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Body Mass Index and the Incidence of Visually Significant Age-Related Maculopathy in Men
Debra A. Schaumberg, ScD, MPH;
William G. Christen, ScD;
Susan E. Hankinson, ScD;
Robert J. Glynn, PhD
Arch Ophthalmol. 2001;119:1259-1264.
ABSTRACT
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Background Reports have suggested relationships of body weight with age-related
maculopathy (ARM), particularly its nonneovascular (dry) forms, but results
are inconsistent and prospective data are scarce.
Objective To examine prospectively relationships of body mass index (BMI; calculated
as weight in kilograms divided by the square of height in meters) with visually
significant dry and neovascular ARM during an average of 14.5 years of follow-up.
Methods Incident ARM was assessed by medical record confirmation of self-reported
ARM among the 21 121 men participating in the Physicians' Health Study
who (1) were followed up for at least 7 years, (2) were free of visually significant
ARM at baseline, and (3) had information on BMI and cigarette smoking. We
used proportional hazards regression models to estimate rate ratios (RRs)
and 95% confidence intervals (CIs) for visually significant dry ARM (256 cases)
and neovascular ARM (84 cases) within 4 categories of BMI: lean (<22.0),
normal (22.0-24.9), overweight (25.0-29.9), and obese ( 30.0).
Results Adjusting for age, randomized aspirin and beta carotene assignments,
and cigarette smoking, the incidence for visually significant dry ARM was
lowest in men with a normal BMI. Compared with these men, the RRs (95% CIs)
were as follows: 1.43 (1.01-2.04) for lean, 1.24 (0.93-1.66) for overweight,
and 2.15 (1.35-3.45) for obese men. Although there was no significant relationship
of BMI with the diagnosis of neovascular ARM, due to the small number of cases
these analyses could not rule out an important relationship.
Conclusions Obesity is a risk factor for visually significant ARM in men, in particular
for dry ARM. However, the relationship of BMI with dry ARM appears to be J-shaped,
and the leanest individuals also appear to be at increased risk.
INTRODUCTION
AGE-RELATED maculopathy (ARM), a degenerative condition affecting the
central regions of the retina and choroid, is the leading cause of blindness
among older adults in developed countries, including the United States.1-5
Because its prevalence increases dramatically with age, ARM is likely to become
an even greater public health problem in the future. Age-related maculopathy
is not treatable in most cases; thus, a preventive approach is desirable.
To this end, epidemiologic studies have been undertaken to identify potentially
modifiable factors associated with the development of ARM.
Although much progress has been made in understanding the disease, the
causes of ARM remain largely unknown. At least as early as 1937, some investigators
proposed that ARM might be related to systemic arterial vascular disease.6-8 In conjunction with
the retinal pigment epithelium and Bruch membrane, choroidal vessels underlying
the macular region of the retina are thought to be involved in clearing metabolic
waste material from the eye. It is plausible that a dysfunction in these vessels
may be associated with increased risk of ARM. Histologic studies of eyes with
ARM have shown a decreased density and cellularity of choroidal capillaries
and thickening of intercapillary pillars9-11;
angiographic studies have demonstrated slowed filling of the choroidal capillaries.12
Consistent with the idea that vascular disease may be a risk factor
for ARM, some,13-14 though not
all,15-16 epidemiologic studies
have found a higher risk of ARM in subjects with cardiovascular disease (CVD).
In addition, a number of studies have found that several CVD risk factors
are also associated with ARM. For example, cigarette smoking, a well-known
cause of CVD, has been consistently identified as a risk factor for ARM, including
in 2 large prospective follow-up studies.17-18
To date, however, studies of other potentially modifiable CVD risk factors
that might also increase risk of ARM, such as overweight and obesity,19-22 have
yielded inconsistent results,19, 23
and there are few prospective studies.20
The Physicians' Health Study (PHS) was a randomized trial of aspirin
and beta carotene in prevention of CVD and cancer in men,24-25
in which information on diagnoses of ARM was also collected.17
In the present study we examined prospectively the relationship of body mass
index (BMI) with the incidence of ARM during an average of 14.5 years of follow-up.
Since it remains unclear whether the factors predisposing to the dry and neovascular
forms of ARM are the same, and previous associations between BMI and ARM appeared
strongest for dry ARM,20, 22 we
looked separately at the relationships of BMI with dry and neovascular ARM.
SUBJECTS AND METHODS
The PHS was a randomized, double blind, placebo-controlled trial that
tested the balance of benefits and risks of alternate-day low-dose aspirin
and beta carotene on cardiovascular disease and cancer, as well as cataract
and macular degeneration.24-26
The PHS population, consisting of 22 071 apparently healthy male US physicians
aged 40 to 84 years at study entry, was free of cancer (except possibly basal
or squamous cell skin cancer), myocardial infarction, stroke, transient cerebral
ischemia, current renal or liver disease, peptic ulcer, and gout. The active
treatment phase of both arms of the trial has ended,24-25
but observational follow-up of the PHS cohort is ongoing.
EXPOSURE MEASURES
At study entry, participants completed a mailed questionnaire on which
they reported their height and weight as well as other characteristics such
as blood pressure, diabetes mellitus, high cholesterol, cigarette smoking,
alcohol consumption, and vitamin use. Relationships of cigarette smoking,17 alcohol consumption,27
and vitamin use28 with ARM in the PHS have
been described in previous reports.
Participants were followed up prospectively every 6 months during the
first year and then annually with mailed questionnaires on which they were
asked to update some exposure data and report diagnoses of health events.
Weight was updated annually starting with the 8-year questionnaire. In a validation
study of 123 male health professionals from a similar cohort, the correlation
between self-reported and technician measurement of weight was 0.97.29
ASCERTAINMENT OF ARM
Beginning with the 7-year follow-up questionnaire, we asked participants
about the diagnosis of macular degeneration. On all subsequent questionnaires,
information was updated with incident cases of ARM, including the month and
year of diagnosis and the name and address of the diagnosing eye doctor, and
signed permission to review medical records. For each report of ARM, we sent
to the identified ophthalmologist or optometrist a letter containing a brief
questionnaire to obtain information on the date of diagnosis, the best-corrected
visual acuity at the time of diagnosis, the date when visual acuity first
reached 20/30 or worse if later than the date of the initial diagnosis, and
the chorioretinal lesions that were observed at diagnosis (drusen; retinal
pigment epithelial changes including atrophy, hypertrophy, and retinal pigment
epithelial detachment; geographic atrophy; subretinal neovascular membrane;
and/or disciform scar). In the presence of other anomalies, the eye doctor
was asked to judge whether, in the absence of the other abnormality, he or
she would expect the visual acuity to be 20/30 or worse because of ARM. For
the present study, ARM was defined as the presence
of 1 or more typical lesions associated with a visual acuity loss to 20/30
or worse from these lesions. The visual acuity criterion was included in the
definition to reduce the possibility of surveillance bias and because we were
interested in determinants of visually significant disease. We defined neovascular macular degeneration as the presence of a retinal
pigment epithelial detachment, subretinal neovascular membrane, or disciform
scar that was not due to other causes (eg, histoplasmosis or choroidal rupture). Dry ARM was defined as confirmed ARM with vision loss as
described above, but with no signs of neovascular macular degeneration.
STUDY POPULATION
We excluded 950 subjects who were not followed up for at least 7 years
(the first time that ARM was assessed) or had missing information on BMI or
cigarette smoking, or who reported a diagnosis of ARM that was made before
study entry. After these exclusions, 21 121 participants were followed
up from their date of study entry until the date of diagnosis of ARM, death,
or December 1997, whichever came first.
STATISTICAL ANALYSIS
In all analyses, we classified individuals rather than eyes, because
the same examiner presumably made assessments at the same time for both eyes
of each participant (ie, classification of the 2 eyes was not independent).
We considered a participant to have ARM at the time it was diagnosed in at
least 1 eye. We initially fit separate models for dry and neovascular ARM
because risk factors for the 2 forms of the disease may differ, and previous
studies indicated that BMI might be a stronger risk factor for the dry form
of the disease.20, 22 Additional
models were also fit for the combined end point of all visually significant
ARM. We examined relationships for categories of BMI formed by means of cutoff
points defined a priori. We calculated each participant's BMI at the time
of each weight assessment as his weight in kilograms divided by the square
of his height in meters. We formed 4 categories of BMI (<22.0, 22.0-24.9,
25.0-29.9, and 30.0). The upper 2 categories correspond to the definitions
of overweight and obesity as adopted by a number of organizations such as
the US National Heart, Lung, and Blood Institute and the World Health Organization.30 For clarity of presentation, we have defined the
lower 2 categories as lean (<22.0) and normal (22.0-24.9).
In initial analyses, we obtained age- and smoking-adjusted rate ratios
(RRs) of ARM by category of BMI in proportional hazards regression models
adjusting for age, cigarette smoking (never, past, current <20 cigarettes
per day, current 20 cigarettes per day), and, because subjects were participants
in a randomized trial, randomized aspirin and beta carotene assignments. In
these analyses, we allowed BMI to vary over time as a time-varying covariate
in the proportional hazards models, using the nearest past BMI measurement
available for each participant. In additional models, we further adjusted
for height in categories of less than 170 cm, 171 to 178 cm, 179 to 183 cm,
and 184 cm or more, as well as other potential risk factors including alcohol
consumption and vitamin supplement use. To investigate the possibility of
residual confounding, we also fit models in which we adjusted for pack-years
of cigarette smoking as described previously,17
as well as alcohol consumption (1 or more drinks per day, 1 to 6 drinks per
week, 1 to 3 drinks per month, and rarely or never), vitamin E (never, past,
and current) and vitamin C (never, past, and current) supplement use, and
mean daily servings of vegetables (sum of servings of broccoli, brussels sprouts,
carrots, spinach, dark green lettuce, yellow squash, yams or sweet potatoes,
tomato juice, and tomatoes), fruits (sum of servings of orange juice, cantaloupe,
peaches, apricots, and nectarines), and cold breakfast cereal. Dietary information
was obtained by means of a brief food frequency questionnaire.31
Finally, we explored whether relationships of BMI with ARM were different
in younger vs older men by fitting separate proportional hazards models for
those who were aged 75 years and older and those who were younger than 75
years. Similarly, we investigated whether the effect of BMI appeared to differ
according to smoking status by fitting separate models for never, past, and
current smokers.
RESULTS
Visually significant dry ARM was confirmed in 256 participants during
a total follow-up of 305 827 person-years (mean, 14.5 years). In addition,
84 participants developed neovascular ARM during 307 341 person-years
(mean, 14.6 years) of follow-up. Table 1 displays the prevalence of potential confounding and intermediate
factors within categories of baseline BMI. The prevalence of diabetes, hypertension,
and cigarette smoking was higher among the men with higher BMI, while the
prevalence of vitamin supplement use and daily alcohol consumption was lower.
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Table 1. Age-Adjusted Relationships of Body Mass Index With Other Potential
Risk Factors for Age-Related Maculopathy in the Physicians' Health Study*
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For visually significant dry ARM, with adjustment for age and cigarette
smoking, the relationship with BMI appeared to be J-shaped (Table 2). Compared with men with a normal BMI, lean men had an RR
(95% confidence interval [CI]) of ARM of 1.43 (1.01-2.04), overweight men
had an RR (95% CI) of 1.24 (0.93-1.66), and obese men had an RR (95% CI) of
2.15 (1.35-3.45). A likelihood ratio test comparing the model with 4 categories
of BMI with one with a single variable indicating the trend across BMI categories
was significant (P = .008), confirming the nonlinear
nature of the BMI and ARM relationship.
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Table 2. Rate Ratios (RRs) and 95% CIs for Visually Significant Dry
Age-Related Maculopathy According to Body Mass Index*
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Adjustment for height as well as vitamin supplement use and alcohol
consumption did not change the magnitude of the association between BMI and
dry ARM (Table 2). Further adjustment
for frequency of consumption of fruits, vegetables, or breakfast cereal, as
well as pack-years rather than 3 categories of cigarette smoking, also had
little impact on the RR estimates for obesity (RR [95% CI], 2.18 [1.29-3.68]
for obese vs normal), although the RR for the lean men was slightly attenuated
(Table 2). The association between
BMI and dry ARM (RR, 2.05; 95% CI, 1.26-3.34, for obese vs normal) also persisted
in models controlling for the potential intermediate variables diabetes mellitus
and hypertension (Table 2).
There was no significant association of BMI with the neovascular form
of ARM in these data (Table 3),
but the small number of neovascular cases limited the analyses. Lean men had
an RR (95% CI) of neovascular ARM of 1.03 (0.56-1.88); overweight men had
an RR (95% CI) of 0.81 (0.49-1.34); and obese men had an RR (95% CI) of 1.15
(0.45-2.94) compared with men whose BMI was normal.
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Table 3. Rate Ratios (RRs) and 95% CIs for Visually Significant Exudative
Age-Related Maculopathy According to Body Mass Index*
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Results of analyses for the combined end point of all visually significant
ARM (dry or neovascular) were similar to those for dry ARM and were most consistent
with a J-shaped relationship, although the magnitude of the RRs was attenuated
compared with the estimates for dry ARM. Compared with men with a normal BMI,
lean men had an RR (95% CI) of ARM of 1.30 (0.95-1.76), overweight men had
an RR (95% CI) of 1.08 (0.84-1.39), and obese men had an RR (95% CI) of 1.92
(1.27-2.89).
In subgroup analyses (Table 4),
the relationship of obesity with dry ARM persisted in men younger than 75
years as well as those aged 75 years and older. However, in these models,
the increased risk of dry ARM among the lean men was most apparent for those
younger than 75 years. Similarly, obese men appeared to have an increased
risk of dry ARM regardless of smoking status, while the increased risk of
dry ARM among the lean men was found primarily among the subgroup who had
never smoked.
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Table 4. Rate Ratios (RRs) and 95% CIs for the Relationship of Body
Mass Index With Visually Significant Dry Age-Related Maculopathy According
to Age and Cigarette Smoking*
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COMMENT
These prospective data from a large cohort of men indicate that obesity
is a risk factor for visually significant dry ARM. In addition, the leanest
men (those with a BMI <22.0) were also at higher risk of dry ARM. This
relationship of BMI with ARM was independent of age and cigarette smoking
and did not appear to be explained by an increased risk of diabetes or hypertension,
plausible intermediate variables. Although there were no significant findings
with regard to neovascular ARM, the number of participants with the neovascular
form of ARM was too small to rule out an important effect of body weight.
Strengths of the present study include its large size, prospective design,
careful data collection, and low loss to follow-up. We were not able to examine
subjects directly, however, so identification of subjects with ARM relied
on their seeking medical attention, being diagnosed, and then reporting their
diagnoses on study questionnaires. Consequently, underascertainment of ARM
is a concern, and the results of the present study must be interpreted in
light of this limitation. However, underascertainment of outcomes does not
bias results in a follow-up study if the specificity of the diagnosis is high.32 Specificity is likely to be high in the present study
because all self-reports of ARM were confirmed by review of medical records,
and this method of case detection has been associated with a high specificity
(>99%) in a similar cohort of nurses.18 Differential
rates of ARM ascertainment by exposure category is of greater concern and
could cause bias in either direction. Unfortunately, we did not have information
on the frequency with which subjects had their eyes examined, so it was not
possible to perform a quantitative assessment of the degree to which detection
bias may have influenced our findings. However, to decrease the likelihood
of such bias, we limited our analysis to cases of ARM with associated vision
loss, since it is less likely that participants with decreased vision would
fail to seek medical attention. In addition, when we controlled in some models
for factors, such as diabetes mellitus and hypertension, that could lead to
more frequent ophthalmic visits, the estimates for BMI were not changed substantially.
All subjects in the present study were male physicians, and therefore
this was not a random sample of the total US population. However, if valid,
the findings would not be generalizable to other men only if the basic biological
mechanisms involved in the development of ARM were somehow different among
physicians as compared with other men,32 which
seems very unlikely. On the other hand, since many basic differences do exist
between men and women, the findings may not be generalizable to women, although
other studies have shown similar relationships of BMI with ARM in women and
men.20, 22 A prospective study
of the relationship of BMI with ARM in a large cohort of women would add important
information on this issue.
Body weight, a strong predictor of coronary heart disease risk and death
from CVD,33-36
was of borderline significance in the Eye Disease Case-Control Study of risk
factors for neovascular macular degeneration,21
and the increased risk appeared to be limited to those with BMI of 30 or more.
Of 3 cross-sectional studies that have looked at the relationship of BMI with
ARM, 1 found no relationship with the combined end point of atrophic or neovascular
macular degeneration,23 and 1 observed an increased
risk of retinal pigment abnormalities but not neovascular ARM in women with
higher BMI.19 In a subsequent report on incidence
and progression of ARM during 5 years, these investigators found a significant
relationship of higher BMI with increases in retinal pigment in both men and
women, but still found no association with other signs of the disease or with
neovascular macular degeneration.20 The possibility
of a nonlinear association was apparently not investigated in these studies.
In a recent cross-sectional study from Australia, a J- or U-shaped association
was observed between BMI and early ARM, diagnosed by fundus photographs.22 Similarly, in the present study, the relationship
of BMI with visually significant ARM appeared to be J-shaped, with the highest
incidence among obese men with a BMI of at least 30 and a somewhat less elevated
incidence among the leanest men with a BMI less than 22. Also similar to other
authors,20, 23 we could identify
no significant relationship of BMI with neovascular ARM in the present study,
but the number of participants with this late form of macular degeneration
was relatively small, and consequently the CIs were too wide to rule out an
important effect. Further study of whether BMI is a risk factor for neovascular
ARM in studies of sufficient size is needed.
Although these results add to the existing evidence that certain CVD
risk factors such as BMI are also related to the development of ARM, the relationship
of BMI with ARM appears to be more complex and nonlinear. In particular, results
of this as well as 1 previous study in which all subjects were examined are
most consistent with an increased risk of dry ARM not only in those who are
obese but also in the leanest men; therefore, the relationship of BMI with
ARM, if causal, may be mediated by mechanisms other than vascular disease
per se, which has a monotonic relationship with BMI. For example, obesity
is related to higher levels of oxidative stress, which has been implicated
as a probable contributing cause of ARM. It is important to consider that
the mechanisms underlying the relationships of ARM with obesity on the one
hand and leanness on the other could be different. A relationship of leanness
with ARM is more difficult to explain biologically, but similar relationships
have been seen, for example, with mortality.36-37
Although the increased risk of mortality among the leanest individuals is
largely attributable to the adverse effects of cigarette smoking in at least
some studies,36-37 this does not
appear to be the case for ARM, for which the relationship of leanness with
ARM was, if anything, strongest among never-smokers. One could speculate that
deficiencies in 1 or more important nutrients in the diets of the leanest
men could have led to the higher risk of ARM we observed among this group.
For example, certain micronutrients have been shown previously to predict
the development of macular degeneration.38
However, when we explored the possibility that the relationship of BMI with
ARM might be explained by differences in consumption of fruits, vegetables,
or cereal, we did not observe any indication of substantial confounding effects.
Whether the relationship of BMI with ARM might be explained by differential
intake of specific nutrients will require further study. Another remaining
possibility is that our findings are due to residual confounding by some other
factor. One possibility in this regard is that the leanest men may have had
a family history of vascular disease that motivated them to remain lean. Indeed,
in the PHS, the prevalence of a history of myocardial infarction in either
parent before age 60 years was U-shaped and highest among the lean and the
obese men. However, controlling for family history of vascular disease did
not have any impact on the J-shaped relationship of BMI with ARM in this study
(data not shown). Residual confounding by other factors not measured in the
current study remains a possible explanation.
In conclusion, results from this prospective study indicate that BMI
is an independent predictor of the dry form of visually significant ARM. The
relationship appears to be J-shaped, and both obese and lean men appear to
have an elevated risk of dry ARM compared with men whose BMI is normal. If
indicative of a causal relationship, these data imply that interventions to
reduce the prevalence of obesity, which would also result in numerous other
health benefits, could help to lessen the incidence of ARM. Our finding of
an apparent excess risk of ARM among the leanest men warrants further study.
AUTHOR INFORMATION
Accepted for publication February 12, 2001.
Corresponding author: Debra A. Schaumberg, ScD, MPH, Division of
Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave E,
Boston, MA 02215 (e-mail: dschaumberg{at}rics.bwh.harvard.edu).
From the Division of Preventive Medicine (Drs Schaumberg, Christen,
and Glynn) and Channing Laboratory (Dr Hankinson), Brigham and Women's Hospital,
Harvard Medical School, and Departments of Epidemiology (Dr Hankinson) and
Biostatistics (Dr Glynn), Harvard School of Public Health, Boston, Mass.
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