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To examine in prospective data the relation between dietary intake of carotenoids and vitamins C and E and risk of cataract in women.
Dietary intake was assessed at baseline in 1993 among 39,876 female health professionals by use of a detailed food-frequency questionnaire. A total of 35,551 of these women provided detailed information on antioxidant nutrient intake from food and supplements and were free of a diagnosis of cataract.
Cataract defined as an incident, age-related lens opacity, responsible for a reduction in best-corrected visual acuity to 20/30 or worse, based on self-report confirmed by medical record review.
A total of 2,031 cases of incident cataract were confirmed during an average of 10 years of follow-up. Comparing women in extreme quintiles, the multivariate relative risk of cataract was 0.82 (95% confidence interval, 0.71-0.95; P, test for trend, 0.045) for lutein/zeaxanthin, and 0.86 (95% confidence interval, 0.74-1.00; P, test for trend, 0.03) for vitamin E from food and supplements.
In these prospective observational data from a large cohort of female health professionals, higher dietary intakes of lutein/zeaxanthin and vitamin E from food and supplements were associated with significantly decreased risks of cataract.
The oxidative hypothesis of cataract formation posits that reactive oxygen species can damage lens proteins and fiber cell membranes, and that nutrients with antioxidant capabilities can protect against these changes (1-3). Results of laboratory studies and studies in animals generally support the antioxidant hypothesis, but observational epidemiologic studies in humans have been inconsistent (4-6). Moreover, results of completed randomized trials indicate that supplemental use of vitamin E, vitamin C, or beta-carotene for as long as 6.5 years (12 years for beta-carotene ) has no marked effect on cataract incidence or progression (7-14). Whether longer duration treatment with these antioxidants can materially reduce risks of cataract, which develop slowly over many years, remains to be determined in recently-completed and ongoing trials (15-17).
In addition to those nutrients tested in completed and ongoing trials, evidence has also accumulated to suggest a possible role for lutein, a xanthophyll carotenoid, in lowering risks of cataract. Lutein is concentrated in tissues of the eye, including the lens (18-20), and may protect against cataract by filtering harmful short-wave blue light and possibly through antioxidant activity (21-23). Findings of observational epidemiologic studies generally support a possible beneficial effect for lutein (24-32). However, as encouraging data have accumulated, enthusiasm for its potential benefits has also led to the advocation of lutein-containing supplements to prevent eye disease even though there are no randomized trial data to assess its effectiveness in the eye, and prospective observational data for cataract are limited to three studies (27-29, 32). For this reason, the National Eye Institute has cautioned that the possible benefit of lutein for the eye remains uncertain and warrants closer examination before conclusions can be drawn (33). In this report, we examine in prospective data the relation of dietary intake of several carotenoids including lutein (and its stereoisomer zeaxanthin), as well as vitamins C and E, with the risk of cataract during 10 years of follow-up in a large cohort of female health professionals.
Study participants were women enrolled in the Women’s Health Study (WHS), a recently completed randomized, double-blind, placebo-controlled trial of low-dose aspirin, vitamin E, and beta-carotene in the primary prevention of CVD and cancer among 39,876 apparently healthy female health professionals aged 45 years and older (34-37). Participants were willing to forego use of individual supplements of beta-carotene, vitamin A, and vitamin E, but could continue using multivitamins for the duration of the trial. Detailed information on antioxidant intake from food and supplements was provided by 39,310 (99%) of the randomized participants, who completed a 131-item validated semiquantitative food-frequency questionnaire (SFFQ) at baseline in 1993 (38). For this analysis we excluded participants who reported total energy intake less than 600 kcal/d or greater than 3500 kcal/d, or who had more than 70 blanks on the SFFQ. Of the remainder, 35,551 participants were without a diagnosis of cataract at baseline and are included. This study was conducted according to the ethical guidelines of Brigham and Women’s Hospital.
For each food item, a standard unit or portion size was specified and participants were asked how often, on average, during the previous year they had consumed that amount. Nine responses were possible, ranging from ”never“ to ”six or more times per day.“ Responses to the individual food items were converted to average daily intake of each nutrient based upon food tables maintained by the Harvard School of Public Health, Boston, MA. Carotenoid content of food items was determined with the use of US Department of Agriculture-National Cancer Institute carotenoid food composition databases (39, 40). Participants also provided information about their current use of multivitamins and supplements of vitamin C, vitamin E, and beta-carotene. The total intakes of antioxidants was calculated by adding the contributions from vitamin supplements and foods. For beta-carotene, vitamin C, and vitamin E we also calculated intake from food sources alone. In our databases, the data for lutein and zeaxanthin have been combined.
The reproducibility and validity of SFFQ estimates of vitamin and carotenoid intake have been examined in a similar population of female nurses. The Pearson correlation coefficient between estimates from the SFFQ and the average of two 1-week diet records was 0.76 for energy-adjusted total vitamin C (41). For vitamin E, the correlation between estimates of intake from the SFFQ and plasma concentrations of alpha-tocopherol was 0.41 (42). For carotenoids, correlations between plasma concentrations and the SFFQ assessments among nonsmoking women were 0.27 for beta-carotene, 0.27 for lutein, 0.32 for beta-cryptoxanthin, 0.48 for alpha-carotene, and 0.21 for lycopene (43). These estimates were similar to those found between plasma levels of these nutrients and estimates from food records (44).
Information on possible risk factors for cataract was collected on the WHS baseline questionnaire. Information included age, height and weight, smoking status, alcohol use, frequency of exercise, parental history of MI at age < 60 years, history of hypertension, history of diabetes, history of hypercholesterolemia, postmenopausal hormone use, and history of an eye exam in the last 2 years.
Following the report of a cataract diagnosis, a written consent identifying the diagnosing ophthalmologist(s) or optometrist(s) was obtained. Ophthalmologist(s) and optometrist(s) were asked to complete a cataract questionnaire supplying information about the presence of lens opacities, date of diagnosis, visual acuity loss, cataract extraction, other ocular abnormalities that could explain visual acuity loss, cataract type, and etiology. Medical record information was obtained for 95% of participants reporting cataract.
The study endpoint was incident cataract defined as a self-report confirmed by medical record review to be initially diagnosed after randomization, age-related in origin, with best-corrected visual acuity of 20/30 or worse and with no alternate ocular pathology to explain the visual acuity loss.
The unit of analysis was individuals, rather than eyes, because eyes were not examined independently, and participants were classified according to the status of the worse eye based on disease severity. Participants were followed until the time of diagnosis of cataract, or until death or February 2004, whichever came first. Nutrient intake was considered as a categorical variable (in quintiles), with adjustment for total energy by the residual method (41). Estimates of relative risks (RR) were computed as the rate of cataract in a specific quintile of intake divided by the corresponding rate in the lowest quintile (reference). Age- and treatment-adjusted RR estimates were obtained by adjusting for age (in years) and randomized treatment assignment in Cox proportional hazards regression models (45). Multivariate RRs were obtained by further adjusting for smoking, alcohol use, history of diabetes, history of hypertension, history of hypercholesterol, body mass index, physical activity, parental history of myocardial infarction, postmenopausal hormone use, and history of an eye exam in the last 2 years. For each relative risk, two-sided P values and 95 percent confidence intervals (CIs) were calculated (46). Tests of linear trend across increasing quintiles of nutrient intake used the medians of intakes within quintiles as scores. We used an interaction term between ordinal scores for each nutrient and length of follow-up to evaluate the adequacy of the proportional hazards assumption over time. For each nutrient, P > 0.05 indicating that the proportionality assumption was not violated. We also performed tests of interaction to evaluate the statistical significance of any modifying effect of age and baseline smoking status (current vs. not current) on the association of nutrient intake with cataract.
We examined the independent contribution of each nutrient to cataract risk by simultaneously entering all nutrients into a Cox regression model using the median scores from quintiles and adjusting for other cataract risk factors. Using a backward selection procedure, nutrients were removed according to level of significance until only those nutrients that were significantly associated with cataract at the P<.05 level remained. We also fit a model that retained only those nutrients that were significantly associated with cataract at the P<.20 level.
Baseline characteristics of the study population are shown in Table 1. Women who were newly diagnosed with cataract during follow-up were older and, after adjusting for age, were more likely to smoke than women without a diagnosis of cataract. Women with diagnosed cataract also had higher body mass index, exercised less, and were more likely to report a history of hypertension, diabetes, and high cholesterol.
Average intake of lutein/zeaxanthin and several other nutrients were highly correlated with one another (p < 0.001 for all correlation coefficients; data not shown). The correlation coefficients between lutein/zeaxanthin and the other carotenoids ranged from 0.22 for lutein/zeaxanthin and beta-cryptoxanthin to 0.72 for lutein/zeaxanthin and beta-carotene from food sources (0.67 for beta-carotene from food and supplements). The correlation coefficients between lutein/zeaxanthin and vitamins C and E ranged from 0.17 for total vitamin E to 0.45 for vitamin C from food sources only.
During an average of 10 years of follow-up, 2,031 cases of incident cataract were confirmed. Significant inverse trends with cataract were observed for dietary intakes of lutein/zeaxanthin and vitamin E. Comparing women in the highest quintile of intake of lutein/zeaxanthin to those in the lowest, the multivariate relative risk (RR) of cataract was 0.82 (95% confidence interval [CI], 0.71-0.95; P, test for trend = 0.045) (Table 2). The RR for vitamin E from food and supplements, comparing women in extreme quintiles, was 0.86 (95% CI, 0.74-1.00; P, test for trend = 0.03). (Table 2). Vitamin E from food sources alone was not significantly associated with risk of cataract. For beta-cryptoxanthin, there was a significant inverse trend with cataract in age- and treatment-adjusted analyses (P, test for trend = 0.04), but not in analyses that also adjusted for other cataract risk factors (P, test for trend = 0.19). Multivariate RRs for the other nutrients (alpha-carotene, beta-carotene, lycopene, and vitamin C), were generally below 1.0 but none of the tests for trend across quintiles attained statistical significance.
We examined the independent contribution of each nutrient in Cox regression models using backward selection procedures. Values for beta-carotene, vitamin E, and vitamin C in this analysis included intake from both food and supplements. After stepwise removal of nonsignificant nutrients, only vitamin E (P, test for trend = 0.03) remained significantly associated with the risk of cataract. When the significance level for retention was set at 0.20, vitamin E (P, test for trend = 0.04) and lutein/zeaxanthin (P, test for trend = 0.06) were retained in the final model.
We also examined whether the associations between nutrient intake and cataract differed by age and smoking status at baseline. We found no evidence that associations between nutrient status and cataract differed by age. For smoking, inverse associations tended to be stronger among women who were nonsmokers at baseline, but formal tests for interaction were not statistically significant for any nutrient.
Because of the inverse association between cataract and lutein/zeaxanthin, we also examined the association of cataract with specific food sources of lutein/zeaxanthin and other carotenoids (Table 3). Women with high overall intake of fruits and vegetables had an approximate 10% lower risk of cataract that was not statistically significant. There was, however, a borderline significant inverse trend between higher intake of green leafy vegetables and risk of cataract (P, test for trend=0.06). When we considered specific foods that are important contributors to lutein/zeaxanthin intake, raw spinach showed a borderline significant inverse relation with risk of cataract in age- and treatment-adjusted analyses (P, test for trend=0.06), but not after adjustment for other cataract risk factors.
In this large population of female health professionals, significant inverse trends with risk of cataract were observed for dietary intake of lutein/zeaxanthin and vitamin E. Comparing women in extreme quintiles, women with high intake of lutein/zeaxanthin had an 18% lower risk of cataract in multivariate analysis (P, test for trend = 0.045). High intake of vitamin E from food and supplements was associated with a 14% lower risk of cataract (P, test for trend = 0.03). The inverse associations for lutein/zeaxanthin and vitamin E from food and supplements persisted in models that mutually adjusted for intake of several other carotenoids and vitamin C.
The prospective design of this study precluded the possibility that participant reports of nutrient intake at baseline were associated with subsequent cataract status. However, random or nondifferential misclassification of dietary intake was likely and would tend to underestimate any association of diet with risk of cataract. Changes in dietary behavior during follow-up seem unlikely to be differential with respect to the cataract endpoint, and thus would also attenuate the true associations. Random misclassification of the cataract endpoint was reduced by the use of medical records to confirm the participant reports and by the use of strict diagnostic criteria. To control for possible surveillance bias, we included a term for the baseline report of an eye exam in the last two years in multivariate analyses. Finally, we controlled for a number of measured confounders (Table 1), but other potential confounders which were either unmeasured or unknown may have contributed to the findings.
There have been three other prospective studies that examined the relationship of dietary intake of lutein and risk of cataract. In the Nurses’ Health Study of 77,466 female nurses, women in the top 10% of lutein/zeaxanthin intake, compared to those in the bottom quintile, had a 22% lower risk of cataract extraction (RR, 0.78; 95% CI, 0.63-0.95; P, test for trend = 0.04) during 12 years of follow-up (28). In another report from that cohort, based on a small subsample of 408 participants, there was no association between intake of lutein/zeaxanthin and 5-year change in nuclear density as measured by analysis of digital images (32). In a second study, data from the Health Professionals Study of 36,644 male health professionals showed that men in the highest quintile of lutein/zeaxanthin intake, compared to those in the lowest, had a 19% lower risk of cataract extraction (RR, 0.81; 95% CI, 0.65-1.01; P, test for trend = 0.03) during 8 years of follow-up (27). A third study, based on data from 1,354 men and women participating in a nutrition substudy in the Beaver Dam Eye Study, showed that those in the highest quintile of intake of lutein/zeaxanthin in the distant past (10 years before baseline), compared to those in the lowest quintile, had a 50% decreased risk of incident nuclear opacity (OR, 0.5; 95% CI, 0.3-0.8; P, test for trend = 0.002) at 5 years of follow-up (29). Our data from a large cohort of female health professionals indicate an approximate 20% decreased risk of cataract for those with high dietary intake of lutein/zeaxanthin, and thus appear most consistent with the findings for cataract extraction reported in the Nurses’ Health Study and Health Professionals Study (27, 28). Of note, lutein/zeaxanthin intake in the reference group in the WHS and the two other cohorts of health professionals (27, 28) appear markedly higher than the reference intake for lutein/zeaxanthin in the population-based sample from Beaver Dam (29), which may at least partially explain the smaller risk reductions observed in the former.
Among the other carotenoids examined in our study, only beta-carotene from food and supplements showed a possible inverse relation with risk of cataract. Women in the highest, compared to the lowest, quintile of intake had a borderline significant (p=0.051) 13% reduced risk of cataract in multivariate analysis. However, the test for trend across quintiles was not significant in the multivariate model, or after adjustment for intake of other nutrients. These findings appear consistent with most earlier prospective studies which report a weak and statistically nonsignificant inverse trend between beta-carotene level in the diet or blood and risk of cataract (27-29, 32, 47, 48). More importantly, results of five randomized trials clearly indicate that supplemental use of beta-carotene (with or without other antioxidant supplements) for as long as 12 years has little impact on risks of cataract (7, 8, 10, 11, 14).
We observed a significant inverse trend between vitamin E intake from food and supplements and risk of cataract in our population of women. This inverse trend persisted after adjustment for other nutrients and appeared to be due largely to a 14% reduced risk of cataract for women in the highest quintile of intake. Median intake of vitamin E for this group of women was 262.4 mg/day, a level of intake difficult to attain from food sources only. The reduction in risk appeared to reflect supplemental use of vitamin E rather than multivitamins. Seventy-one percent of women in the highest quintile of vitamin E intake reported using supplements of vitamin E at baseline, and adjustment for use of multivitamins had little impact on the RR estimate (RR comparing extreme quintiles of vitamin E intake, 0.86; 95% CI, 0.73-1.00; p-trend = 0.048). Results of other prospective studies have been mixed with some supporting an inverse association between dietary or serum vitamin E and cataract (32, 47-51) while others report no association (29, 52, 53). Data from five randomized trials completed to date provide little evidence that use of vitamin E supplements, alone or in combination with other vitamin supplements, for treatment periods as long as 6.5 years has any material impact on cataract development and progression (8, 10-13). The final results for cataract during the 10 year treatment period for vitamin E in the WHS will be reported elsewhere.
Our data for vitamin C indicate a weak, and statistically nonsignificant, inverse association with risk of cataract. This finding appears to conflict with cross-sectional data presented in two recent reports from the Nurses’ Health Study (30, 31), but is consistent with the results of several other prospective studies (29, 50-53) including 5-year follow-up data in the Nurses’ Health Study subsample (32). Furthermore, findings in three randomized trials indicate no major benefit for combined treatment with vitamin C and other antioxidants for treatment durations as long as 6.5 years (8, 11, 12).
The hypothesis that antioxidant nutrients may protect against age-related damage to the human lens was derived from laboratory and animal studies, and has been generally supported by findings of observational epidemiologic studies in humans. However, the results of completed randomized trials testing vitamin E, vitamin C, or beta-carotene have been disappointing and ongoing trials will determine whether observable benefits on cataract can emerge with longer-term treatment with these antioxidant vitamins. In the meantime, the results of the present study add to the growing body of observational evidence to suggest a possible beneficial effect for lutein/zeaxanthin in delaying cataract formation. Lutein and zeaxanthin are the only carotenoids detected in the human lens (18-20), and the presence of oxidation products of lutein and zeaxanthin in the lens (54) further supports a functional role for xanthophylls in maintaining lens clarity.
In conclusion, these prospective data from a large cohort of female health professionals indicate that higher intakes of lutein/zeaxanthin and vitamin E are associated with decreased risks of cataract. While reliable data from randomized trials are accumulating for vitamin E and other antioxidant vitamins, randomized trial data for lutein/zeaxanthin are lacking. Such information will help to clarify the benefits of supplemental use of lutein/zeaxanthin, and provide the most reliable evidence on which to base public health recommendations for cataract prevention by vitamin supplementation.
Supported by research grants CA 47988, HL 43851, and EY 06633 from the National Institutes of Health, and by DSM Nutritional Products, Inc. (Roche). DSM Nutritional Products, Inc., had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of this manuscript. Dr. Christen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.