Cigarette smoking and age-related macular degeneration in the EUREYE Study.

Abstract

To examine the association between cigarette smoking and age-related maculopathy (ARM) including age-related macular degeneration (AMD) in the European population.
Cross-sectional study.
Four thousand seven hundred fifty randomly sampled > or =65-year-olds from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain).
Participants underwent an eye examination and digital retinal photography. The images were graded at a single center. Smoking history was ascertained by a structured questionnaire administered by trained fieldworkers. Multinomial and binary logistic regressions were used to examine the association between smoking history and ARM grade and type of AMD, taking account of potential confounders and the multicenter study design.
Photographic images were graded according to the International Classification System for ARM and stratified using the Rotterdam staging system into 5 exclusive stages (ARM 0-3 and ARM 4, also known as AMD). Age-related macular degeneration also was classified as neovascular AMD or geographic atrophy (GA).
One hundred fifty-eight cases were categorized as AMD (109 neovascular AMD and 49 GA); 2260 had no signs of ARM (ARM 0). Current smokers had increased odds of neovascular AMD (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.4-4.8) or GA (OR, 4.8; 95% CI, 2.1-11.1), whereas for ex-smokers the odds were around 1.7. Compared with people with unilateral AMD, those with bilateral AMD were more likely to have a history of heavy smoking in the previous 25 years (OR, 5.1; 95% CI, 1.3-20.0). The attributable fraction for AMD due to smoking was 27% (95% CI, 19%-33%). There was no consistent association with ARM grades 1 to 3 and smoking.
These findings highlight the need for increasing public awareness of the risks associated with smoking and the benefit of quitting smoking. Patients with unilateral disease who are current smokers should be advised of the risk of second-eye disease.

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Cigarette Smoking and Age-Related Macular
Degeneration in the EUREYE Study
U. Chakravarthy, MD,1C. Augood, MD,2G. C. Bentham, PhD,3P. T. V. M. de Jong, MD,4M. Rahu, PhD,5
J. Seland, MD,6G. Soubrane, MD,7L. Tomazzoli, MD,8F. Topouzis, MD,9J. R. Vingerling, MD,10
J. Vioque, MD, PhD,11I. S. Young, MD,12A. E. Fletcher, PhD2
Objective:
including age-related macular degeneration (AMD) in the European population.
Design:
Cross-sectional study.
Participants:
Four thousand seven hundred fifty randomly sampled ?65-year-olds from 7 study centers
across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain).
Methods:
Participants underwent an eye examination and digital retinal photography. The images were graded
at a single center. Smoking history was ascertained by a structured questionnaire administered by trained fieldwork-
ers. Multinomial and binary logistic regressions were used to examine the association between smoking history and
ARM grade and type of AMD, taking account of potential confounders and the multicenter study design.
Main Outcome Measures:
Photographic images were graded according to the International Classification
System for ARM and stratified using the Rotterdam staging system into 5 exclusive stages (ARM 0–3 and ARM
4, also known as AMD). Age-related macular degeneration also was classified as neovascular AMD or geographic
atrophy (GA).
Results:
One hundred fifty-eight cases were categorized as AMD (109 neovascular AMD and 49 GA); 2260 had
no signs of ARM (ARM 0). Current smokers had increased odds of neovascular AMD (odds ratio [OR], 2.6; 95%
confidence interval [CI], 1.4–4.8) or GA (OR, 4.8; 95% CI, 2.1–11.1), whereas for ex-smokers the odds were around
1.7. Compared with people with unilateral AMD, those with bilateral AMD were more likely to have a history of heavy
smoking in the previous 25 years (OR, 5.1; 95% CI, 1.3–20.0). The attributable fraction for AMD due to smoking was
27% (95% CI, 19%–33%). There was no consistent association with ARM grades 1 to 3 and smoking.
Conclusions:
These findings highlight the need for increasing public awareness of the risks associated with
smoking and the benefit of quitting smoking. Patients with unilateral disease who are current smokers should be
advised of the risk of second-eye disease. Ophthalmology 2007;114:1157–1163 © 2007 by the American Academy
of Ophthalmology.
To examine the association between cigarette smoking and age-related maculopathy (ARM)
The two late manifestations of age-related maculopathy
(ARM) are important causes of adult blindness.1These late
manifestations are commonly termed age-related macular
degeneration (AMD). Neovascular AMD is characterized
by invasion of blood vessel into subretinal spaces. The other
type of AMD, geographic atrophy (GA), is characterized by
Originally received: February 21, 2006.
Accepted: September 20, 2006.
1Department of Ophthalmology, Queen’s University of Belfast, Belfast,
United Kingdom.
2Department of Epidemiology & Population Health, London School of
Hygiene & Tropical Medicine, London, United Kingdom.
3Centre for Environmental Risk, University of East Anglia, Norwich,
United Kingdom.
4Netherlands Ophthalmic Research Institute, Royal Netherlands Academy
of Arts and Sciences, and Department of Ophthalmology, Academic Med-
ical Center Amsterdam, Amsterdam, The Netherlands.
5Department of Epidemiology and Biostatistics, National Institute for
Health Development, Tallinn, Estonia.
6Øyeavdelingen, Haukeland Sykehus University of Bergen, Bergen, Norway.
7Clinique Ophthalmologique, Universitaire de Créteil, Paris, France.
8Clinica Oculistica, Università degli Studi di Verona, Verona, Italy.
9Department of Ophthalmology, Aristotle University of Thessaloniki
School of Medicine, Thessaloniki, Greece.
Manuscript no. 2006-225.
10Departments of Ophthalmology and Epidemiology & Biostatistics, Eras-
mus Medical Centre Rotterdam, Rotterdam, The Netherlands.
11Dipartimento Salud Publica Universidad Miguel Hernandez, Alicante,
Spain.
12Centre for Clinical and Population Sciences, Queen’s University of
Belfast, Belfast, United Kingdom.
Financial support: European Commission Vth Framework, Brussels, Belgium
(contract no. QLK6-CT-1999-02094). Additional funding for cameras was
provided by the Macular Disease Society, Andover, United Kingdom. Prof
Rahu was financed by the Ministry of Education and Science, Tallinn, Estonia
(targetfundingno.01921112s02).AdditionalfundinginAlicantewasreceived
from the Fondo de Investigacion Sanitaria, Madrid, Spain (grant nos. FIS
01/1692E, RCESP C 03/09), and Oficina de Ciencia y Tecnologia Generalitat
Valenciana, Valencia, Spain (grant no. CTGCA/2002/06). European Eye in-
vestigator meetings were supported by travel grants from Novartis, Basel,
Switzerland, and Pfizer Inc., New York, New York.
Correspondence and reprint requests to Prof Astrid Fletcher, Department of
Epidemiology & Population Health, London School of Hygiene & Tropical
Medicine, Keppel Street, WCIE 7HT, London, United Kingdom. E-mail:
astrid.fletcher@lshtm.ac.uk.
1157
© 2007 by the American Academy of Ophthalmology
Published by Elsevier Inc.
ISSN 0161-6420/07/$–see front matter
doi:10.1016/j.ophtha.2006.09.022

Page 2

extensive loss of the choriocapillaris and overlying retinal
pigment epithelium. The ratio of visually impairing neovas-
cular AMD to GA is around 2-fold.2The rapid pace of
population aging in many countries is likely to increase the
burden of vision loss due to AMD. Identification of major
risk factors for AMD is crucial to identifying strategies to
reduce or delay the development of this disabling condition.
The appearance of drusen and focal pigmentary irregu-
larities of the posterior retina without overt accompanying
vision loss are considered to represent early features of
AMD and usually are referred to as early ARM.3Although
not all persons with early ARM will develop the late man-
ifestations, epidemiological studies have investigated the
association of risk factors with earlier features and whether
these predict progression to AMD. Smoking has been asso-
ciated with early ARM in some studies4,5but not all,6,7and
is a predictor of incident AMD in 2 of 3 population-based
longitudinal studies.8For AMD, the evidence is more con-
sistent. A recent systematic review of the case–control,
cross-sectional, and cohort studies concluded that cigarette
smoking is an important risk factor for AMD, with the
estimates of risk of around 2- to 3-fold in smokers when
compared with nonsmokers in 13 studies.9Notably, the
review also identified the absence of any association in 5
studies and inconsistencies in the relationship between
smoking and GA and neovascular AMD and for smoking
cessation or years since smoking cessation. The effect of
smoking on severity of AMD (e.g., as measured by bilateral
disease) has not been reported. We therefore investigated
the association of cigarette smoking history with ARM,
AMD, type of AMD, and bilaterality of AMD in the EUR-
EYE Study, which is a population-based study of early
ARM and AMD in people 65 years and older in 7 European
countries using a common protocol for ophthalmic exami-
nation and grading and risk factor assessment. The main
objectives of the EUREYE Study are to investigate potential
lifestyle and environmental risk factors for early ARM and
AMD in the European setting, with a particular focus on
solar radiation and antioxidants. The study was designed
specifically to maximize the heterogeneity of these expo-
sures by inclusion of 7 centers from north to south Europe.
The EUREYE Study has a larger number of cases of both
GA and neovascular AMD than some previous population
studies due to the older age of the participants.
Materials and Methods
Methods have been described in detail elsewhere.10Briefly, a
population sample older than 65 years was drawn in each of the 7
centers: Bergen (Norway), Tallinn (Estonia), Belfast (United
Kingdom), Paris–Créteil (France), Verona (Italy), Thessaloniki
(Greece), and Alicante (Spain). People who were institutionalized,
such as those living in nursing or residential homes, were included
in the sample. A potential study participant was considered ineli-
gible if the forms were returned specifying that the person had died
or moved from the address. Participants were recruited between
November 2000 and July 2003. Letters of invitation to participate
were sent to all persons in the sample. Home visits were offered to
persons who indicated inability to travel to the study center and to
those meeting predefined criteria (e.g., in institutional care). Non-
respondents were sent up to 3 letters of invitation, and persons
refusing to participate were not contacted again. No financial
incentives were offered for taking part in the study.
Current status and smoking history were ascertained using
questions previously validated in a large study of retired British
civil servants (Whitehall study).11The questionnaire was trans-
lated into the language of the participating center and back-
translated for verification with the original English questionnaire.
Questions attempted to determine age at start of smoking, age at
cessation of smoking, and amounts smoked at different periods (up
to 25 years previously). The Whitehall study questionnaire did not
include information on amounts smoked before the previous 25
years on the basis that, in the elderly, recall might be poor beyond
this period.
At the clinical examination, after pupillary dilation two 35°
nonsimultaneous stereoscopic color fundus images were taken of
each eye, centered on the fovea. Images from participants were
saved without manipulation as raw TIFF files to compact disks and
sent to the grading center in Rotterdam. Grading was performed
using the International Classification System for ARM, which
records the presence and location of all features of ARM including
AMD within an area with a diameter of 6000 ?m centered on the
fovea.12When GA and neovascular AMD coexisted in the same
eye, this was categorized as neovascular AMD. The signs of ARM
were stratified using the Rotterdam staging system into 5 exclusive
stages: ARM 0 (no signs), ARM 1 to 3 (early ARM), and ARM 4
(also known as AMD).13Graders had no access to information on
the clinical or exposure history of participants other than center,
age, and gender. Images classified as AMD were reviewed inde-
pendently by 3 senior ophthalmologists (PTVMdJ, JRV, UC), and
differences were adjudicated. In case of doubt, cases were not
classified as AMD.
Statistical Analysis
The grading results were sent to the coordinating center at the
London School of Hygiene and Tropical Medicine and merged
with the data sent from the 7 study centers, including the smoking
variables. Standard procedures for data checks and editing were
carried out. Statistical analysis was carried out using Stata (release
8.0, Stata Corp., College Station, TX). Participants were catego-
rized as “never smokers,” ex-smokers, and current smokers. Ex-
smokers were dichotomized further into 2 groups based on the
median of the number of years since quitting smoking (20). To
obtain a quantitative value of smoking exposure, pack-years were
calculated, defined as the number of cigarettes smoked per day
divided by 20 (standard size of pack) and multiplied by the number
of years of smoking history. Pack-years were analyzed as zero and
categorized by 2 groups based on equal distribution of numbers.
Seven hundred forty-eight people who had ever smoked could not
be categorized for pack-years, either because the information was
not given (n ? 372, including 13% of current smokers) or because
they had quit smoking more than 25 years previously (n ? 376),
and our questionnaire asked only about the amount smoked in the
previous 25 years. The lower group had a mean of 7.2 pack-years
(median, 6.1), and the higher group had a mean of 20.0 pack-years
(median, 18.5). The comparison group for all analyses was never
smokers.
Multinomial (polytomous) logistic regression (relative risk ra-
tios) was used to examine the association between smoking vari-
ables and the 4 stages of ARM and for large drusen (?125 ?m.).
These categories were compared with those with ARM 0. Tests for
heterogeneity between centers and an association with ARM and
smoking were carried out. Possible confounding variables identi-
fied a priori were age, gender, diabetes, socioeconomic status, and
history of cardiovascular disease. Participants with AMD were
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subcategorized further into those with neovascular AMD or GA
and having unilateral or bilateral AMD. We used binary logistic
regression (odds ratios [ORs]) to examine smoking associations
by type and whether unilateral or bilateral AMD. The attribut-
able fraction was calculated as OR?1/OR*proportion of smok-
ers in cases, with 95% confidence intervals (CIs) calculated for
the ORs. All analyses took account of the survey design (7
centers) in the estimation of standard errors and corresponding
P values and 95% CIs.
Results
Data were complete for 4752 study participants (45% response
rate) from the 7 locations. A detailed report on participant demo-
graphics, participation rate, and prevalence of ARM and AMD is
presented elsewhere.14Two people had missing smoking data.
Overall, just over half of all EUREYE Study participants (2260)
were never smokers, and under a fifth (675) were current smokers.
No significant interactions were found between country and asso-
ciation with smoking, for early ARM, type of AMD, or bilateral
AMD, or presence of large drusen (?125 ?m.).
In analyses adjusted for age and gender, there was no consis-
tency in association between increasing severity of early ARM
(stages 1–3) and smoking (Table 1). There was a small reduced
association with ARM 1 for those who quit smoking within the
previous 20 years, but no association was observed in those who
quit smoking more than 20 years ago or when all ex-smokers were
grouped together (data not shown). Ex-smokers were more likely
to have ARM 3, but there was no association between current
smoking and ARM 3. A clear gradient between smoking history
and ARM 4 (AMD) was seen. The strongest associations were
observed for current smokers, intermediate associations were ob-
served for those who had stopped smoking within 20 years, and
associations close to 1 were observed in smokers who had quit
more than 20 years previously (Table 1).
For current smokers versus never smokers, odds of GA were
nearly 5-fold and odds of neovascular AMD were 2.5-fold
(Table 2). Ex-smokers who quit more than 20 years ago had an
OR similar to that of never smokers for GA, and for neovascular
AMD, the OR was raised (1.49) but the 95% CI overlapped 1 (P
? 0.4). Ex-smokers who had stopped smoking within the previous
20 years had around 2-fold odds of GA or neovascular AMD.
Compared with controls with no ARM, current smokers had nearly
5-fold odds of bilateral AMD (Table 3). In the comparison of
participants with unilateral AMD with those with bilateral AMD,
those who quit more than 20 years ago were significantly less
likely to have bilateral involvement.
There was no association between pack-years and ARM grades
1, 2, or 3.
There was evidence for a dose–response effect between pack-
years smoked and neovascular AMD (Table 4). The higher pack-
years group had ?5-fold odds of having bilateral advanced neo-
vascular AMD. For GA, higher ORs were observed in the lower
Table 1. Associations (Relative Risk Ratios [RRR]* and 95% Confidence Intervals [CIs]) of Smoking History with Grade of Age-
Related Maculopathy (ARM) Compared with Controls with ARM Grade 0†
Smoking Category
ARM 1‡(n ? 1733) vs.
ARM 0 (n ? 2260)
RRR (95% CI)
ARM 2§(n ? 482) vs.
ARM 0 (n ? 2260)
RRR (95% CI)
ARM 3?(n ? 117) vs.
ARM 0 (n ? 2260)
RRR (95% CI)
ARM 4¶(n ? 158) vs.
ARM 0 (n ? 2260)
RRR (95% CI)
PPPP
Never smokers (n ? 2507)
Quit ?20 yrs ago (n ? 670)
Quit ?20 yrs ago (n ? 898)
All ex-smokers (n ? 1568)
Current smokers (n ? 675)
1111
0.95 (0.68–1.33)
0.80 (0.69–0.94)
0.86 (0.72–1.03)
0.97 (0.72–1.31)
0.7
0.02
0.1
0.8
1.20 (0.76–1.89)
0.96 (0.83–1.11)
1.06 (0.84–1.32)
1.03 (0.78–1.36)
0.4
0.5
0.6
0.8
1.61 (0.94–2.78)
1.33 (0.84–2.13)
1.44 (1.03–2.03)
0.78 (0.37–1.67)
0.1
0.2
0.04
0.5
1.17 (0.51–2.69)
2.15 (1.65–2.79)
1.69 (1.10–2.59)
2.91 (1.66–5.08)
0.7
?0.0001
0.02
0.003
*Adjusted for age, age squared, and gender.
†Absence of any of the features of grades 1 to 4.
‡Presence of soft distinct drusen (?63 ?m and ?125 ?m) only or pigmentary irregularities only.
§Soft indistinct (?125 ?m) or reticular drusen only or soft distinct drusen with pigmentary irregularities.
?Soft indistinct or reticular drusen with pigmentary irregularities.
¶Neovascular age-related macular degeneration (presence of any of the following: serous or hemorrhagic retinal or retinal pigment epithelial detachment,
subretinal neovascular membrane, periretinal fibrous scar) or geographic atrophy (well-demarcated area of retinal pigment atrophy with visible choroidal
vessels).
Table 2. Associations (Odds Ratios [ORs] and 95% Confidence Intervals [CIs]) between Smoking
History and Type of Age-Related Macular Degeneration (AMD) (Geographic Atrophy [GA] or
Neovascular AMD), Compared with Controls with Age-Related Maculopathy (ARM) Grade 0
Smoking Category
Geographic Atrophy (n ? 49)
vs. ARM 0 (n ? 2260)
OR* (95% CI)
Neovascular AMD (n ? 109)
vs. ARM 0 (n ? 2260)
OR* (95% CI)
PP
Never smokers (n ? 1254)
Quit ?20 yrs ago (n ? 324)
Quit ?20 yrs ago (n ? 453)
Current smokers (n ? 324)
11
1.07 (0.35–3.25)
2.24 (1.16–4.34)
4.81 (2.08–11.08)
0.9
0.02
0.007
1.49 (0.56–3.94)
2.01 (1.42–2.84)
2.56 (1.36–4.84)
0.4
0.003
0.01
*Adjusted for age, age squared, and gender.
Chakravarthy et al ? Cigarette Smoking and AMD in the EUREYE Study
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pack-years group. Odds ratios for any history of smoking were
1.99 (95% CI, 1.41–2.79) for neovascular AMD and 2.49 (95% CI,
1.32–4.69) for GA. Attributable fractions were 24% (95% CI,
14%–30%) for neovascular AMD due to smoking and 33% (95%
CI, 13%–44%) for GA. Among those with neovascular AMD,
mean ages were 77.4 years (standard deviation [SD], 6.5) for
current smokers; 77.6 (SD, 6.6), ex-smokers; and 81.9 (SD 7.5),
never smokers. None of the results were altered materially by
inclusion of potential confounders in the models.
Smoking history, interval since stopping smoking, and pack-
years smoked were not associated with the presence of large
drusen (?125 ?m) (data not shown).
Discussion
Results from the EUREYE Study regarding the associa-
tion between AMD and current smoking history are
highly consistent with those previously reported from
other population-based studies (Table 5).5,8,15–21Our es-
timates for ex-smoking are also of the same order of
magnitude as those in other studies, although all studies
show greater variability in the estimates for ex-smoking,
probably because (as shown in the EUREYE Study) the
association varies according to the time since quitting
smoking. The point estimates from the EUREYE Study
for the ORs for the association of AMD with both current
smoking and ex-smoking fall within the 95% CIs for the
ORs from other studies, and conversely, the 95% CIs of
the estimates from the EUREYE Study include point
estimates of the ORs from the other studies.
The EUREYE Study had a lower participation rate14
when compared with some of the other major population-
based studies.15Because a participation rate of 100% is
rarely, if ever, achieved in epidemiological studies, all stud-
ies are prone to some degree of potential selection bias
because responders and nonresponders may differ.
Other large studies that have shown associations between
smoking and AMD also have suffered from selection bias,
which may have affected the effect estimates—for example,
the Pathologies Oculaires Liees a l’Age17and Age-Related
Eye Disease Study5were volunteer samples, and whether
study participants were representative of the background
population of cases and controls and their smoking expo-
sures is unknown. The extent to which the estimates of the
association between smoking and AMD are influenced by
selection bias in studies is also unknown because informa-
tion is not available on the smoking or case status of the
nonresponders. Although many studies of the general pop-
ulation have documented that smokers are less likely to
participate in studies, this would lead to a biased estimate of
effect of smoking on disease only if there were a differential
response by both smoking and case (or control) status—for
example, if AMD cases who were smokers were less likely
to attend and cases who were not smokers were more likely
to attend and the distribution of smoking in controls was the
same as that observed in the responders (or other variants on
Table 3. Associations (Odds Ratios [ORs] and 95% Confidence Intervals [CIs]) for Bilateral Age-Related Macular Degeneration
(AMD) and Smoking Status Compared with Controls with Age-Related Maculopathy (ARM) Grade 0 and Cases with
Unilateral AMD
Bilateral AMD (n ? 74) vs. ARM 0 (n ? 2260)
Smoking Category
Bilateral AMD (n ? 74) vs. Unilateral AMD (n ? 84)
Smoking CategoryOR* (95% CI)
P
OR* (95% CI)
P
Never smokers (n ? 1254)
Quit ?20 yrs ago (n ? 324)
Quit ?20 yrs ago (n ? 488)
Current smokers (n ? 352)
1Never smokers (n ? 78)
Quit ?20 yrs ago (n ? 17)
Quit ?20 yrs ago (n ? 35)
Current smokers (n ? 28)
1
0.76 (0.43–1.48)
2.58 (1.21–5.48)
4.84 (1.92–12.21)
0.4
0.02
0.01
0.49 (0.34–0.71)
1.94 (0.39–9.70)
2.44 (0.64–9.34)
0.004
0.35
0.15
*Adjusted for age, age squared, and gender.
Table 4. Associations (Odds Ratios [ORs] and 95% Confidence Intervals [CIs]) between Pack-Years of Smoking in Previous 25 Years
and (1) Type of Age-Related Macular Degeneration (AMD) (Geographic Atrophy [GA] or Neovascular AMD), Compared with
Controls with Age-Related Maculopathy (ARM) Grade 0, and (2) Cases with Bilateral AMD, Compared with Unilateral AMD*
Smoking Category
Geographic Atrophy
(n ? 45) vs. ARM 0
(n ? 1928)
OR†(95% CI)
Neovascular AMD
(n ? 93) vs. ARM 0
(n ? 1928)
OR†(95% CI)
Bilateral AMD
(n ? 65) vs. Unilateral
AMD (n ? 73)
OR†(95% CI)
PPP
Never smokers (n ? 1254)
Median of 6 pack-years (n ? 404)
Median of 18.5 pack-years (n ? 408)
Never smokers (n ? 78)
Median of 6 pack-years (n ? 29)
Median of 18.5 pack-years (n ? 31)
11
3.90 (2.17–7.03)
2.27 (1.27–4.05)
0.001
0.01
1.82 (1.13–2.96)
2.86 (1.69–4.85)
0.02
0.003
1
0.94 (0.23–3.92)
5.08 (1.29–20.00)
0.8
0.03
*Excludes 354 people (235 quit more than 25 yrs previously and 119 with missing information on amount smoked).
†Adjusted for age, age squared, and gender.
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this theme). In the example above, the OR due to smoking
for AMD would be higher in the group of nonresponders
than in the responders, and thus, the OR in the study sample
would be underestimated. In the EUREYE Study, we con-
sider that a differential response rate by smoking history and
case status is unlikely, as case and control status was not
ascertained before the invitation to participate. The consis-
tency of the estimates for smoking and AMD across the
many population-based cross-sectional and cohort studies
and clinic-based studies therefore suggests that differential
selection by smoking and case–control status is likely to be of
a small order.
The EUREYE Study also has provided additional evi-
dence for the association between smoking and both late
manifestations of AMD. Other population-based studies
have examined associations between smoking and type of
advanced AMD; however, the small number of prevalent
cases with either GA or neovascular AMD has limited their
power to detect associations (Table 5). The Beaver Dam
Eye Study reported no significant relationship between
Table 5. Association of Smoking and Age-Related Macular Degeneration (AMD) in the EUREYE and Other Studies (Odds or Risk
Ratios and 95% Confidence Intervals)
Study NameDesign
Cases of AMD/Controls or
Population Size Ex-smoker
Current
Smoker
Odds ratio (95% confidence interval)
Cross-sectional or case–control studies
EUREYE (present study)Population based cross-sectional,
ages ?65 yrs
158/2245, all AMD
49/2245, GA
109/2245, neovascular AMD
74/6109, all AMD
30/6065, GA
35/6070, neovascular AMD
72/3253, all AMD
21/3202, GA
41/3222, neovascular AMD
48/2936, all AMD
12/2900, GA
33/2921, neovascular AMD
41/1500, AMD
1.70 (1.14–2.56)
1.79 (0.90–3.56)
1.75 (1.13–2.71)
1.34 (0.75–2.37)
1.38 (0.57–3.30)
2.53 (0.99–6.44)
1.47 (0.87–2.49)
2.10 (0.85–5.17)
1.46 (0.71–2.97)
1.21 (0.62–2.36)
1.14 (0.30–4.31)
1.11 (0.50–2.48)
2.8 (1.1–6.9)
3.01 (1.72–5.26)
4.89 (2.12–11.27)
2.55 (1.40–4.66)
3.11 (1.72–5.62)
2.62 (1.03–6.62)
7.07 (2.80–17.84)
2.39 (1.14–4.96)
0.77 (0.09–6.34)
3.32 (1.39–7.90)
4.22 (1.90–2.37)*
5.82 (1.27–26.71)
4.18 (1.66–10.53)
3.6 (1.0–12.5)
Rotterdam15
Population based cross-sectional,
ages ?55 yrs
Beaver Dam15
Population based cross-sectional,
ages 43–86 yrs
Blue Mountains15
Population based cross-sectional,
ages ?49 yrs
Pathologies Oculaires Liees a
l’Age17
Medical Research Council
Screening Study18
Volunteer community sample,
ages ?60 yrs
Community survey of visual
impairment and causes, ages
?75 yrs
Clinic based case–control, ages
?55 yrs
Cross-sectional associations at
baseline from participants in
randomized controlled trial
of vitamin supplements, ages
55–80 yrs
513/4357, all AMD 1.13 (0.88–1.44)2.33 (1.61–3.37)
Eye Disease Case-Control Study16
421/615, neovascular AMD 1.5 (1.2–2.1) 2.2 (1.4–3.5)
Age-Related Eye Disease Study5
776/1115, all AMD (GA,
118; neovascular AMD,
658)
Ever smoked for at
least 6 mos
1.61 (1.06–2.42)
1.91 (1.57–2.33)
Risk ratio (95% confidence interval)
Prospective incidence studies
Rotterdam15
5-yr follow-up of population-
based cross-sectional study
38/3620, all AMD
15/3615, GA
25/3629, neovascular AMD
30/3496, all AMD
12/3506, GA
19/3494, neovascular AMD
34/2314, all AMD
11/2291, GA
23/2322, neovascular AMD
215/31 843, AMD
3.29 (1.17–9.22)
1.81 (0.36–9.10)
5.52 (1.44–21.3)
0.95 (0.39–2.31)
0.82 (0.21–3.23)
1.14 (0.38–3.39)
0.98 (0.42–2.29)
0.93 (0.21–4.19)
1.00 (0.37–2.72)
2.0 (1.2–3.4)
6.32 (2.10–19.1)
6.65 (1.34–32.9)
6.19 (1.37–27.9)
0.33 (0.04–2.51)
Not estimated
0.54 (0.07–4.48)
3.19 (1.16–8.75)
5.32 (1.16–24.5)
2.08 (0.55–7.88)
?25 cigarettes
daily
2.4 (1.4–4.0)
?20 cigarettes
daily
2.46 (1.60–3.79)
Beaver Dam15
5-yr follow-up of population-
based cross-sectional study
Blue Mountains8
Prospective cohort study, 5-yr
follow-up of population-based
cross-sectional study
Prospective cohort study,
average 17-yr follow-up,
visually impairing AMD
Prospective follow-up, average
12-yr follow-up, visually
impairing AMD
Nurses Health Study19
Physicians Health Study20
268/21 157, AMD1.30 (0.99–1.70)
GA ? geographic atrophy.
*Estimate and confidence intervals from reference cited (confidence interval not consistent with estimate).
Chakravarthy et al ? Cigarette Smoking and AMD in the EUREYE Study
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smoking status and prevalent GA, whereas it established an
adverse association with neovascular AMD.15There were
only 21 GA cases, and the CIs included an OR of 6.34 (i.e.,
close to the estimates of the EUREYE Study for GA). The
Rotterdam Eye Study also found an increased association of
current smoking with GA, although of a smaller magnitude
than that observed in the EUREYE Study and the Blue
Mountains Eye Study and lower than the association re-
ported for neovascular AMD in the Rotterdam Eye Study15
(Table 5). The Blue Mountains Eye Study found that ciga-
rette smoking increased the risk for both forms of late
disease, and the OR for current smoking and GA was 5.8
(CI, 1.3–26.7), which is consistent with the magnitude of
effect observed in the EUREYE Study (Table 5). The ORs
for ex-smoking and current smoking in the Eye Disease
Case Control Study were slightly lower than ours but fell
within our 95% CIs.17
In the EUREYE Study, ORs steadily increased for both
GA and neovascular AMD, with those who ceased smoking
more than 20 years previously having a risk similar to those
of never smokers, and those who quit within 20 years
exhibiting a risk approximately half that of current smokers.
These findings are similar to a recently reported study in an
older British cohort in which those who had stopped 20
years or more previously had no excess risk of AMD.18The
relationship between pack-years of smoking and neovascu-
lar AMD was consistent with a dose–response effect. How-
ever, an inexplicable finding in the present study was the
higher OR of GA seen in the lower median pack-years
group compared with the higher median pack-years group
(4.02 vs. 2.41, P?0.04). It is possible that the findings are
a reflection of the increased mortality associated with the
longer periods of smoking habit in the higher median pack-
years group.
The EUREYE Study is the first to report an excess risk
of bilateral advanced AMD in current smokers and heavy
smokers. This finding highlights the importance of promot-
ing smoking cessation advice to patients with unilateral
disease who are current smokers.
In the EUREYE Study, consistent relationships were not
observed between history of cigarette smoking and the
different levels of ARM severity. For ARM 3 alone, we
found an association with past smoking but not with current
smoking. It is possible that this association could represent
a change in smoking habit after a diagnosis of AMD. We
did not collect information on reasons for stopping smok-
ing; however, similar weak and inconsistent associations
between smoking and early ARM features have been ob-
served in other epidemiological studies, including those in
which incidence was monitored. These findings suggest that
the majority of the group of subjects classified as having
early ARM are at low risk of progression to AMD, and
hence, the effects of smoking on early ARM in a cross-
sectional study are likely to be diluted substantially. Al-
though 5-year progression rates are low in those with early
ARM, current smoking was associated with a 3- to 6-fold
risk of incident AMD in the Blue Mountains Eye and
Rotterdam Eye studies but not in the Beaver Dam Eye
Study8(Table 5), whereas in the Age-Related Eye Disease
Study trial, progression from bilateral drusen to neovascular
AMD or central GA was associated with cigarette smoking,
with estimates of risk of 1.6 and 1.8, respectively.21
There has been considerable debate on the cellular mech-
anisms leading to choroidal neovascularization that are in-
volved in mediating the toxic effects of cigarette smoking.
Studies show that exposure to constituents of cigarette
smoke increases the presence of proinflammatory cytokines
in ex vivo tissue preparations22and the size and severity of
choroidal neovascularization in experimental animal mod-
els,23suggesting direct toxic effects. The discovery that a
common coding variant (Y402H) in the complement factor
H gene24–29could be responsible for up to half of all cases
of advanced AMD has generated much discussion about
possible gene–environment interactions (e.g., with smok-
ing). Cigarette smoking has been shown to trigger the al-
ternative pathway of complement activation and increase
leukocyte recruitment in both endothelial and epithelial
tissues.30,31At present, it is unclear how the tyrosine–
histidine change in the complement factor H gene influences
susceptibility to advanced AMD in smokers with the at-risk
allele. However, these foregoing findings are consistent
with the present study, which shows that current smokers
are more likely to have bilateral involvement and develop
disease earlier. Recently, the LOC387715 variant emerged
as a second major gene for AMD risk, with a strong statis-
tical interaction found between this variant and a history of
cigarette smoking.32
The EUREYE Study is the first major pan-European
study that has examined the prevalence of and risk factors
for AMD. It has confirmed the risk of AMD from smoking
and, in particular, highlighted the association between
smoking and GA and the increased risk of blindness through
bilateral involvement. We estimate that around 1 in 4 cases
of neovascular AMD and a third of cases of GA could be
prevented by not smoking. These estimates of attributable
risk are based on a prevalence of ever smoking of 47%
(74% in men and 24% in women). These figures are very
similar to those reported from a survey of 12 European
countries (including 5 of the countries represented in the
EUREYE Study) showing that 71% of men ages 45 to 74
years and 24% of women reported ever smoking.33The
same study also reported that although smoking prevalence
was slightly lower (64%) in younger men (ages 20–44) than
in older men, smoking prevalence was substantially higher
in younger women (46%) than in older women. It is likely,
therefore, that the attributable risks for smoking and AMD
will rise considerably as these cohorts age. On a more
positive note, our results show that the adverse effects of
smoking can be reduced with long-term cessation. These
findings highlight the need for increasing public awareness
of the risks associated with smoking and benefits of quitting
smoking.
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