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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Ophthalmol. Author manuscript; available in PMC Nov 6, 2006.
Published in final edited form as:
PMCID: PMC1634828
NIHMSID: NIHMS13380

Body Mass Index and the Incidence of Visually Significant Age-Related Maculopathy in Men

Abstract

Objective

Previous reports have suggested relationships of body weight with age-related maculopathy (ARM), particularly the non-neovascular (dry) forms of the disease, but results are inconsistent and prospective data are scarce. The present study was undertaken to examine prospectively relationships of body mass index (BMI) with visually significant dry and neovascular ARM over an average of 14.5 years of follow-up in the Physicians’ Health Study (PHS).

Methods

Incident ARM was assessed by medical record confirmation of self-reported ARM among the 21,121 male U.S. physicians participating in the PHS who 1) were followed 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 (RR) and 95% confidence intervals (CI) for visually significant dry ARM (256 cases) and neovascular ARM (84 cases), as well as for the combined end point of all visually significant ARM (340 cases), within four categories of BMI defined as: lean (<22 kg/m2), normal (22–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2).

Results

After adjusting for age, randomized aspirin and beta-carotene assignments, and cigarette smoking the incidence rate for visually significant dry ARM was lowest in men with a normal BMI. Compared to these men, the RR (CI) were: 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, the small number of cases resulted in wide CI, and these analyses could not rule out an important relationship. Results of analyses combining all cases of visually significant ARM were similar to those for the dry subtype.

Conclusions

This prospective study suggests that obesity is a risk factor for visually significant ARM in men, in particular for the dry forms of the disease. 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 (15). Because its prevalence increases dramatically with older age, ARM is likely to become an even greater public health problem in the future. ARM is not treatable in the majority of 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 etiology of ARM remains largely unknown. At least as early as 1937, some investigators proposed that ARM might be related to systemic arterial vascular disease (68). In conjunction with the retinal pigment epithelium (RPE) and Bruch’s 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 pillars (911); and 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 two 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/obesity (1922) 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 over 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 relations of BMI with dry and neovascular ARM.

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 (2426). 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

Baseline 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 use (28) with ARM in the PHS have been described in previous reports.

Longitudinal measures

Participants were followed prospectively every six 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 a letter to the identified ophthalmologist or optometrist 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 chorio-retinal lesions that were observed at diagnosis (drusen; RPE changes including atrophy, hypertrophy and RPE detachment; geographic atrophy; subretinal neovascular membrane; 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 due to ARM. For the present study, ARM was defined by the presence of one or more typical lesions associated with a visual acuity loss of 20/30 or worse from these lesions. The visual acuity criterion was included in the definition to reduce the possibility of surveillance bias, and since we were interested in determinants of visually significant disease. We defined neovascular macular degeneration as the presence of an RPE detachment, subretinal neovascular membrane, or disciform scar that was not due to other causes (e.g. histoplasmosis, choroidal rupture). Dry age-related maculopathy 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 for at least seven 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 prior to study entry. After these exclusions, a total of 21,121 participants were followed 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 (i.e., classification of the two eyes was not independent). We considered a participant to have ARM at the time it was diagnosed in at least one eye. We initially fit separate models for dry and neovascular ARM because risk factors for the two 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 using cut 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 four categories of BMI (<22, 22–24.9, 25–29.9, and [exists]30 kg/m2). The upper two categories correspond to the definitions of overweight and obesity as adopted by a number of organizations such as the U.S. National Heart, Lung, and Blood Institute and the World Health Organization (30). For clarity of presentation, we have defined the lower two categories as lean (<22) and normal (22–24.9).

In initial analyses, we obtained age- and smoking-adjusted rate ratios (RR) of ARM by category of BMI in proportional hazards regression models adjusting for age, cigarette smoking (never, past, current <20 cigarettes per day, current [exists]20 cigarettes per day) and, since 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 <170 cm, 171 to 178 cm, 179 to 183 cm, and ≥184 cm, 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, rarely or never), vitamin E (never, past, current) and vitamin C (never, past, 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, or tomatoes), fruits (sum of servings of orange juice, cantaloupe, peaches, apricots or nectarines), and cold breakfast cereal. Dietary information was obtained using a brief food frequency questionnaire (31). Finally, we explored whether relationships of BMI with ARM were different in younger versus older men by fitting separate proportional hazards models for those who were 75 and older and those who were younger than 75 years of age. 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.

Table 1
Age-adjusted relationships of body mass index with other potential risk factors for age-related maculopathy in the Physicians’ Health Study.

For visually significant dry ARM, adjusting for age and cigarette smoking, the relationship also appeared to be J-shaped (Table 2). Compared to men with a normal BMI, lean men had a RR (CI) of ARM of 1.43 (1.01 – 2.04), overweight men had a RR (CI) of 1.24 (0.93 –1.66), and obese men had a RR (CI) of 2.15 (1.35 – 3.45). A likelihood ratio test comparing the model with 4 categories of BMI to one with a single variable indicating the trend across BMI categories was significant (P=0.008), confirming the non-linear nature of the BMI and ARM relationship.

Table 2
Rate ratios (RR) and 95% confidence intervals (CI) for visually significant dry age-related maculopathy according to body mass index.

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 three categories of cigarette smoking also had little impact on the RR estimates for obesity (RR (CI)=2.18 (1.29 – 3.68) for obese versus normal), though the RR for the lean men was slightly attenuated (Table 2). The association between BMI and dry ARM (RR=2.05, CI=1.26 – 3.34 for obese versus 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 these analyses. Lean men had a RR (CI) of neovascular ARM of 1.03 (0.56 – 1.88); overweight men had a RR (CI) of 0.81 (0.49 – 1.34); and obese men had a RR (CI) of 1.15 (0.45 – 2.94) compared to men whose BMI was normal.

Table 3
Rate ratios (RR) and 95% confidence intervals (CI) for visually significant exudative age-related maculopathy according to body mass index.

Results of analyses for the combined end point of all visually significant ARM (dry or neovascular) were quite similar to those for dry ARM, and were most consistent with a J-shaped relationship, though the magnitude of the RR were attenuated compared to the estimates for dry ARM. Compared to men with a normal BMI, lean men had a RR (CI) of ARM of 1.30 (0.95 – 1.76), overweight men had a RR (CI) of 1.08 (0.84 – 1.39), and obese men had a RR (CI) of 1.92 (1.27 – 2.89).

In subgroup analyses (Table 4), the relationship of obesity with dry ARM persisted in both men <75 years of age as well as those aged 75 and older. However, in these models, the increased risk of dry ARM among the lean men was most apparent for those <75 years of age. 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 that had never smoked.

Table 4
Rate ratios (RR) and 95% confidence intervals (CI) for the relationship of body mass index with visually significant dry age-related maculopathy according to age and cigarette smoking.

DISCUSSION

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 less than 22) 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, under-ascertainment of ARM is a concern and the results of the present study must be interpreted in light of this limitation. However, under-ascertainment 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, in order 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 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 to 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[exists]30 kg/m2. Of three cross-sectional studies that have looked at the relationship of BMI with ARM, one found no relationship with the combined end point of atrophic or neovascular macular degeneration (23), and one 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 over 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 non-linear 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 kg/m2 and a somewhat less elevated incidence among the leanest men with a BMI <22 kg/m2. 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 confidence intervals 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 non-linear. In particular, since results of this as well as one 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, 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 one or more important nutrients in the diets of the leanest men could have lead 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 prior to age 60 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 as well as lean men appear to have an elevated risk of dry ARM compared to 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.

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