Study nameSubgroup within studyComparisonPoint (raw) and 95% CI
Point Lower Upper
(raw)limit limit
CCChaine 1998, GA-AMDCCPrevious surgery 1.7801.227 2.583
CCChaine 1998, NV-AMDCC Previous surgery 1.4401.094 1.896
CCBaatz 2008, NV-AMDCCCataract surgery 1.3000.522 3.240
CC1.5371.239 1.906
CSFreeman 2003, Late AMD CSCataract surgery 1.700 1.106 2.614
CSWang 1999, Late AMDCS Past cataract1.2000.498 2.890
CS 1.5891.080 2.339
PCBuch 2005, Late AMD PCCataract extraction1.600 0.800 3.200
PCCugati 2006, Late AMDPCNonphakic3.3101.110 9.870
PCKlein 2002, Late AMD PCCataract surgery 3.8101.889 7.685
PCWang 2003, Late AMD PCNonphakic5.700 2.394 13.569
PC3.054 2.049 4.552
0.01 0.11 10100
Cataract Surgery
Figure 6 Pooled odds ratio for late AMD by history of previous
cataract surgery.
Group by
Subgroup within study
Study nameSubgroup within study ComparisonPoint (raw) and 95% CI
Point Lower Upper
(raw)limitlimit
CC
CC
CC
CC
CC
CC
CC
CS
CS
CS
CS
CS
CS
CS
CS
PC
PC
PC
PC
PC
PC
AREDS group, NV-AMD
AREDS group, GA-AMD
Blumenkranz 1986, NV-AMD
Hyman 1983, Late AMD
Tamakoshi 1997, NV-AMD
Hogg, NV-AMD
CC
CC
CC
CC
CC
CC
Current smoker1.910
Current smoker1.610
Current smoker1.250
Current smoker1.200
Current smoker2.970
Current smoker3.710
1.568 2.327
1.066 2.433
0.328 4.762
0.781 1.843
0.999 8.830
1.247 11.036
1.515 2.085
2.084 11.102
1.352 4.811
1.002 12.225
1.249 5.166
2.743 7.548
1.402 10.245
0.997 25.385
2.679 4.791
0.629 4.072
0.893 4.256
0.284 2.545
0.507 10.439
1.297 4.259
1.272 2.726
1.777
Chakravarthy 2007, GA-AMD
Chakravarthy 2007, NV-AMD
Delcourt 1998, Late AMD
Smith 2001, GA-AMD
Smith 2001, NV-AMD
Cakett 2008, Late AMD
Kawasaki 2008, Late AMD
CS
CS
CS
CS
CS
CS
CS
Current smoker4.810
Current smoker2.550
Current smoker3.500
Current smoker2.540
Current smoker4.550
Current smoker3.790
Current smoker5.030
3.582
Buch 2005, Late AMD
Christen 1996, NV-AMD
Klein 2002, NV-AMD
Leske 2006, Late AMD
Tomany 2004, Late AMD
PC
PC
PC
PC
PC
Current smoker1.600
Current smoker1.950
Current smoker0.850
Current smoker2.300
Current smoker2.350
1.862
0.01 0.1110 100
Smoking

Figure 7 Pooled odds ratio for late AMD by smoking status
(current vs. never).
Group by
Subgroup
within study
Study name
Subgroup
within study
Comparison
Point (raw) and 95% CI
Point
(raw)
Lower
limit
Upper
limit
Iris Color
CCBlumenkranz 1986, NV-AMD CCBrown
1.490
0.439
5.055
CC Hyman 1983, Late AMDCC Brown
0.290
0.150
0.560
CC
0.6040.123
2.979
CS
Smith 2001, GA-AMD a
CS
Hazel/green 0.710
0.3291.534
CS
Smith 2001, NV-AMD a
CS
Hazel/green0.790
0.4461.398
CS
Smith 2001, GA-AMD b
CS
Tan/brown 0.640
0.319 1.285
CS
Smith 2001, NV-AMD b
CS
Tan/brown 1.150
0.730 1.811
CS
0.876
0.6541.174
PC
Buch 2005, Late AMD a
PC
Gray/green0.900
0.413 1.962
PC
Buch 2005, Late AMD b
PC
Brown 1.300
0.531
3.184
PC
Tomany 2003, Late AMD a
PC
Green 0.960
0.511 1.804
PC
Tomany 2003, Late AMD b
PC
Brown0.720
0.369 1.405
PC
Tomany 2004, Late AMD
PC
Brown 1.130
0.6591.937
PC
0.977
0.723 1.319
Figure 8 Pooled odds ratio for late AMD by iris color (brown
vs. blue eyes).
Group by
Subgroup
within study
within study
Study nameStudy name Study name
Subgroup
within study within study
ComparisonComparison
Point (raw) and 95% CIPoint (raw) and 95% CI
Point Lower Upper
(raw) limit (raw) limitlimit limit
Body Mass Index Body Mass Index
PC PC
PC
Buch 2005, Late AMDBuch 2005, Late AMD
Buch 2005, Late AMD
PCPC
PC
BMI>27BMI>27
BMI>27
1.300 0.672 2.5151.300 0.672 2.515
1.300 0.672 2.515
PCPC
PC
Klein 2003, Late AMDKlein 2003, Late AMD
Klein 2003, Late AMD
PC PC
PC
BMI>30BMI>30
BMI>30
1.100 0.632 1.9151.100 0.632 1.915
1.100 0.632 1.915
PCPC
PC
Schaumberg 2001, Late AMD a Schaumberg 2001, Late AMD a
Schaumberg 2001, Late AMD a
PC PC
PC
BMI 25-30 BMI 25-30
BMI 25-30
0.780 0.452 1.3460.780 0.452 1.346
0.780 0.452 1.346
PC PC
PC
Schaumberg 2001, Late AMD bSchaumberg 2001, Late AMD b
Schaumberg 2001, Late AMD b
PCPC
PC
BMI>30BMI>30
BMI>30
1.280 0.489 3.3511.280 0.489 3.351
1.280 0.489 3.351
PCPC
PC
Seddon 2003, Late AMD aSeddon 2003, Late AMD a
Seddon 2003, Late AMD a
PC PC
PC
BMI 25-30BMI 25-30
BMI 25-30
2.320 1.321 4.074 2.320 1.321 4.074
2.320 1.321 4.074
PC PC
PC
Seddon 2003, Late AMD b Seddon 2003, Late AMD b
Seddon 2003, Late AMD b
PCPC
PC
BMI>30 BMI>30
BMI>30
2.350 1.271 4.3452.350 1.271 4.345
2.350 1.271 4.345
PCPC
PC
Tan 2007, Late AMD aTan 2007, Late AMD a
Tan 2007, Late AMD a
PCPC
PC
Overweight Overweight
Overweight
1.220 0.678 2.195 1.220 0.678 2.195
1.220 0.678 2.195
PC PC
PC
Tan 2007, Late AMD b Tan 2007, Late AMD b
Tan 2007, Late AMD b
PCPC
PC
Obese Obese
Obese
1.200 0.566 2.544 1.200 0.566 2.544
1.200 0.566 2.544
PC PC
PC
Tomany 2004, Late AMD Tomany 2004, Late AMD
Tomany 2004, Late AMD
PC PC
PC
BMI>30BMI>30
BMI>30
0.870 0.512 1.478 0.870 0.512 1.478
0.870 0.512 1.478
PC PC
PC
1.278 0.976 1.673 1.278 0.976 1.673
1.278 0.976 1.673
0.01
0.01
0.01
0.1
0.1
0.1
1
1
1
10
10
10
100
100
100
CCCC AREDS group, Late AMDAREDS group, Late AMD
CCCC BMI >31BMI >31
1.430 1.075 1.9021.430 1.075 1.902
CCCC Hogg, NV-AMDHogg, NV-AMD
CCCC BMI 27-30BMI 27-30
3.820 1.218 11.9853.820 1.218 11.985
CCCC 1.515 1.149 1.9971.515 1.149 1.997
CSCS
Delcourt 2001, Late AMD aDelcourt 2001, Late AMD a
CSCS
BMI 25-30BMI 25-30
0.940 0.442 1.9990.940 0.442 1.999
CSCS
Delcourt 2001, Late AMD bDelcourt 2001, Late AMD b
CSCS
BMI >30BMI >30
2.290 1.001 5.2382.290 1.001 5.238
CSCS
Smith 2001, GA-AMD aSmith 2001, GA-AMD a
CSCS
BMI 26-30BMI 26-30
1.520 0.820 2.8181.520 0.820 2.818
CSCS
Smith 2001, GA-AMD bSmith 2001, GA-AMD b
CSCS
BMI>30BMI>30
1.510 0.719 3.1721.510 0.719 3.172
CSCS
Smith 2001, NV-AMD aSmith 2001, NV-AMD a
CSCS
BMI 26-30BMI 26-30
0.940 0.596 1.4820.940 0.596 1.482
CSCS
Smith 2001, NV-AMD bSmith 2001, NV-AMD b
CSCS
BMI>30BMI>30
1.190 0.694 2.0411.190 0.694 2.041
CSCS
Cakett 2008, Late AMD aCakett 2008, Late AMD a
CSCS
BMI 25-30BMI 25-30
0.930 0.349 2.4810.930 0.349 2.481
CSCS
Cakett 2008, Late AMD bCakett 2008, Late AMD b
CSCS
BMI>30BMI>30
1.370 0.408 4.6041.370 0.408 4.604
CSCS
Fraser-Bell 2008, Late AMD aFraser-Bell 2008, Late AMD a
CSCS
BMI 25-30BMI 25-30
1.220 0.362 4.1071.220 0.362 4.107
CSCS
Fraser-Bell 2008, Late AMD bFraser-Bell 2008, Late AMD b
CSCS
BMI>30BMI>30
1.280 0.376 4.3561.280 0.376 4.356
CSCS 1.214 0.965 1.5271.214 0.965 1.527
Group by
Subgroup
Subgroup
Point Lower Upper
Figure 9 Pooled odds ratio for late AMD by body mass index
(obese vs. non-obese).
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
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Page 9

Biological markers
Five prospective cohort studies [26,33,40,46] (including
one pooled estimate), and six cross-sectional studies
[28,30,52] (including one pooled estimate [25]), one case
control [67] of serum total cholesterol and of serum
high-density lipoprotein cholesterol contributed to the
meta-analysis (data not shown). Three studies [49,57,82]
were not included in the meta-analysis. The pooled
odds ratios and relative risks were non-significant for
both serum cholesterol measures.
Neither the two prospective cohort studies [27,46] (RR
1.0; 95% CI 0.77 - 1.30) nor the cross-sectional studies
[28,52,60] (OR 1.08; 95% CI 0.89 - 1.30), found an asso-
ciation between serum triglycerides and late AMD (data
not shown).
A significant increase in risk of late AMD with
increased plasma fibrinogen was observed in two cross-
sectional studies [58-60], (OR 1.45; 95% CI 1.22 - 1.73).
There was only one estimate from a prospective study
[46] and it did not support this finding (OR 1.03; 95%
CI 0.81 - 1.32) of significance in the cross-sectional stu-
dies (Figure 14).
None of the studies which measured C-reactive pro-
tein [36] were eligible for inclusion in our meta-analysis.
Discussion
Identifying patients at high risk of late AMD, particu-
larly neovascular AMD, is important from both public
health and clinical perspectives as this would facilitate
detection of disease before the onset of irreversible
visual loss enabling earlier intervention. Of the 16 risk
factors identified in our systematic review and meta-
analysis, age, current smoking, cataract surgery, and
potentially family history were strongly and consistently
associated with late AMD. All of these are easily
assessed through discussions with patients and do not
entail a lengthy medical history taking or laboratory eva-
luations. Other significant factors with a lower strength
of association (risk estimates generally 1.5 or less) were
BMI, hypertension, a history of cardiovascular disease
and plasma fibrinogen. All of these factors are associated
with cardiovascular disease and are also likely to be
measured and monitored in the primary care setting.
Our meta-analysis confirmed the increased risks of
late AMD associated with advancing age (especially for
the oldest age groups of 80 years and over), current
cigarette smoking, and previous cataract surgery. The
relationship of cataract surgery and late AMD was pre-
viously reported in a pooled analysis of 3 studies in dif-
ferent continents [26]. Although this association could
reflect shared risk factors and the fact that both are dis-
eases that affect the ageing eye, there is concern that
surgery may predispose the operated eye to the
Group by
Subgroup within study
Study nameSubgroup within study Comparison Point (raw) and 95% CI
Point Lower Upper
(raw)limitlimit
CCAREDS group, Late AMD CCHypertension1.4501.197 1.756
CCBlumenkranz 1986, Late AMDCCHypertension0.6000.089 4.045
CCHogg, NV-AMDCCHypertension3.2101.144 9.009
CC 1.476 1.224 1.780
CSDelcourt 2001, NV-AMD CSHypertension1.050 0.548 2.012
CSSmith 2001, GA-AMDCS Hypertension0.7200.391 1.325
CS Smith 2001, NV-AMD CSHypertension1.480 0.988 2.217
CSFraser-Bell 2008, Late AMDCSHypertension1.3000.577 2.927
CSCakett 2008, Late AMDCSHypertension0.8700.248 3.054
CSKawasaki 2008, Late AMDCSHypertension1.0600.253 4.447
CS1.1540.882 1.510
PCBuch 2005, Late AMDPCHypertension0.9800.503 1.910
PC Leske 2006, Late AMDPCHypertension1.500 0.506 4.448
PC Tan 2007, Late AMDPCHypertension0.920 0.548 1.544
PCTomany 2004, Late AMDPC Hypertension1.050 0.699 1.577
PC1.022 0.773 1.351
0.01 0.11 10100
Hypertension
Figure 10 Pooled odds ratio for late AMD by hypertension
(presence or absence).
Group by
Subgroup within study
Study name Subgroup within studyComparisonPoint (raw) and 95% CI
Point Lower Upper
(raw)limit limit
CC Blumenkranz 1986, NV-AMDCCDiabetes 0.5500.062 4.873
CC0.5500.062 4.873
CS Delcourt 2001, Late AMDCS Diabetes 1.220 0.451 3.300
CSSmith 1998, Late AMD CSDiabetes 1.1800.450 3.093
CSFraser-Bell 2008, Late AMD CS Diabetes0.8800.321 2.410
CS1.0860.614 1.921
PCLeske 2006, Late AMDPCDiabetes 2.7000.999 7.296
PCTan 2007, Late AMD PCDiabetes1.920 0.838 4.399
PCTomany 2004, Late AMD PCDiabetes1.210 0.620 2.361
PC1.6591.046 2.630
0.010.1110 100
Diabetes
Figure 11 Pooled odds ratio for late AMD by diabetes
(presence or absence).
Group by
Subgroup
within study
Study name
Subgroup
within study
Comparison
Point (raw) and 95% CI
Point
(raw)
Lower
limit
Upper
limit
CC
Blumenkranz, NV-AMD
CC
Angina
4.0000.23967.002
CC
Chaine, NV-AMD
CC
CVD
3.1901.8075.631
CC
Chaine, GA-AMD
CC
CVD
1.4901.031 2.153
CC
Hyman, Late AMD a
CC
CVD History
1.7001.078 2.682
CC
Hyman, Late AMD b
CC
Angina
1.700 1.0852.663
CC
Hogg, NV-AMD
CC
CVD History
7.530 2.77920.403
CC2.198 1.4843.255
CS
CS
CS
CS
CS
CS
CS
CS
CS
CS
Delcourt, Late AMD
Klein, GA-AMD
Smith 2001, NV-AMD a
Smith 2001, GA-AMD a
Smith 2001, NV-AMD b
Smith 2001, GA-AMD b
Cakett, Late AMD
Fraser-Bell, Late AMD a
Fraser-Bell, Late AMD b
CS
CS
CS
CS
CS
CS
CS
CS
CS
Any CVD
MI
Angina
Angina
Acute MI
Acute MI
MI History
MI History
Angina
1.460
2.020
1.030
0.560
0.940
0.760
1.290
1.880
2.720
1.121
0.719
0.679
0.603
0.220
0.520
0.327
0.371
0.532
0.890
0.857
2.965
6.010
1.759
1.423
1.700
1.765
4.484
6.639
8.316
1.468
PC
PC
PC
PC
PC
PC
PC
PC
Buch, Late AMD a
Buch, Late AMD b
Leske, Late AMD
Tan 2007, Late AMD a
Tan 2007, Late AMD b
Tan 2007, Late AMD c
Tomany, Late AMD
PC
PC
PC
PC
PC
PC
PC
Angina
CVD
CVD History
Any CVD
Angina
MI
MI History
1.100
0.600
1.200
1.450
1.560
1.400
0.810
1.222
0.588
0.080
0.280
0.804
0.821
0.616
0.401
0.917
2.058
4.475
5.138
2.614
2.964
3.181
1.635
1.629
0.010.11 10100
Cardiovascular Disease
Figure 12 Pooled odds ratio for late AMD by cardiovascular
disease (presence or absence).
Group by
Subgroup within study
Study name Subgroup within studyComparison Point (raw) and 95% CI
Point Lower Upper
(raw)limitlimit
CSDelcourt 2001, Late AMDCSStroke 0.9100.208 3.981
CSSmith 2001, GA-AMDCSStroke0.720 0.260 1.997
CSSmith 2001, NV-AMDCSStroke1.0700.550 2.081
CSFraser-Bell 2008, Late AMD CS Stroke2.330 0.712 7.628
CS Cakett 2008, Late AMDCSStroke1.230 0.161 9.423
CS1.101 0.692 1.752
PC Tan 2007, Late AMDPCStroke1.9800.789 4.966
PCTomany 2004, Late AMD PCStroke1.240 0.523 2.938
PC 1.5440.823 2.896
0.010.11 10 100
Stroke/Cerebrovascular
Figure 13 Pooled odds ratio for late AMD by cerebrovascular
disease (presence or absence).
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
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development of neovascular AMD. We further con-
firmed the association with family history of AMD, con-
sistent with the growing recognition of major genes
involved in AMD (e.g., complement factor H and C3,
LOCS 3877, HTRA 1) [21,83-86].
Vascular diseases, including myocardial infarction,
stroke, angina, and hypertension are thought to be
pathogenic factors for the development of late AMD.
Our meta-analysis showed that while the magnitude of
the ORs were inconsistent across studies, the pooled
estimates for case-control studies were statistically sig-
nificant for both cardiovascular disease (OR 2.20; 95%
CI 1.49 - 3.26) and hypertension (OR 1.48, 95% CI 1.22
- 1.78). The association of diabetes and late AMD is
also less consistent, and while prospective studies
showed a significant association, this was not significant
in the cross-sectional or case-control studies. The rela-
tionship between higher BMI and late AMD could be
explained by shared risk factors (e.g., hypertension), or
potential unmeasured confounders (e.g., nutritional fac-
tors). Our analysis also indicated that, based only on US
data, people of European origin were at increased risk
compared to other ethnic groups but at present the evi-
dence for risks associated with other specific ethnic
groups is inadequate. These are areas of future research.
Our study has several limitations. Although we
selected only studies that reported some adjustment for
confounding factors, we could not ascertain the appro-
priateness or completeness of adjustment in the studies.
Second, the data included in some studies may have
been too crude and also subject to measurement error.
For example, a ‘history of cardiovascular disease’ may
encompass a spectrum of conditions, from asympto-
matic angina to myocardial infarction; this was not
often specified. Such potential measurement errors
would likely dilute effects in the meta-analysis. Third,
we did not consider ocular factors (e.g., presence of
large drusen), that have been found to be strong predic-
tors of progression to late AMD, as we felt they could
not be easily ascertained by family physicians. Neither
did we consider dietary factors, such as the consumption
of vegetables rich in carotenoids (lutein and zeaxanthin)
or zinc and antioxidant vitamin supplementation, fish or
omega-3 fatty acids in the diet, or glycemic index,
because the methods for estimating such risk factors in
the setting of primary health care is difficult without
access to specialised personnel and resources [6,87-89].
Fourth, despite strong associations of AMD with genetic
factors, we felt that genetic testing was not readily avail-
able in general clinical practice. Fifth, we included only
English language articles because a preliminary assess-
ment did not identify any non-English language articles
that fitted our inclusion criteria. Nonetheless, many stu-
dies included in this review were from non-white popu-
lations (e.g., Chinese, Malay Asians) and thus, we
believe our results can be generalisable to different
populations in different countries around the world.
Sixth, we only included articles that were identified in
the Medline and Cochrane databases. Expanding the
search to EMBASE may have identified additional arti-
cles; however, given the extensive hand searching of bib-
liographies and the experience of the authors we feel it
is unlikely any relevant articles were missed. Seventh,
the assessment of the quality of the publications was
performed as part of this study to provide supplemen-
tary evidence of the internal and external validity of the
data. However, ultimately, we decided to present
the data based on the type of study design reported in
the publication: cohort, cross sectional and case control.
Large, epidemiological, cohort studies had the advantage
over other study designs in that they removed any tem-
poral or causal ambiguity as the exposure precedes the
disease and if follow-up is not biased selection bias is
less of a problem than in other study designs [90].
Finally, whether the study findings could be used as
prognostic information to refer patients with higher risk
of AMD requires further research. The observed odds
ratios were generally small, and there are limited inter-
ventions to prevent AMD.
Conclusions
Our systematic review and meta-analysis identified four
strong and consistent risk factors for late AMD (increas-
ing age, current smoking, previous cataract surgery and
an AMD family history) and a further four risk factors
showing significant and moderate strength of associa-
tions (high BMI, history of cardiovascular disease,
hypertension and plasma fibrinogen). This study pro-
vides additional information for primary care physicians,
general ophthalmologists and other eye care profes-
sionals to counsel their patients on AMD risk.
Acknowledgements
Funding/Support
The research was supported by Pfizer Inc, New York, New York.
Other acknowledgements
Group by
Subgroup within study
Study nameSubgroup within studyComparison Point (raw) and 95% CI
Point Lower Upper
(raw)limitlimit
CS Klein 1999, Late AMDCS Fibronogen 1.670 1.023 2.727
CS Klein 2008, Late AMDCS Fibronogen 1.330 0.889 1.989
CSSmith 1998, NV-AMDCS Fibronogen 1.450 1.174 1.791
CS1.4521.220 1.730
PC Tan 2007, Late AMDPCFibronogen 1.0300.807 1.315
PC1.0300.807 1.315
0.01 0.11 10100
Fibrinogen
Figure 14 Pooled odds ratio for late AMD by plasma
fibrinogen.
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
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This study was sponsored by Pfizer Inc. Assistance with the literature
screening, database development, data retrieval, analysis, and manuscript
development was provided by L. Chen, an employee of Pfizer Inc, and Daria
Pelech and Steve Hwang both employees of MAPI Values and funded by
Pfizer Inc. Christopher Evans and Elisabeth Piault in their capacity of
employees of Mapi Values were paid consultants in connection with the
development of this manuscript.
Usha Chakravarthy, Tien Wong, Astrid Fletcher, and Paul Mitchell received an
honorarium from Pfizer Inc for their participation in two consensus meetings
related to this study.
Author details
1Centre for Vision Science, Queen’s University Belfast, Northern Ireland, UK.
2Singapore Eye Research Institute, National University of Singapore,
Singapore.3Centre for Eye Research Australia, University of Melbourne, Royal
Victorian Eye and Ear Hospital, Melbourne, Australia.4Dept of Epidemiology
& Population Health, London School of Hygiene & Tropical Medicine,
London, UK.5Mapi Values, Boston, Massachusetts, USA.6Pfizer Inc, New York,
New York, USA.7Novartis, East Hanover, New Jersey, USA.8Centre for Vision
Research, Westmead Millennium Institute, University of Sydney, Sydney,
Australia.
Authors’ contributions
UC, TW, AF, EP, CE, GZ, RB, AP, PM participated in the design and review of
the systematic research; EP and CE managed the data collection. EP, CE GZ,
RB, AP provided technical expertise for the analysis and interpretation of the
data. UC, TW, AF, PM provided clinical and technical expertise for the
analysis and interpretation of the data. All authors (UC, TW, AF, EP, CE, GZ,
RB, AP, PM) were involved with the manuscript development, and reviewed
and approved the final version of the manuscript. AU and TW had full
access to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis.
Competing interests
Drs. Chakravarthy, Wong, Fletcher, and Mitchell were paid consultants to
Pfizer Inc and Ms Piault and Dr. Evans were employees of Mapi Values,
Boston, Massachusetts at the time the research was conducted and the
manuscript was developed. Mapi Values is a consultancy whose activities on
the project were funded by Pfizer. Drs. Zlateva and Pleil are employees of
Pfizer Inc. Dr. Buggage was an employee of Pfizer during part of the study
and now is an employee of Novartis, East Hanover, NJ. Usha Chakravarthy
has served on advisory boards to Pfizer, Oraya Therapeutics, Allergan and
Novartis and has received honoraria and travel support. She has been and
continues to be an investigator on controlled clinical trials and observational
studies sponsored by Pfizer, Novartis, Alcon and Bausch and Lomb and her
department has received funds for the conduct of these studies.
Tien Wong has been on advisory boards for Pfizer, Allergan and Novartis,
and has received honoraria and travel and accommodation payments from
them. He has also received research support from Pfizer. He has also been
an investigator on clinical trials sponsored by them and has received
payments to support the conduct of these trials.
Astrid Fletcher has been on advisory boards for Pfizer and has received
honoraria and travel and accommodation payments from them.
Elisabeth Piault and Chris Evans are employed by Mapi Values that has
received research support from Pfizer. They have not been an investigator
on clinical trials sponsored by them and has not received payments to
support the conduct of any trials
Gergana Zlateva and Andreas Pleil are paid employees of Pfizer and have no
other conflicts.
Paul Mitchell has been on advisory boards for Novartis, Pfizer, Allergan and
Solvay, and has received honoraria and travel and accommodation
payments from them. He has also been an investigator on clinical trials
sponsored by these companies, as well as Lilly and Bayer, and has received
payments to support the conduct of these trials.
Received: 23 April 2010 Accepted: 13 December 2010
Published: 13 December 2010
References
1.Bressler NM: Age-related macular degeneration is the leading cause of
blindness. JAMA 2004, 291:1900-1.
2.
3.
Chakravarthy U: Age related macular degeneration. BMJ 2006, 333:869-70.
Jager RD, Mieler WF, Miller JW: Age-related macular degeneration. N Engl
J Med 2008, 358:2606-17.
Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L: The Wisconsin
age-related maculopathy grading system. Ophthalmology 1991,
98:1128-34.
Mitchell P, Smith W, Attebo K, Wang JJ: Prevalence of age-related
maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology
1995, 102:1450-60.
Age-Related Eye Disease Study Research Group: A randomized, placebo-
controlled, clinical trial of high-dose supplementation with vitamins C
and E, beta carotene, and zinc for age-related macular degeneration
and vision loss: AREDS report no. 8. Archives of Ophthalmology 2001,
119:1417-36.
Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, et al:
The natural history and prognosis of neovascular age-related macular
degeneration: A systematic review of the literature and meta-analysis.
Ophthalmology 2008, 115:116-26.
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al:
Ranibizumab versus verteporfin for neovascular age-related macular
degeneration. N Engl J Med 2006, 355:1432-44.
Chakravarthy U, Lim JI: New treatments for neovascular acute macular
degeneration. BMJ 2007, 334:269-70.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al:
Ranibizumab for neovascular age-related macular degeneration. New
England Journal of Medicine 2006, 355:1419-31.
Wong TY, Liew G, Mitchell P: Clinical update: new treatments for age-
related macular degeneration. Lancet 2007, 370:204-6.
Chakravarthy U, Augood C, Bentham GC, De Jong PT, Rahu M, Seland J,
et al: Cigarette Smoking and Age-Related Macular Degeneration in the
EUREYE Study. Ophthalmology 2007, 114:1157-63.
Chong EW, Wong TY, Kreis AJ, Simpson JA, Guymer RH: Dietary
antioxidants and primary prevention of age related macular
degeneration: systematic review and meta-analysis. BMJ 2007, 335:755.
Fletcher AE, Bentham GC, Agnew M, Young IS, Augood C, Chakravarthy U,
et al: Sunlight exposure, antioxidants, and age-related macular
degeneration. Arch Ophthalmol 2008, 126:1396-403.
Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, et al:
Systematic review and meta-analysis of the association between
complement factor H Y402H polymorphisms and age-related macular
degeneration. Hum Mol Genet 2006, 15:2784-90.
Van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, De Jong PT: The risk
and natural course of age-related maculopathy: follow-up at 6 1/2 years
in the Rotterdam study.[erratum appears in Arch Ophthalmol. 2003
Jul;121(7):955]. Archives of Ophthalmology 2003, 121(4):519-26.
Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH: Dietary omega-3
fatty acid and fish intake in the primary prevention of age-related
macular degeneration: a systematic review and meta-analysis. Arch
Ophthalmol 2008, 126:826-33.
Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH: Alcohol
consumption and the risk of age-related macular degeneration: a
systematic review and meta-analysis. Am J Ophthalmol 2008, 145:707-15.
Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML:
Association of CFH Y402H and LOC387715 A69S with progression of
age-related macular degeneration. JAMA 2007, 297:1793-800.
Haines JL, Pericak-Vance MA: Rapid dissection of the genetic risk of age-
related macular degeneration: achieving the promise of the genomic
era. JAMA 2007, 297:401-2.
Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP,
et al: Complement factor H polymorphism, complement activators, and
risk of age-related macular degeneration. JAMA 2006, 296:301-9.
Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, et al: A
simplified severity scale for age-related macular degeneration: AREDS
Report No. 18. Archives of Ophthalmology 2005, 123:1570-5174.
Sholl HP, Fleckenstein M, Charbel IP, Keihauer C, Holz FG, Weber BH: An
update on the genetics of age-related macular degeneration. Mol Vis
2007, 13:196-205.
Wang JJ, Klein R, Smith W, Klein BE, Tomany S, Mitchell P: Cataract surgery
and the 5-year incidence of late-stage age-related maculopathy: pooled
findings from the Beaver Dam and Blue Mountains eye studies.
Ophthalmology 2003, 110:1960-7.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
http://www.biomedcentral.com/1471-2415/10/31
Page 11 of 13

Page 12

25.Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, et al: Risk factors
for age-related macular degeneration: Pooled findings from three
continents. Ophthalmology 2001, 108:697-704.
Tomany SC, Wang JJ, Van Leeuwen R, Klein R, Mitchell P, Vingerling JR,
et al: Risk factors for incident age-related macular degeneration: pooled
findings from 3 continents. Ophthalmology 2004, 111:1280-7.
Buch H, Nielsen NV, Vinding T, Jensen GB, Prause JU, la Cour M: 14-year
incidence, progression, and visual morbidity of age-related
maculopathy: the Copenhagen City Eye Study. Ophthalmology 2005,
112:787-98.
Cackett P, Wong TY, Aung T, Saw SM, Tay WT, Rochtchina E, et al: Smoking,
cardiovascular risk factors, and age-related macular degeneration in
Asians: the Singapore Malay Eye Study. Am J Ophthalmol 2008, 146:960-7.
Congdon N, O’Colmain B, Klaver CC, Klein R, Munoz B, Friedman DS, et al:
Causes and prevalence of visual impairment among adults in the United
States. Archives of Ophthalmology 2004, 122:477-85.
Kawasaki R, Wang JJ, Ji GJ, Taylor B, Oizumi T, Daimon M, et al: Prevalence
and risk factors for age-related macular degeneration in an adult
Japanese population: the Funagata study. Ophthalmology 2008,
115:1376-81, 1381.
Kawasaki R, Wang JJ, Aung T, Tan DT, Mitchell P, Sandar M, et al:
Prevalence of age-related macular degeneration in a Malay population:
the Singapore Malay Eye Study. Ophthalmology 2008, 115:1735-41.
Klein R, Klein BE, Knudtson MD, Wong TY, Shankar A, Tsai MY: Systemic
markers of inflammation, endothelial dysfunction, and age-related
maculopathy. Am J Ophthalmol 2005, 140:35-44.
Buch H, Vinding T, la Cour M, Jensen GB, Prause JU, Nielsen NV: Risk
factors for age-related maculopathy in a 14-year follow-up study: the
Copenhagen City Eye Study. Acta Ophthalmologica Scandinavica 2005,
83:409-18.
Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE: A prospective
study of cigarette smoking and risk of age-related macular degeneration
in men. JAMA 1996, 276:1147-51.
Cugati S, Mitchell P, Rochtchina E, Tan AG, Smith W, Wang JJ: Cataract
surgery and the 10-year incidence of age-related maculopathy: the Blue
Mountains Eye Study. Ophthalmology 2006, 113:2020-5.
Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP,
et al: Complement factor H polymorphism, complement activators, and
risk of age-related macular degeneration. JAMA 2006, 296:301-9.
Klein R, Klein BE, Jensen SC, Cruickshanks KJ: The relationship of ocular
factors to the incidence and progression of age-related maculopathy.
Archives of Ophthalmology 1998, 116:506-13.
Klein R, Klein BE, Wong TY, Tomany SC, Cruickshanks KJ: The association of
cataract and cataract surgery with the long-term incidence of age-
related maculopathy: the Beaver Dam eye study. Archives of
Ophthalmology 2002, 120:1551-8.
Klein R, Klein BE, Tomany SC, Moss SE: Ten-year incidence of age-related
maculopathy and smoking and drinking: the Beaver Dam Eye Study.
American Journal of Epidemiology 2002, 156:589-98.
Klein R, Klein BE, Marino EK, Kuller LH, Furberg C, Burke GL, et al: Early age-
related maculopathy in the cardiovascular health study. Ophthalmology
2003, 110:25-33.
Klein R, Klein BE, Knudtson MD, Wong TY, Cotch MF, Liu K, et al: Prevalence
of age-related macular degeneration in 4 racial/ethnic groups in the
multi-ethnic study of atherosclerosis. Ophthalmology 2006, 113:373-80.
Leske MC, Wu SY, Hennis A, Nemesure B, Yang L, Hyman L, et al: Nine-year
incidence of age-related macular degeneration in the Barbados Eye
Studies. Ophthalmology 2006, 113:29-35.
Mitchell P, Wang JJ, Smith W, Leeder SR: Smoking and the 5-year
incidence of age-related maculopathy: the Blue Mountains Eye Study.
Archives of Ophthalmology 2002, 120:1357-63.
Schaumberg DA, Christen WG, Hankinson SE, Glynn RJ: Body mass index
and the incidence of visually significant age-related maculopathy in
men. Archives of Ophthalmology 2001, 119:1259-65.
Seddon JM, Cote J, Davis N, Rosner B: Progression of age-related macular
degeneration: association with body mass index, waist circumference,
and waist-hip ratio. Archives of Ophthalmology 2003, 121:785-92.
Tan JS, Mitchell P, Smith W, Wang JJ: Cardiovascular Risk Factors and the
Long-term Incidence of Age-Related Macular Degeneration The Blue
Mountains Eye Study. Ophthalmology 2007, 114:1143-50.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.Tomany SC, Klein R, Klein BE, Beaver Dam ES: The relationship between iris
color, hair color, and skin sun sensitivity and the 10-year incidence of
age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology
2003, 110:1526-33.
Van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, De Jong PT: The risk
and natural course of age-related maculopathy: follow-up at 6 1/2 years
in the Rotterdam study.[erratum appears in Arch Ophthalmol. 2003
Jul;121(7):955]. Archives of Ophthalmology 2003, 121(4):519-26.
Vinding T, Appleyard M, Nyboe J, Jensen G: Risk factor analysis for
atrophic and exudative age-related macular degeneration. An
epidemiological study of 1000 aged individuals. Acta Ophthalmologica
(Copenhagen) 1992, 70:66-72.
Baatz H, Darawsha R, Ackermann H, Scharioth GB, de Ortueta D, Pavlidis M,
et al: Phacoemulsification does not induce neovascular age-related
macular degeneration. Invest Ophthalmol Vis Sci 2008, 49:1079-83.
Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L: Smoking and age-related
macular degeneration. The POLA Study. Pathologies Oculaires Liees a
l’Age. Archives of Ophthalmology 1998, 116:1031-5.
Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH:
Associations of cardiovascular disease and its risk factors with age-
related macular degeneration: the POLA study. Ophthalmic Epidemiology
2001, 8:237-49.
Fraser-Bell S, Donofrio J, Wu J, Klein R, Azen SP, Varma R, et al:
Sociodemographic factors and age-related macular degeneration in
Latinos: the Los Angeles Latino Eye Study. American Journal of
Ophthalmology 2005, 139:30-8.
Fraser-Bell S, Wu J, Klein R, Azen SP, Hooper C, Foong AW, et al:
Cardiovascular risk factors and age-related macular degeneration: the
Los Angeles Latino Eye Study. Am J Ophthalmol 2008, 145:308-16.
Freeman EE, Munoz B, West SK, Tielsch JM, Schein OD: Is there an
association between cataract surgery and age-related macular
degeneration? Data from three population-based studies.[see comment].
American Journal of Ophthalmology 2003, 135(6):849-56.
Klein R, Klein BE, Franke T: The relationship of cardiovascular disease and
its risk factors to age-related maculopathy. The Beaver Dam Eye Study.
[see comment]. Ophthalmology 1993, 100(3):406-14.
Klein R, Klein BE, Linton KL, DeMets DL: The Beaver Dam Eye Study: the
relation of age-related maculopathy to smoking. American Journal of
Epidemiology 1993, 137:190-200.
Klein R, Klein BE, Jensen SC, Mares-Perlman JA, Cruickshanks KJ, Palta M:
Age-related maculopathy in a multiracial United States population: the
National Health and Nutrition Examination Survey III. Ophthalmology
1999, 106:1056-65.
Klein R, Knudtson MD, Klein BE, Wong TY, Cotch MF, Liu K, et al:
Inflammation, complement factor h, and age-related macular
degeneration: the Multi-ethnic Study of Atherosclerosis. Ophthalmology
2008, 115:1742-9.
Smith W, Mitchell P, Leeder SR, Wang JJ: Plasma fibrinogen levels, other
cardiovascular risk factors, and age-related maculopathy: the Blue
Mountains Eye Study. Archives of Ophthalmology 1998, 116:583-7.
Varma R, Fraser-Bell S, Tan S, Klein R, Azen SP, Los Angeles Latino Eye Study
Group: Prevalence of age-related macular degeneration in Latinos: the
Los Angeles Latino eye study. Ophthalmology 2004, 111:1288-97.
Vingerling JR, Hofman A, Grobbee DE, De Jong PT: Age-related macular
degeneration and smoking. The Rotterdam Study. Archives of
Ophthalmology 1996, 114:1193-6.
Wang JJ, Mitchell PG, Cumming RG, Lim R: Cataract and age-related
maculopathy: the Blue Mountains Eye Study. Ophthalmic Epidemiology
1999, 6:317-26.
Age-Related Eye Disease Study Research Group: Risk factors associated
with age-related macular degeneration. A case-control study in the age-
related eye disease study: Age-Related Eye Disease Study Report
Number 3. Ophthalmology 2000, 107:2224-32.
Blumenkranz MS, Russell SR, Robey MG, Kott-Blumenkranz R, Penneys N:
Risk factors in age-related maculopathy complicated by choroidal
neovascularization. Ophthalmology 1986, 93:552-8.
Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D,
et al: Case-control study of the risk factors for age related macular
degeneration. France-DMLA Study Group. British Journal of Ophthalmology
1998, 82:996-1002.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
Chakravarthy et al. BMC Ophthalmology 2010, 10:31
http://www.biomedcentral.com/1471-2415/10/31
Page 12 of 13

Page 13

67.Hogg RE, Woodside JV, Gilchrist SE, Graydon R, Fletcher AE, Chan W, et al:
Cardiovascular disease and hypertension are strong risk factors for
choroidal neovascularization. Ophthalmology 2008, 115:1046-52.
Hyman LG, Lilienfeld AM, Ferris FL III, Fine SL: Senile macular
degeneration: a case-control study. American Journal of Epidemiology
1983, 118:213-27.
Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, De Jong PT:
Genetic risk of age-related maculopathy. Population-based familial
aggregation study. Archives of Ophthalmology 1998, 116:1646-51.
Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y:
Smoking and neovascular form of age related macular degeneration in
late middle aged males: findings from a case-control study in Japan.
Research Committee on Chorioretinal Degenerations. British Journal of
Ophthalmology 1997, 81:901-4.
Freeman EE, Munoz B, West SK, Tielsch JM, Schein OD: Is there an
association between cataract surgery and age-related macular
degeneration? Data from three population-based studies.[see comment].
American Journal of Ophthalmology 2003, 135(6):849-56.
Klein R, Klein BE, Franke T: The relationship of cardiovascular disease and
its risk factors to age-related maculopathy. The Beaver Dam Eye Study.
[see comment]. Ophthalmology 1993, 100(3):406-14.
Van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, De Jong PT: The risk
and natural course of age-related maculopathy: follow-up at 6 1/2 years
in the Rotterdam study.[erratum appears in Arch Ophthalmol. 2003
Jul;121(7):955]. Archives of Ophthalmology 2003, 121(4):519-26.
Varma R, Ying-Lai M, Francis BA, Nguyen BB, Deneen J, Wilson MR, et al:
Prevalence of open-angle glaucoma and ocular hypertension in Latinos:
the Los Angeles Latino Eye Study. Ophthalmology 2004, 111:1439-48.
Van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, De Jong PT: The risk
and natural course of age-related maculopathy: follow-up at 6 1/2 years
in the Rotterdam study.[erratum appears in Arch Ophthalmol. 2003
Jul;121(7):955]. Archives of Ophthalmology 2003, 121(4):519-26.
Klein R, Klein BE, Tomany SC, Cruickshanks KJ: The association of
cardiovascular disease with the long-term incidence of age-related
maculopathy: the Beaver Dam eye study.[republished in Ophthalmology.
2003 Jun;110(6):1273-80; PMID: 12799274]. Ophthalmology 2003,
110(4):636-43.
Freeman EE, Munoz B, West SK, Tielsch JM, Schein OD: Is there an
association between cataract surgery and age-related macular
degeneration? Data from three population-based studies.[see comment].
American Journal of Ophthalmology 2003, 135(6):849-56.
Freeman EE, Munoz B, West SK, Tielsch JM, Schein OD: Is there an
association between cataract surgery and age-related macular
degeneration? Data from three population-based studies.[see comment].
American Journal of Ophthalmology 2003, 135(6):849-56.
Klein R, Klein BE, Linton KL: Prevalence of age-related maculopathy. The
Beaver Dam Eye Study. Ophthalmology 1992, 99:933-43.
Klein R, Klein BE, Tomany SC, Cruickshanks KJ: The association of
cardiovascular disease with the long-term incidence of age-related
maculopathy: the Beaver Dam eye study.[republished in Ophthalmology.
2003 Jun;110(6):1273-80; PMID: 12799274]. Ophthalmology 2003,
110(4):636-43.
Klein R, Klein BE, Franke T: The relationship of cardiovascular disease and
its risk factors to age-related maculopathy. The Beaver Dam Eye Study.
[see comment]. Ophthalmology 1993, 100(3):406-14.
Klein R, Klein BE, Franke T: The relationship of cardiovascular disease and
its risk factors to age-related maculopathy. The Beaver Dam Eye Study.
[see comment]. Ophthalmology 1993, 100(3):406-14.
Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML:
Association of CFH Y402H and LOC387715 A69S with progression of
age-related macular degeneration. JAMA 2007, 297:1793-800.
Haines JL, Pericak-Vance MA: Rapid dissection of the genetic risk of age-
related macular degeneration: achieving the promise of the genomic
era. JAMA 2007, 297:401-2.
Despriet DD, van Duijn CM, Oostra BA, Uitterlinden AG, Hofman A,
Wright AF, et al: Complement component C3 and risk of age-related
macular degeneration. Ophthalmology 2009, 116:474-80.
Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al:
Complement C3 variant and the risk of age-related macular
degeneration. N Engl J Med 2007, 357:553-61.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.Goldberg J, Flowerdew G, Smith E, Brody JA, Tso MO: Factors associated
with age-related macular degeneration. An analysis of data from the
first National Health and Nutrition Examination Survey. American Journal
of Epidemiology 1988, 128:700-10.
Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, et al: Dietary
carotenoids, vitamins A, C, and E, and advanced age-related macular
degeneration. Eye Disease Case-Control Study Group. JAMA 1994,
272:1413-20.
Snellen EL, Verbeek AL, Van Den Hoogen GW, Cruysberg JR, Hoyng CB:
Neovascular age-related macular degeneration and its relationship to
antioxidant intake. Acta Ophthalmologica Scandinavica 2002, 80(4):368-71.
Wong TY, Hyman L: Population-based studies in ophthalmology. Am J
Ophthalmol 2008, 146:656-63.
Freeman EE, Munoz B, West SK, Tielsch JM, Schein OD: Is there an
association between cataract surgery and age-related macular
degeneration? Data from three population-based studies.[see comment].
American Journal of Ophthalmology 2003, 135(6):849-56.
Klein R, Klein BE, Franke T: The relationship of cardiovascular disease and
its risk factors to age-related maculopathy. The Beaver Dam Eye Study.
[see comment]. Ophthalmology 1993, 100(3):406-14.
Munoz B, Klein R, Rodriguez J, Snyder R, West SK: Prevalence of age-
related macular degeneration in a population-based sample of Hispanic
people in Arizona: Proyecto VER. Archives of Ophthalmology 2005,
123:1575-80.
Van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, De Jong PT: The risk
and natural course of age-related maculopathy: follow-up at 6 1/2 years
in the Rotterdam study.[erratum appears in Arch Ophthalmol. 2003
Jul;121(7):955]. Archives of Ophthalmology 2003, 121(4):519-26.
88.
89.
90.
91.
92.
93.
94.
Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2415/10/31/prepub
doi:10.1186/1471-2415-10-31
Cite this article as: Chakravarthy et al.: Clinical risk factors for age-
related macular degeneration: a systematic review and meta-analysis.
BMC Ophthalmology 2010 10:31.
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Chakravarthy et al. BMC Ophthalmology 2010, 10:31
http://www.biomedcentral.com/1471-2415/10/31
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