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Prospective Study of Intake of Fruits, Vegetables, Vitamins, and Carotenoids and Risk of Age-Related Maculopathy
Eunyoung Cho, ScD;
Johanna M. Seddon, MD;
Bernard Rosner, PhD;
Walter C. Willett, MD, DrPH;
Susan E. Hankinson, ScD
Arch Ophthalmol. 2004;122:883-892.
ABSTRACT
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Objective To examine the intake of antioxidant vitamins and carotenoids as well as fruits and vegetables in relation to the development of age-related maculopathy (ARM).
Methods We conducted a prospective follow-up study of women in the Nurses' Health Study and men in the Health Professionals Follow-up Study. We followed 77 562 women and 40 866 men who were at least 50 years of age and had no diagnosis of ARM or cancer at baseline for up to 18 years for women and up to 12 years for men. Fruit and vegetable intakes were assessed with a validated semiquantitative food-frequency questionnaire up to 5 times for women and up to 3 times for men during follow-up.
Results A total of 464 (329 women and 135 men) incident cases of early ARM and 316 (217 women and 99men) cases of neovascular ARM, all with visual loss of 20/30 or worse due primarily to ARM, were diagnosed during follow-up. Fruit intake was inversely associated with the risk of neovascular ARM. Participants who consumed 3 or more servings per day of fruits had a pooled multivariate relative risk of 0.64 (95% confidence interval, 0.44-0.93; P value for trend = .004) compared with those who consumed less than 1.5 servings per day. The results were similar in women and men. However, intakes of vegetables, antioxidant vitamins, or carotenoids were not strongly related to either early or neovascular ARM.
Conclusion These data suggest a protective role for fruit intake on the risk of neovascular ARM.
INTRODUCTION
Among individuals 65 years and older, late age-related maculopathy (ARM) is a leading cause of vision loss, which severely affects quality of life.1-2 Because of increasing longevity, the impact of this disease continues to grow in the United States.
Because effective treatments do not exist to treat the late stages of ARM,3 prevention is important. Smoking is the most consistently identified modifiable risk factor,4 and antioxidant vitamin and mineral supplementation has also been found to be beneficial.5 Several other factors including dietary intake of antioxidants,6-8 dietary fats,9-11 obesity,12 other cardiovascular disease risk factors, exposure to sunlight, and nonmodifiable factors including family history of ARM and ocular characteristics have been reported.13
Intake of antioxidant vitamins and carotenoids has been hypothesized to reduce the risk of ARM by protecting the retina from oxidative damage.14 In a recent randomized trial, supplementation with high-dose vitamins C and E, beta carotene, and zinc delayed progression of ARM in participants at high risk of progression.5 In previous epidemiologic studies of dietary intake or blood levels of antioxidant vitamins or carotenoids, one case-control study6 of a large population with neovascular, advanced macular degeneration showed a protective effect of dietary carotenoids, whereas other studies of primarily early maculopathy showed no clear associations with ARM risk.7, 15-24 However, few studies have examined intake of fruits and vegetables in relation to ARM.6, 19, 25
We therefore examined intake of antioxidant vitamins, carotenoids, fruits, and vegetables in relation to the incidence of ARM in 2 large prospective studies of women and men with up to 18 years of follow-up.
METHODS
STUDY PARTICIPANTS
The Nurses' Health Study (NHS) enrolled 121 700 female registered nurses aged 30 to 55 years in 1976. The Health Professionals Follow-up Study (HPFS) included 51 529 male health professionals (dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, and podiatrists) aged 40 to 75 years in 1986. We have sent follow-up questionnaires to both cohorts biennially to update information regarding diet and lifestyle and to ascertain new diagnoses of major illnesses.
ASSESSMENT OF DIETARY INTAKE
A semiquantitative food-frequency questionnaire (FFQ) with approximately 60 food items was sent to members of the female cohort in 1980. An expanded FFQ with approximately 130 food items was administered to women in 1984, 1986, 1990, and 1994 and to men in 1986, 1990, and 1994. The NHS 1980 FFQ had 5 questions for fruits and 10 questions for vegetables. Subsequent FFQs in the NHS and the FFQs in the HPFS had at least 15 questions for fruits and at least 22 questions for vegetables. Participants were asked how often, on average, they had consumed each type of food during the past year. Serving sizes (eg, 1 banana or  cup broccoli) were specified for each food in the FFQ. The questionnaire had 9 possible responses, ranging from never or less than once per month to 6 or more times per day. Intake of total fruits and total vegetables was calculated by multiplying the reported frequency by a given serving size for each food item. Participants also reported their current use and dose of vitamin A, C, and E supplements and brands and types of multivitamins biennially. For current users of multivitamins or vitamin supplements at baseline, duration of use was also ascertained. A comprehensive database on multivitamin preparations that provides the dose of the vitamins in each preparation has been developed and updated biennially. Intakes of vitamins and carotenoids from foods were calculated from US Department of Agriculture (USDA) sources.26 To calculate vitamin intake from food and supplements combined, the contributions from multivitamins and other supplements were added to vitamin intakes from food only. Food composition data for specific types of carotenoids were based on the USDA–National Cancer Institute carotenoid database developed by Chung-Ahuja et al27 and Mangels et al.28 The carotenoid content of tomato-based food products was updated with values from the USDA.29
The reproducibility and validity of food intake was assessed in both cohorts.30-31 The correlation coefficients between diet records and the FFQ for fruits and vegetables averaged 0.59 for women (range, 0.17-0.84) and 0.59 for men (range, 0.25-0.95) after correction for attenuation due to random error in diet records.
The reproducibility and validity of intakes of vitamins and carotenoids was assessed in both cohorts using diet records32-33 and plasma levels.34-35 Pearson correlation coefficients between estimates from the FFQ and the average of 4 1-week diet records were 0.49 for total vitamin A (including contributions from food and supplements) and 0.75 for total vitamin C in women.32 Similarly, the average correlation between estimates from the FFQ and the average of 2 1-week diet records for vitamins and carotenoids was 0.74 (range, 0.48 to 0.92) in men after correction for attenuation due to random error in diet records.33 Vitamin E intake estimated from the FFQ was positively correlated with its plasma concentration (r = 0.41 for women and 0.51 for men).34 The Pearson correlation coefficient between dietary carotenoid intake and plasma concentrations of carotenoids was 0.18 to 0.47 in nonsmoking women and 0.31 to 0.48 in nonsmoking men.35
POPULATION FOR ANALYSIS
For this analysis, we began follow-up when diet was first measured, in 1980 for women and in 1986 for men. We excluded those who did not complete a baseline FFQ, who had implausible energy intakes (<2510 or >14 644 kJ/d for women and <3347 or >17 573 kJ/d for men), or who left more than 70 items blank on the FFQ (6291 women and 1595 men). Participants who reported a diagnosis of ARM or cancer (except nonmelanoma skin cancer) at baseline were excluded (3625 women and 2012 men), and these exclusions were updated every 2 years. We also excluded participants who did not respond to any of the follow-up questionnaires asking about a diagnosis of ARM (1986-1998 in the NHS and 1988-1998 in the HPFS; 2080 women and 987 men). Finally, we excluded those who did not report having an eye examination during follow-up (7235 women and 4787 men) to minimize any influence of undiagnosed cases. Because ARM is rare in younger populations, we restricted our analysis to participants 50 years and older. Participants who were younger than 50 years at baseline were included in the cycle after they reached age 50. A total of 30 078 women and 26 703 men were included in the analysis at baseline. By 1996, 77 562 women and 40 866 men contributed to the analyses. For carotenoid analysis for women, we began follow-up in 1984 because important foods contributing to carotenoid intake were not assessed in 1980.
DIAGNOSIS OF ARM
In this report, we defined all stages of the disease as ARM. According to one classification system, the late stages of ARM are also referred to as age-related macular degeneration.36
Cases were defined as incident ARM when their best-corrected visual loss was 20/30 or worse (ie, a person could recognize at 20 ft a symbol that could be recognized by a person with normal acuity at 30 or more feet) due primarily to ARM in at least one eye. We obtained data on the diagnosis of ARM beginning in 1986 for women (regarding diagnoses received from 1980-1986) and in 1988 for men. If people reported diagnoses of ARM, we requested permission to review their medical records and contacted their ophthalmologists to either complete a standardized questionnaire or to send us copies of ocular records to confirm the diagnosis. The questionnaire included the date of initial diagnosis, best-corrected visual acuity, signs of ARM (drusen, retinal pigment epithelial hypopigmentation or hyperpigmentation, geographic atrophy, retinal pigment epithelial detachment, subretinal neovascular membrane, or disciform scar), and whether there was visual acuity loss due mainly to ARM.
We conducted analyses based on subgroups of ARM (early and neovascular) because these subtypes may have different etiologies and risk factors. The early form of ARM was defined as the presence of drusen or retinal pigment epithelial changes.36 The neovascular form of ARM, usually associated with greater visual impairment, included retinal pigment epithelial detachment, choroidal neovascular membrane, or disciform scar. Because of limited numbers of cases with geographic atrophy, we were not able to conduct an analysis for them. The person was used as the unit of analysis, and, if a participant had bilateral ARM with different degrees of progression, the more severe status was used.
Our case definition of ARM has been validated by 2 retinal specialists who conducted a standardized review of fundus slides in a subset of cases (those ascertained from the 1990 follow-up in the NHS).4 Among cases with photographs of sufficient quality to grade, 36 (86%) of 42 were classified as having definite ARM and 39 (93%) of 42 were classified as definite or probable ARM by both readers. Regarding the classification of subtypes of ARM, there was 100% (23/23) concordance between the retinal specialist and the reporting ophthalmologist for early ARM and 86% (12/14) for neovascular ARM.
A total of 3283 women and 1573 men reported a diagnosis of ARM during follow-up; 1452 women (44%) and 677 men (42%) were confirmed to have ARM by their ophthalmologist. For the remainder of participants reporting ARM, one of the following was true: (1) they did not grant permission to contact their ophthalmologist (357 NHS [11%]; 176 HPFS [11%]), (2) they indicated the initial report was in error (651 NHS [20%]; 368 HPFS [23%]), (3) they did not have the diagnosis confirmed by their ophthalmologist (709 NHS [22%]; 275 HPFS [17%]), or (4) we were not able to contact either the participant or their ophthalmologist (114 NHS [3%]; 100 HPFS [6%]). For those whose diagnosis was not confirmed by their ophthalmologist, the doctor frequently indicated other maculopathies (eg, macular hole) or other eye diseases (eg, diabetic retinopathy). We then excluded women and men who did not have visual loss of 20/30 or worse (590 NHS; 230 HPFS) or whose visual loss was not attributable to ARM (191 NHS; 66 HPFS); 670 women and 357 men met our case definition. Among them, after excluding subjects without plausible dietary information, with a previous diagnosis of cancer, or with a diagnosis given before completing the baseline FFQ or after the end of follow-up, 546 women and 234 men were included in the analysis.
STATISTICAL ANALYSIS
Participants were divided into absolute intake categories or quintiles according to their fruit, vegetable, or nutrient intake. In the primary analysis, intake data were updated according to the cumulative average of intake during the follow-up period examined. For example, in women, 1980 intake was used for 1980-1984 follow-up and the average of 1980 and 1984 intake was used for 1984-1986 follow-up and so on. Baseline and most recent intake were each examined alone in secondary analyses. Study participants contributed person-time in each 2-year interval from the time the baseline FFQ was returned or from the time the first questionnaire was returned after they reached 50 years of age until a diagnosis of ARM or cancer, death, time of last questionnaire return, or end of the follow-up period (June 1, 1998, for women and January 1, 1998, for men), whichever came first.
We used Cox proportional hazards regression models to account for potential effects of other risk factors for ARM.37 To control as finely as possible for confounding by age, calendar time, and any possible 2-way interactions between these 2 time scales, we stratified the analysis jointly by age in months at the start of follow-up and calendar year of the current questionnaire cycle. Multivariate models also adjusted for smoking, body mass index, energy intake, alcohol intake, fish intake, physical activity (metabolic equivalents per week in quintiles in men, hours of vigorous activity in quintiles in women), history of hypertension and high blood cholesterol levels, postmenopausal hormone use (women), and occupation (men). To adjust for smoking, pack-years of smoking (the number of years smoked multiplied by the average number of packs of cigarettes per day) was used, since this best reflects the cumulative effect of smoking and is more strongly associated with ARM than current smoking status.4 Among these covariates, pack-years of smoking, body mass index, and postmenopausal hormone use were updated in every 2-year period. Dietary covariates were updated using cumulative averaged intake. We used SAS PROC PHREG38 (SAS Institute Inc, Cary, NC) for all analysis, and the Anderson-Gill data structure39 was used to handle time-varying covariates efficiently, with a new data record created for every questionnaire cycle at which a participant was at risk and covariates set to their values at the time the questionnaire was returned. For all relative risks (RRs), 95% confidence intervals (CIs) were calculated. Tests for trend across categories of intake were conducted by using the median within each category as a continuous variable.40 All P values were 2-sided.
We conducted separate analyses for each cohort and pooled the 2 studies to achieve maximum statistical power. Tests for heterogeneity between the 2 studies were conducted, and meta-analytic methods using a random-effects model were used to pool the RRs from the cohorts.41
To confirm the results for neovascular ARM from the primary analyses, we conducted additional restricted analyses among nonsmokers and among nonusers of multivitamins or vitamin A, C, and E supplements as well as among those who, at baseline, reported they had not changed their fruit intake in the past 10 years.
To test whether the estimates for fruit intake for early vs neovascular ARM were statistically different, we conducted polychotomous logistic regression42 in each cohort using fruit intake as a continuous variable, early and neovascular ARM as 2 different outcome variables, and a likelihood ratio test with 2 df.
RESULTS
We documented 464 cases of early ARM (329 women and 135 men) and 316 cases of neovascular ARM (217 women and 99 men) with visual loss of 20/30 or worse due primarily to ARM during up to 18 years of follow-up in women (923 926 person-years) and up to 12 years of follow-up in men (345 366 person-years).
Table 1 presents the distribution of potential risk factors for ARM by categories of fruit and vegetable intake in 1990. Participants with higher fruit or vegetable intake were less likely to smoke and more likely to be physically active and to consume fish.
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Table 1. Characteristics of the Cohorts According to Fruit and Vegetable Intake Among Participants Who Were 50 Years of Age or Older in 1990*
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Total fruit intake was inversely related to neovascular ARM risk (Table 2). The pooled multivariate RR for participants who consumed 3 or more servings per day of fruits was 0.64 (95% CI, 0.44-0.93; P for trend = .004) compared with those who consumed less than 1.5 servings per day. The results were similar for women and men (P for heterogeneity for top vs bottom categories = .70). There was a nonsignificant inverse association between fruit intake and early ARM. However, the difference in results for early vs neovascular ARM was not statistically significant for fruit intake (P = .45). Vegetable intake was not related to early or neovascular ARM risk in either cohort. The results were similar after adjusting for total fat intake.
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Table 2. Multivariate Relative Risk (RR) and 95% Confidence Interval (CI) of Age-Related Maculopathy (ARM) According to Categories of Fruit and Vegetable Intake*
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To confirm the inverse association between fruit intake and neovascular ARM, we repeated analyses examining baseline intake as well as most recent intake. The pooled multivariate RR for the highest category of intake was 0.62 (95% CI, 0.40-0.96) for baseline intake and 0.71 (95% CI, 0.40-1.25) for most recent intake. We also examined whether the association remained among those who did not change their fruit intake in the past 10 years at baseline (n = 214 neovascular ARM cases); the pooled multivariate RR for the highest category of intake was 0.80 (95% CI, 0.50-1.27). In women, more comprehensive information on fruit intake was collected from 1984 onward. The inverse association between fruit intake and neovascular ARM was similar, although slightly weaker, when the analysis was started from 1984 in women; the multivariate RR for the highest category of fruit intake was 0.83 (95% CI, 0.50-1.38).
Since fruit intake was related to smoking status (Table 1), we conducted analyses among never-smokers only (n = 96 with neovascular ARM) to avoid any confounding by smoking habits. The pooled multivariate RR for the highest category of fruit intake was not statistically significant, probably owing to limited power (RR, 0.87; 95% CI, 0.42-1.82). We also tried adjusting for continuous pack-years of smoking instead of a categorical variable to avoid residual confounding by a categorical smoking variable; however, the results were similar to those using a categorical smoking variable (data not shown). We also assessed the association between fruit intake and neovascular ARM among those who did not take multivitamins and vitamin A, C, and E supplements (n = 154 with neovascular ARM) to minimize any confounding by these supplements or other related healthy lifestyle factors. The pooled multivariate RR for the highest category of fruit intake was 0.79 (95% CI, 0.46-1.33).
To examine whether fruit overall or specific fruit were related to neovascular ARM risk, we examined 5 fruit questions that were asked of women at baseline (Table 3). Although all of these items had a suggestive inverse association, only higher intakes of oranges and bananas achieved statistical significance; the pooled multivariate RRs for the highest intake category ( 3 servings/wk) compared with those in the lowest (<2 servings/mo) were 0.61 (95% CI, 0.44-0.86; P for trend = .01) for oranges and 0.63 (95% CI, 0.44-0.90; P for trend = .18) for bananas. Because consumption of these foods may be related, we adjusted for both items simultaneously; the results did not change materially (data not shown). Banana intake was also inversely related to early ARM; the pooled multivariate RR for participants who consumed 3 or more servings per week of banana was 0.67 (95% CI, 0.49-0.90; P for trend = .05) compared with those who consumed less than 2 servings per month.
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Table 3. Multivariate Relative Risk (RR) and 95% Confidence Interval (CI) of Age-Related Maculopathy (ARM) According to Categories of Individual Fruit and Vegetable Intake*
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None of the vegetable items appeared to be strongly related to either early or neovascular ARM risks, except that carrot intake had a weak, nonsignificant inverse association with the neovascular form (Table 3). For example, increasing intake of spinach or other greens had pooled multivariate RRs of 1.00, 1.14, 1.10, and 1.05 (95% CI, 0.66-1.67) for neovascular ARM (Table 3).
To examine whether any specific nutrients were responsible for the inverse association between ARM risk and fruit intake, we examined intakes of antioxidant vitamins and carotenoids from foods, mainly fruits and vegetables (Table 4). None of the antioxidant vitamins and carotenoids was strongly related to either early or neovascular ARM risk, although many of them, including total carotenoids, had a suggestive inverse association with neovascular ARM risk. Intake of  -cryptoxanthin was related to a lower risk of neovascular ARM (P for trend = .03), although the pooled multivariate RR for the highest quintile of intake was not statistically significant. Because we might have missed some associations in quintile analyses, we also examined deciles of the nutrient intake; again, no strong association was found (data not shown). The overall results were similar when baseline intake was examined. However, when we examined the most recent intake (prior to diagnosis for ARM cases), alpha carotene appeared to be significantly inversely related to neovascular ARM risk; the pooled multivariate RR for the highest quintile of intake was 0.63 (95% CI, 0.43-0.93; P for trend = .04) for alpha carotene. Other carotenoids remained similar to the results using cumulative update intake (eg, pooled multivariate RR for top vs bottom quintile of baseline lutein/zeaxanthin intake, 1.02; 95% CI, 0.68-1.54).
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Table 4. Multivariate Relative Risk (RR) and 95% Confidence Interval (CI) of Age-Related Maculopathy (ARM) According to Quintiles of Intake of Vitamins and Carotenoids*
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We also examined use of multivitamins and vitamin C and E supplements (Table 5); because too few participants were taking vitamin A and beta carotene supplements, we were not able to examine them separately. None of the supplements was related to either early or neovascular ARM risk. These vitamin supplements were not related to either early or neovascular ARM when current users were grouped into 2 dose categories (data not shown). Participants who had taken both vitamin C and E supplements for more than 4 years also did not benefit compared with never-users of both supplements; the pooled multivariate RRs were 1.16 (95% CI, 0.84-1.60) for early ARM and 0.87 (95% CI, 0.56-1.34) for neovascular ARM.
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Table 5. Multivariate Relative Risk (RR) and 95% Confidence Interval (CI) of Age-Related Maculopathy (ARM) by Vitamin Supplement Use in Women and Men*
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COMMENT
In this prospective study of women and men, intakes of antioxidant vitamins or carotenoids either from food only or from food and supplements were not strongly related to ARM risk. Similarly, no substantial associations were observed between vegetable intake and ARM. However, fruit intake was inversely related to ARM, particularly neovascular ARM, the form of this disease that frequently involves severe visual loss.
One of the etiologic hypotheses for development of ARM is related to oxidative stress, such that a deficit of important antioxidant vitamins or carotenoids may adversely affect the retina.43 Dietary as well as serum carotenoids were associated with a reduction in risk of neovascular, advanced ARM in a large multicenter case-control study.6, 8 However, other epidemiologic studies found no clear inverse association between intake of antioxidant vitamins and carotenoids and ARM risk, possibly owing to small sample size and the small number of neovascular ARM cases.7, 15-24 In the Age-Related Eye Disease Study,5 a large multicenter randomized trial of 3640 participants with 6.3 years of follow-up, supplementation with high-dose vitamins C and E, beta carotene, and zinc reduced progression to advanced ARM by 25% across 5 years among those with signs of intermediate ARM or advanced disease in one eye. The combination of vitamins C and E and beta carotene was also associated with a reduction in risk in this group of patients, but this finding did not achieve statistical significance (odds ratio, 0.76; 99% CI, 0.55-1.05).5 The relationships between dietary sources of the nutrients and ARM in this study have not yet been published.
Fruits and vegetables are rich sources of antioxidant nutrients, but few studies have examined intake in relation to ARM risk. A cross-sectional study suggested an inverse association between intake of fruits and vegetables rich in vitamin A and ARM (n = 178).25 Seddon et al6 examined consumption of carotenoid-rich vegetables and found that intake of green leafy vegetables such as spinach or collard greens was inversely related to neovascular ARM risk. In a small cohort study of only 103 early ARM cases, a modest inverse association was observed between fruit and vegetable intake and large drusen.16
We found that fruit intake was related to a reduced risk of neovascular ARM but not early ARM. Early and neovascular ARM have been hypothesized to have different etiologies and risk factors, and abnormal vascular circulation may be related to development of neovascular ARM.44-45 Neovascular ARM (or late ARM, which includes neovascular ARM and geographic atrophy) has been related to cardiovascular disease risk factors45 such as smoking,4 obesity,12 dietary fat,9, 11 elevated plasma fibrinogen levels,46 atherosclerosis,47 and hypertension.13, 48-49 Fruit (but not vegetable) intake has been related to a reduced risk of ischemic stroke in these cohorts.50 Both fruit and vegetable intake have been associated with a lower risk of cardiovascular disease.51-53
Among types of fruit, the suggestive inverse associations were significant only for oranges and bananas. Although the results were similar in women and men, this may be a chance finding because many foods were considered. In addition, differences in measurement error in reporting fruit intake may also contribute to the results. However, since none of the antioxidant vitamins and carotenoids contributed substantially to the apparent inverse association, other factors in fruit may also contribute to the reduced risk. Other constituents of fruits with potential health benefit include flavonoids, isothiocyanates, phenols, fiber, folate, and potassium.54
We observed no association with intake of lutein/zeaxanthin or foods rich in lutein/zeaxanthin such as green leafy vegetables, which is inconsistent with many recent experimental studies that have suggested the importance of these carotenoids as a macular pigment and as a possible preventive factor for ARM.55-56 However, a significant inverse association was found mainly in a large case-control study of neovascular ARM.6, 8 Other epidemiologic studies of lutein/zeaxanthin have been inconclusive, possibly owing to the smaller study sizes as well as the mixture of disease stages.16, 21, 23, 57-58 However, some of these latter studies did find associations with other specific carotenoids.16, 23, 58 One possible explanation for the null finding in our cohort is that lutein/zeaxanthin intake might be already high enough; for example, the median lutein/zeaxanthin intake in the first quintile in both cohorts was higher than the median value of the second quintile in the Eye Disease Case-Control Study.6 However, the RRs were quite flat across quintiles, and analyses using deciles of intake also did not show any substantial association in our study.
This is the first large-scale prospective study examining dietary intake comprehensively in relation to ARM risk. We had repeated measures of diet and were able to examine dietary intake in different ways (baseline, cumulative updated, and most recent). Cumulative updated intake can minimize measurement error due to a onetime dietary assessment and thus best reflect long-term dietary intake, which may be most relevant to chronic diseases like ARM with a long duration of development.59 However, because the period during which diet might modify the development of ARM is unclear, it is also meaningful to examine remote (baseline) and most recent intakes. Indeed, for alpha carotene intake, we observed a significant inverse association only with recent intake.
Study limitations also need to be considered. Because higher fruit intake may be related to a more healthy lifestyle, the results might be confounded by other risk factors related to a healthy lifestyle, such as nonsmoking. Although we adjusted for smoking, some residual confounding might remain. A healthy lifestyle may also be associated with more medical screening, including eye examination, and thus increase the chance of being diagnosed with ARM. To minimize this possibility, we limited our analysis to participants who had at least 1 eye examination during follow-up and included cases with a visual acuity loss of at least 20/30 due to ARM. In addition, the fact that an inverse association was found between neovascular ARM (but not early ARM) and fruits (but not vegetables) in both cohorts suggests that results were minimally influenced by confounding by other aspects of healthy lifestyles or biased by differential disease diagnosis. Even in this large study, the number of cases was somewhat limited, especially for neovascular ARM.
In conclusion, in these large prospective cohorts of women and men, we found that higher fruit intake was related to a reduced risk of neovascular ARM. However, none of the vitamins or carotenoids examined was clearly related to disease. Further studies are needed to confirm our findings and to identify the relevant compound(s) in fruits.
AUTHOR INFORMATION
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Corresponding author and reprints: Eunyoung Cho, ScD, Channing Laboratory,181 Longwood Ave, Boston, MA 02115 (e-mail: eunyoung.cho{at}channing.harvard.edu).
Submitted for publication August 11, 2003; final revision received January 6, 2004; accepted January 6, 2004.
This study was supported by research grants CA87969, CA55075, EY09611, and HL35464 from the National Institutes of Health, Bethesda, Md.
We thank Maureen Ireland, BA, and Stacey DeCaro, BA, for data compilation and Jae Hee Kang, ScD, and Mary Louie, PhD, for computer support.
From the Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital (Drs Cho, Rosner, Willett, and Hankinson); the Departments of Epidemiology (Drs Seddon, Willett, and Hankinson), Biostatistics (Dr Rosner), and Nutrition (Dr Willett), Harvard School of Public Health; and the Epidemiology Unit, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School (Dr Seddon), Boston, Mass. The authors have no relevant financial interest in this article.
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