Carotenoids in Age-Related Eye Disease Study (CAREDS) data collection timeline. WHI-OS indicates Women's Health Initiative Observational Study; FFQ, food frequency questionnaire.
Moeller SM, Voland R, Tinker L, Blodi BA, Klein ML, Gehrs KM, Johnson EJ, Snodderly DM, Wallace RB, Chappell RJ, Parekh N, Ritenbaugh C, Mares JA, CAREDS Study Group. Associations Between Age-Related Nuclear Cataract and Lutein and Zeaxanthin in the Diet and Serum in the Carotenoids in the Age-Related Eye Disease Study (CAREDS), an Ancillary Study of the Women's Health Initiative. Arch Ophthalmol. 2008;126(3):354-364. doi:10.1001/archopht.126.3.354
To evaluate associations between nuclear cataract (determined from slitlamp photographs between May 2001 and January 2004) and lutein and zeaxanthin in the diet and serum in patients between 1994 and 1998 and macula between 2001 and 2004.
A total of 1802 women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intakes of lutein and zeaxanthin above the 78th (high) and below the 28th (low) percentiles in the Women's Health Initiative Observational Study (1994-1998) were recruited 4 to 7 years later (2001-2004) into the Carotenoids in Age-Related Eye Disease Study.
Women in the group with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio, 0.77; 95% confidence interval, 0.62-0.96) compared with those with low levels. Multivariable adjustment slightly attenuated the association (odds ratio, 0.81; 95% confidence interval, 0.65-1.01). Women in the highest quintile category of diet or serum levels of lutein and zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.97; P for trend = .04; and multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P for trend = .01, respectively). Cross-sectional associations with macular pigment density were inverse but not statistically significant.
Diets rich in lutein and zeaxanthin are moderately associated with decreased prevalence of nuclear cataract in older women. However, other protective aspects of such diets may in part explain these relationships.
Age-related cataract is a common condition among older adults that has been gaining increased health policy importance. An estimated 20.5 million Americans (17%) older than 40 years have cataract in either eye, and 6.1 million (5%) have had cataracts extracted.1 The number of Americans affected by cataract and undergoing cataract surgery is expected to increase dramatically during the next 20 years as the US population ages.1 The large increase in cataract surgical procedures predicted for the US population as a whole is of significant health policy concern because treatment for cataract accounts for approximately 60% of vision-related Medicare expenditures.2 As more aging Americans need cataract surgery, there is concern about the ability of health care systems, particularly Medicare, to fund cataract surgery.2 Therefore, identifying modifiable risk factors is of critical importance to improving health of older Americans and to the economic stability of the health care system.
Nuclear cataract is the most common type of cataract among older Americans3 and the most common type of cataract for which cataract surgery is performed.4 It is more common in women than men and among white individuals.1 The pathogenesis of nuclear cataract is known to involve the accumulated stressors resulting from the inability to sufficiently defend against or repair the damage due to a variety of environmental stressors, including photochemical formation of free radicals. Accordingly, diets high in the antioxidant vitamins C and/or E have been inversely associated with nuclear cataract in many previous epidemiologic studies.5- 11Lutein and zeaxanthin, the most abundant lens carotenoids,12 scavenge superoxide and hydroxyl radicals,13 protect against UV-B–induced lipid peroxidation in cultured lens epithelial cells,14 and may further play a role in membrane stability.15Diets high in lutein plus zeaxanthin have also been inversely associated with nuclear cataract or cataract extraction in 1 recent study16 and several previous studies (reviewed by Moeller et al17 and Mares18).
The Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative (WHI), was designed in part to evaluate the relationships of the carotenoids lutein and zeaxanthin to the prevalence of age-related nuclear cataract. This study provides data on these carotenoids in the diet, serum, and retina as well as on numerous potential risk and protective factors. Women at high and low extremes of lutein plus zeaxanthin intake at WHI enrollment were recruited into the CAREDS to maximize statistical power to evaluate these associations and associations with age-related macular degeneration (previously described by Moeller et al19). The a priori hypothesis was that women with high intakes of lutein plus zeaxanthin in 1994 to 1998 have a lower prevalence of age-related nuclear cataract in 2001 to 2004 compared with women with low intakes of these carotenoids. We also report odds ratios (ORs) for nuclear cataract across the full range of intakes and serum levels in this sample and describe whether these relationships are altered after accounting for other dietary, lifestyle, and health attributes that may be correlated with high intakes or serum levels of lutein plus zeaxanthin and nuclear cataract.
The uptake of carotenoids into the intestine and eye is widely known to be highly variable, but conditions that predict levels in the eye are largely unknown.20 Levels in the retina and lens may be reflected by the optical density (OD) of these carotenoids in the macula. Two previous studies have reported macular pigment (MP) OD to be cross-sectionally related to lens OD in 114 persons older than 50 years21 and in 39 people older than 55 years.22 Our study also reports cross-sectional associations of MPOD with nuclear cataract in the larger sample of women in the CAREDS.
The WHI Observational Study was a prospective cohort study of the most common causes of mortality and morbidity among 93 676 postmenopausal women aged 50 to 79 years at enrollment at 40 sites around the United States. The original cohort was recruited to the WHI at each of these sites through regional mass mailings and mass media strategies from among women ineligible for or uninterested in participation in the WHI Clinical Trials. Participants were followed up on average 7 years after enrollment. Women were excluded if they had medical conditions that predicted survival of less than 3 years, alcoholism, drug dependency, or mental illness.23,24
The CAREDS population consisted of women who were enrolled in the observational study of the WHI at 3 of 40 sites, the University of Wisconsin, Madison, the University of Iowa, Iowa City, and the Kaiser Center for Health Research, Portland, Oregon, and had intakes of lutein plus zeaxanthin that were above the 78th or below the 28th percentiles as assessed at baseline enrollment into the WHI in 1994 through 1998 (Figure). This sampling strategy was used to maximize statistical power as previously described.20 Of the 3143 women who fulfilled these criteria and formed the recruitment pool, 96 died or were lost to follow-up between sample selection in year 2000 and enrollment in the CAREDS in May 2001 through January 2004. Those remaining were sent letters inviting them to participate in the CAREDS. A total of 1042 women declined participation and 2005 (64%) were enrolled. Of those enrolled, 1894 participated in study visits.
Of those enrolled, 1 participant was later excluded because the WHI found that her diet data were unreliable. We excluded 32 women reporting a history of trauma to both eyes, 1 woman reporting cataract extraction before age 40 years, and 132 women with missing or ungradable nuclear lens photographs. Thirty-seven participants were excluded because of missing covariate data. Thus, 1802 women composed the analysis data set for this investigation. All of the procedures conformed to the Declaration of Helsinki and were approved by the institutional review board at each university.
To evaluate potential bias due to lack of participation in the CAREDS, we compared characteristics of women in the recruitment data set who did not enroll in the CAREDS (1138 women who declined, were lost to follow-up, or died) with those who did (2005 women). Women with high lutein intakes were more likely than those with low intakes to join the CAREDS (69% vs 60%, respectively; P < .001). There was a slight but statistically nonsignificant (P = .11) difference in the prevalence of self-reported cataract between the participants and nonparticipants (18% vs 21%, respectively).
We further compared women in the recruitment data set who were included in the final analysis data set (n = 1802) with those who were not (n = 1341). At the WHI baseline, women included in the final analysis data set as compared with those who were not had higher age-adjusted mean intakes of lutein plus zeaxanthin (1.8 mg/d vs 1.6 mg/d, respectively) and lower mean intakes of total fat (31% kcal vs 33% kcal, respectively), saturated fat (10.8% vs 11.2%, respectively), and polyunsaturated fat (6.4% vs 6.7%, respectively); they were younger (median age, 63 years vs 65 years, respectively), had more formal education (78% vs 68% with post–high school education, respectively), and were more likely to have never been smokers (58% vs 54%, respectively), to consume alcohol (73% vs 68%, respectively), to use hormone replacement therapy (54% vs 46%, respectively), to take dietary supplements (76% vs 71%, respectively), to be physically active (≥ 21 kcal/wk/kg in 27% vs 20%, respectively), and to perceive their health as very good or excellent (63% vs 55%, respectively). They were more likely to report a history of macular degeneration (5% vs 4%, respectively) and less likely to have hypertension (32% vs 36%, respectively) or a body mass index (calculated as weight in kilograms divided by height in meters squared) greater than 30 (24% vs 33%, respectively) (P < .05 for all of the characteristics). There was no statistically significant difference in the prevalence of self-reported cataract between those included and those excluded from the analytic data set (20% vs 19%, respectively;P = .74).
Primary dietary estimates were made from responses to a previously validated, semiquantitative food frequency questionnaire (FFQ)25 at the WHI baseline (1994-1998). We also obtained estimates at CAREDS visits using the same questionnaire, querying intake 15 years prior to the CAREDS (1986-1989) to estimate long-term diet stability. Retrospective FFQs have been found to be reliable indicators of past diet.26,27 Nutrient and food group estimates in the WHI and the CAREDS were computed from responses to FFQs at the Fred Hutchinson Cancer Research Center. Data from the 2004 participants with reliable FFQ data (≥ 600 kcal and ≤ 5000 kcal) at the WHI baseline25 and the 1995 participants with CAREDS 15-year past FFQ data collected retrospectively were used to generate quintiles of nutrient intake and tertiles of food and food group intake for each time.
Serum samples were obtained from participants at the WHI baseline examinations (1994-1998) after a fast for 10 or more hours and were stored at −80°C.28 Serum levels of lutein, zeaxanthin, and tocopherols were determined at Tufts University (2004-2005) by a reverse-phase high-performance liquid chromatography analysis.29 Levels of lutein and zeaxanthin represent the sum of the trans isomers. Blind duplicates were analyzed in each batch of serum analyses (in a total of 57 subjects). Mean coefficients of variation were 7.0% for all trans-lutein and 9.6% for all trans-zeaxanthin. The total triglycerides level was determined by an automated chemistry analyzer based on an enzymatic method with a glycerol blank,30 and the total cholesterol level was determined enzymatically by the cholesterol oxidase method.31
Measurements were made using a standardized protocol by the psychophysical method of heterochromatic flicker photometry during CAREDS visits conducted between May 2001 and January 2004. This protocol, described in detail previously,20,32 had high test-retest reliability (r = 0.9) and participant responses at 2 wavelengths that are consistent with the absorption spectrum of lutein and zeaxanthin.32 Briefly, participants viewed a small test field superimposed on a blue background with the right eye. The test field alternates between a wavelength (blue or blue-green) that is absorbed by the MP and a reference (green to yellow-green) wavelength that is outside the absorption band of the MP. When the frequency of alternation is chosen correctly, the test field appears to flicker. When making measurements, the participant is instructed to adjust the energy of the bluish test light so that the flicker stops. The amount of bluish light that is required to produce this flicker null provides a measure of the MPOD at the retinal location of the test light. The subject was instructed to fixate at the center of the following targets: 0.25°, 0.50°, 1.00°, and 1.75° from the foveal center so that the MPOD at different eccentricities was measured in reference to a target at 7° from the center. We used data from 0.50° from the foveal center, the target with the lowest within- to between-person variability.32
Lens photography and eye examinations were part of CAREDS visits that took place between 2001 and 2004 using the standardized Early Treatment Diabetic Retinopathy Study protocol33 modified as in the Age-Related Eye Disease Study for which grading reliability has been previously reported.34 Briefly, both eyes were examined with slitlamp biomicroscopy. After pharmacological dilation of the pupils, a single nonstereoscopic photograph was taken of each eye with a modified slitlamp camera (Topcon, Paramus, New Jersey) to grade nuclear sclerosis and nuclear color using the Age-Related Eye Disease Study protocol.35 The OD of nuclear opacity was graded against a series of 7 standard photographs producing continuous scores on a decimal scale that can range from 0.0 to 7.1. Severity of nuclear sclerosis was determined in eyes that had not previously undergone cataract extraction.
The CAREDS questionnaires completed before study visits were reviewed with participants at the time of the CAREDS visit. Eye history queries included dates of cataract surgery in each eye, trauma to eyes, physician-diagnosed histories of cataract, glaucoma, and macular degeneration, and treatments and lifestyle changes that accompanied these conditions. Family history of cataract was also assessed, identifying all of the immediate family members who had physician-diagnosed cataracts prior to age 75 years.
The primary outcome was nuclear cataract, defined as a nuclear sclerosis severity score of 4 or greater in the worst eye and/or a history of cataract extraction in either eye. It was previously determined in a similar population that the incidence of cataract surgery was highest among people with photographically evident cataracts in the nuclear region of the lens,4 suggesting that nuclear cataracts were likely in women who had received cataract extractions. All of the 1802 women in this data set (described earlier) were eligible for this end point. A nuclear sclerosis severity score of 4 or greater was an additional outcome among women who had at least 1 natural lens for which lens photographs were gradable (1577 women).
Age, family history of cataract (immediate family member aged < 75 years when diagnosed), UV-B sunlight exposure (since age 18 years and in the last 20 years based on outdoor activities during routine and vacation periods, living location, and use of protective gear [hats or sunglasses]), and use of nutritional supplements were queried in questionnaires submitted at the CAREDS visit. Iris color was classified from photographs taken at the CAREDS eye examination. Additional demographic, lifestyle, and health history data were available from questionnaires completed at WHI study entry (education, smoking, physical activity, height, weight, hormone replacement therapy use, alcohol use, pulse pressure, diabetes, hypertension, and cardiovascular disease).
We performed t tests, analyses of covariance, and χ2tests to assess the statistical significance of potential covariates in the groups with high vs low lutein plus zeaxanthin intake and by the presence or absence of nuclear cataract. The ORs and 95% confidence intervals (CIs) for nuclear cataract and for nuclear sclerosis scores of 4 or greater (yes or no) were calculated comparing the group with high lutein plus zeaxanthin intake vs the group with low intake using logistic regression (PROC LOGISTIC in SAS version 8.2 statistical software [SAS Institute, Inc, Cary, North Carolina]).
A cataract risk factor model was determined for the CAREDS sample that first considered nonnutritional variables significantly related to nuclear cataract (P < .10). The model included age (continuous) and the following variables that influenced the age-adjusted ORs by 10% or more: smoking status (never, past, or current), iris color (blue, green, light brown, or dark brown or black), physical activity (in kilocalories per week per kilogram: < 3, 3 ≤ x < 10, 10 ≤ x < 21, or ≥ 21), multivitamin use (> 2 years vs nonusers), hormone replacement therapy use (never, past, or current), pulse pressure (in millimeters of mercury), and body mass index.
Additional nutritional variables that were statistically significantly related (P ≤ .10) to both nuclear cataract and lutein plus zeaxanthin intake in the CAREDS or that were previously suspected to be biologically plausible confounders were tested by adding them singly to the risk factor model described earlier. These variables included intakes at the WHI baseline of total energy (in kilocalories), total fat (in percentage of kilocalories), saturated fat (in percentage of kilocalories), polyunsaturated fat (in percentage of kilocalories), fruits (in servings per day), vegetables (in servings per day), vitamin C (in milligrams per day from food), vitamin E (in milligrams per day from food), and γ-tocopherol (in milligrams per day) as well as the use of high-dose antioxidants at the CAREDS baseline (daily intake of ≥ 2 of the following 3 antioxidant supplements: ≥ 120 mg of vitamin C, ≥ 60 IU [40 mg] of vitamin E, and ≥ 10 000 μg of beta carotene for ≥ 2 years). Exposure to UV-B sunlight (measured in Maryland sun years36) was not found to be a significant confounder.
If addition of the covariate changed the OR by 10% or more, the covariate was selected for addition to a larger model. For both the cataract and nuclear sclerosis end points, the covariate that changed the OR the most was added to the model first. The ORs comparing the groups with high vs low lutein plus zeaxanthin intake were reassessed after the addition of each potential covariate. Only those covariates that still changed the OR by 10% or more in the fuller model were retained in the final model. Dietary variables that met these criteria but were strongly correlated with dietary lutein plus zeaxanthin (r ≥ 0.5) were not included in the final model to limit issues of colinearity.
We tested for interactions to determine whether the associations between lutein plus zeaxanthin intake and nuclear cataract differed according to levels of other risk factors (age, smoking, and UV-B sunlight exposure). An α level of .10 was used to determine statistical significance.
In exploratory analyses, we examined the odds for nuclear cataract in women with high and low intakes of specific foods rich in lutein plus zeaxanthin, including spinach, dark green leafy vegetables, and fruits and vegetables in general. Tertiles of food intake were created using data for the 2004 CAREDS participants with reliable WHI baseline FFQ data both overall and within age strata. Because of the low intake of cooked greens in our sample (spinach, mustard greens, turnip greens, and collards), comparisons were made in those eating less than 1 vs 1 or more servings per month.
Serum levels of lutein, zeaxanthin, and lutein plus zeaxanthin were divided into quintile categories. The ORs and 95% CIs were calculated as described earlier using the lowest quintile category as the referent group.
Exploratory analyses examined the cross-sectional relationship between levels of lutein and zeaxanthin in the macula (MPOD) and nuclear cataract. The MPOD values were divided into quintile categories, and ORs and 95% CIs were calculated as described earlier.
The median level of lutein plus zeaxanthin in the diet was approximately 3 times higher in women in the group with high lutein intake compared with those in the group with low intake (Table 1). Women in the group with high lutein intake were more likely to be older, nonwhite, college educated, in a higher income bracket, and more physically active and to have lower body mass indexes and serum triglycerides levels compared with those in the group with low lutein intake. They also were more likely to rate their general health status as excellent or very good. Women with lower dietary levels of lutein plus zeaxanthin were more likely to live in Iowa and have blue eyes. The total energy intake was higher in the group with high lutein intake, although the percentages of dietary fats in the diet in that group were less than in the group with low lutein intake. Intakes of dietary fiber, fruits, vegetables, many micronutrients and carotenoids, alcohol, and high-dose antioxidant supplements were also higher in the group with high lutein intake as compared with the group with low lutein intake, as were serum levels of lutein, zeaxanthin, and α-tocopherol. Despite higher intakes of γ-tocopherol, women in the group with high lutein intake had lower serum levels of this tocopherol compared with the group with low lutein intake. Results were similar when examining intakes as nutrient densities, except for ω-3 fatty acids (0.79 g/1000 kcal/d in the low lutein group vs 0.76 g/1000 kcal/d in the high lutein group; P = .003) and alcohol (3.3 g/1000 kcal/d in the low lutein group vs 2.9 g/1000 kcal/d in the high lutein group; P = .15).
The prevalence of nuclear cataract was lower among women in the group with high lutein intake as compared with those in the group with low lutein intake after adjusting for age (Table 1). The prevalence of nuclear sclerosis scores of 4 or greater was marginally lower among women in the high lutein group vs the low lutein group, as was the prevalence of cataract extraction surgery. Women in the group with high lutein intake were 23% less likely to have nuclear cataract after adjusting for age(Table 2). Further adjustment for other cataract risk factors did not substantially alter the OR, although it was only marginally statistically significant (P = .08). The ORs for nuclear sclerosis scores of 4 or greater were similar. In analyses in which both eyes were used as units of analyses, in generalized estimating equations, results were nearly identical (data not shown).
The associations were strengthened when women in this sample were further categorized by quintiles of lutein and zeaxanthin in the diet. Women in the highest quintile category of dietary lutein plus zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable-adjusted OR) (Table 3). Associations with nuclear sclerosis scores of 4 or greater were similar to those observed for nuclear cataract.
We explored the possibility that age, smoking status, and UV-B exposure were modifying the relationship between dietary lutein plus zeaxanthin and nuclear cataract. No statistically significant interactions were observed for age (P for interaction = .67), smoking status (P for interaction = .64), or UV-B exposure (P for interaction = .60) with lutein intake group.
A 32% lower prevalence odds of nuclear cataract was observed for women in the highest quintile category of serum lutein plus zeaxanthin compared with those in the lowest category(multivariable-adjusted OR) (Table 3). Associations with nuclear sclerosis scores of 4 or greater were attenuated compared with those observed for overall nuclear cataract and were not statistically significant.
Intake of total dietary fat (in percentage of kilocalories) significantly attenuated the associations between dietary lutein plus zeaxanthin and nuclear cataract (Table 4). The associations with serum lutein plus zeaxanthin were less strongly attenuated. The Pearson age-adjusted correlation coefficient between total dietary fat (in percentage of kilocalories; continuous) and lutein intake group was −0.35 (P < .001).
Several other nutrients and food components attenuated the association between nuclear cataract and dietary lutein plus zeaxanthin, including vitamin C, lycopene, beta carotene, and fiber. These were not included in statistical models because of their high correlations with dietary lutein (Pearson age-adjusted correlation coefficients ranged from 0.61-0.77).
Preliminary data suggested fluctuations in the level of lutein plus zeaxanthin in the diets of women in our sample prior to their enrollment in the WHI. Thus, we examined associations in women whose intake of lutein plus zeaxanthin did not change more than 1 quintile category between the CAREDS 15-year past FFQ and the WHI baseline FFQ (n = 1421). The association with nuclear cataract was similar to that observed in the overall data set (comparing the highest vs lowest quintile categories: age-adjusted OR, 0.65; 95% CI, 0.44-0.95; P for trend = .07).
In exploratory analyses, we examined the odds for nuclear cataract in women with high and low intakes of fruits, vegetables, and specific foods rich in lutein and zeaxanthin. Women in the highest tertile categories of intake of fruits, vegetables, and fruits plus vegetables were approximately 30% less likely to have nuclear cataract than women in the lowest tertiles of intake(Table 5). After multivariable adjustment, the ORs were slightly attenuated and only the association with vegetable intake remained statistically significant (P = .03). Associations with specific foods rich in lutein and zeaxanthin, such as cooked greens, dark green lettuces, and broccoli, were in protective directions but not statistically significant.
Exploratory, cross-sectional analyses found a nonsignificant decrease in the prevalence odds of nuclear cataract for women in the highest quintile category of MPOD (median, 0.63 OD units) compared with those in the lowest category (median, 0.08 OD units) (age-adjusted OR, 0.80; 95% CI, 0.56-1.12; P for trend = .23) among the 1714 participants in these analyses who had MPOD values. The association was slightly attenuated after adjusting for other risk factors (smoking, iris pigmentation, physical activity, use of hormone replacement therapy, multivitamin use, and pulse pressure) (OR, 0.84; 95% CI, 0.59-1.19) and further attenuated after adding to the model variables that explain MPOD (lutein intake and body mass index)20(OR, 0.88; 95% CI, 0.61-1.25). In analyses in which both eyes were used as units of analyses for the outcome, in generalized estimating equations, results were identical (data not shown).
We observed a moderate decrease in the prevalence of nuclear cataract among women with diets high in lutein plus zeaxanthin compared with those with diets lower in these carotenoids. This association was stronger when examining intake of lutein plus zeaxanthin across all of the levels of intake in this sample (by quintile categories) than when comparing the 2 groups of women sampled who had lutein and zeaxanthin intakes above the 78th and below the 28th quintiles. Associations were similarly strong for serum lutein plus zeaxanthin.
These results are consistent with a body of evidence that supports a protective relationship between lutein and zeaxanthin and nuclear cataract. Lutein and zeaxanthin are the predominant carotenoids in the lens12 and have been demonstrated to protect against photodamage in vitro.14 Results of several previous epidemiological studies of samples with average intakes of lutein and zeaxanthin over wide ranges (0.8-3.3 mg /d) have suggested protective associations between high intakes of lutein and zeaxanthin and nuclear cataract,6,16,37- 40 although the association in one study was no longer significant after adjusting for vitamin C40 and the inverse association was not significant in another.41 Serum levels of lutein and zeaxanthin combined have been associated with nuclear cataract in longitudinal42 but not cross-sectional43- 45 studies, possibly reflecting error and bias related to recent diet change because serum carotenoid levels reflect recent, not long-term, carotenoid intake.
There have been no significant associations reported between the intake of lutein and zeaxanthin and opacities in other regions of the lens. This may be owing to the fact that opacities in other regions are less common and there is commonly low statistical power to assess these relationships. In 1 previous study,16 the prevalence of cortical and posterior subcapsular opacities were lower among persons with intakes of lutein and zeaxanthin in the highest quintile as compared with those in the lowest quintile, but this was not statistically significant. In this study, we did not obtain lens photographs that would permit us to accurately determine the presence of lens opacities in these regions of the lens.
The associations observed between nuclear cataract and lutein and zeaxanthin in the diet and serum might reflect in part the overall benefits of diets high in fruits and vegetables or related diet patterns. Diets high in fruits and vegetables were associated with decreased prevalence of nuclear cataract in this study and were also related to decreased cataract extractions or cataracts of any type in 2 previous studies.46,47 Nonsignificant inverse associations between the intake of fruits and vegetables and nuclear cataract were observed in a substudy of the Nurse's Health Study48 and in the Beaver Dam Eye Study6,37 in which the level of fruit and vegetable intake in the highest quintile was about half of that in the Nurse's Health Study. However, among specific fruits and vegetables, spinach, which is a concentrated source of lutein and zeaxanthin, has been the food item most consistently inversely associated with both nuclear opacities6,37,49 and opacities in any location.38,39,50,51
We found that the association between nuclear cataract and dietary intakes of lutein and zeaxanthin were attenuated after adjusting for total dietary fat intake as a percentage of calories. To our knowledge, no other studies have reported dietary fat as a confounder of this relationship or as a risk factor for nuclear cataract. Two studies of dietary fat and cataract reported relationships between nuclear cataract and certain types of fat,41 in one study relationships of linoleic and linolenic acids to cataract and in another long-chain ω-3 fatty acids to cataract extraction.52 Because the biological plausibility of a direct association between dietary fat and cataract risk is weak at this time, we speculate that low dietary fat could be a marker for a diet pattern that has a high density of several micronutrients that could protect against cataract and may have contributed to the attenuation of the association by dietary fat (Table 4).
The observed protective associations of lutein and zeaxanthin in the diet and serum to nuclear cataract could reflect other aspects of diet or lifestyle that differ in women with diets high and low in fruits and vegetables that are unknown and unmeasured. We further evaluated cross-sectional associations of nuclear cataract with MP that may reflect the status of these carotenoids in the eye more specifically. Compared with the CIs observed for the relationship of diet and serum lutein plus zeaxanthin to nuclear cataract, those for MPOD are not only weaker but also wider. This may be owing to the cross-sectional nature of these analyses as well as the variable retinal response to dietary carotenoids. The results are consistent in direction with 2 previous cross-sectional studies21,22 of lens OD and MPOD. The stronger ORs and tighter CIs observed for the association of lutein plus zeaxanthin in the diet and serum may reflect the prospective nature of the analyses, the lack of confounding by recent diet change, or the fact that diets rich in lutein plus zeaxanthin reflect other unmeasured aspects of diet or lifestyle that protect against nuclear cataract. They might also reflect imperfect correlations between the levels of carotenoids in the macula and the lens. Prospective studies of MPOD and nuclear cataract are needed to clarify relationships with lutein and zeaxanthin status in the eye.
In summary, we observed that diets rich in lutein and zeaxanthin were moderately associated with decreased prevalence of age-related nuclear cataract in women. Associations were similarly strong across quintiles of dietary and serum lutein plus zeaxanthin. High intakes of fruits and vegetables were also associated with reduced prevalence of nuclear cataract. These observations are consistent with those from previous observational studies. The possibility of a confounding influence of total dietary fat, which might reflect micronutrient-rich diet patterns, should be explored in further studies. Overall, our results suggest that diets rich in lutein and zeaxanthin protect against age-related nuclear cataract. However, other protective aspects of these diets may in part explain the observed relationships.
Barbara Alving, Jacques Rossouw, Shari Ludlam, Linda Pottern, Joan McGowan, Leslie Ford, Nancy Geller, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
Clinical Coordinating Center
Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L. Kooperberg, Ruth E. Patterson, Anne McTiernan, Fred Hutchinson Cancer Research Center, Seattle, Washington; Sally Shumaker, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Evan Stein, Medical Research Labs, Highland Heights, Kentucky; Steven Cummings, University of California at San Francisco.
Sylvia Wassertheil-Smoller, Albert Einstein College of Medicine, Bronx, New York; Jennifer Hays, Baylor College of Medicine, Houston, Texas;JoAnn Manson, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Annlouise R. Assaf, Brown University, Providence, Rhode Island; Lawrence Phillips, Emory University, Atlanta, Georgia;Shirley Beresford, Fred Hutchinson Cancer Research Center, Seattle, Washington; Judith Hsia, George Washington University Medical Center, Washington, DC; Rowan Chlebowski, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California; Evelyn Whitlock, Kaiser Permanente Center for Health Research, Portland, Oregon;Bette Caan, Kaiser Permanente Division of Research, Oakland, California;Jane Morley Kotchen, Medical College of Wisconsin, Milwaukee; Barbara V. Howard, MedStar Research Institute, Howard University, Washington, DC; Linda Van Horn, Northwestern University, Chicago and Evanston, Illinois; Henry Black, Rush Medical Center, Chicago; Marcia L. Stefanick, Stanford Prevention Research Center, Stanford, California; Dorothy Lane, State University of New York at Stony Brook; Rebecca Jackson, The Ohio State University, Columbus; Cora E. Lewis, University of Alabama at Birmingham; Tamsen Bassford, University of Arizona, Tucson and Phoenix; Jean Wactawski-Wende, University at Buffalo, Buffalo, New York; John Robbins, University of California at Davis, Sacramento; F . Allan Hubbell, University of California at Irvine; Howard Judd, University of California at Los Angeles; Robert D. Langer, University of California at San Diego, La Jolla and Chula Vista; Margery Gass, University of Cincinnati, Cincinnati, Ohio; Marian Limacher, University of Florida, Gainesville and Jacksonville; David Curb, University of Hawaii, Honolulu; Robert Wallace, University of Iowa, Iowa City and Davenport; Judith Ockene, Fallon Clinic, University of Massachusetts, Worcester;Norman Lasser, University of Medicine and Dentistry of New Jersey, Newark; Mary Jo O’Sullivan, University of Miami, Miami, Florida; Karen Margolis, University of Minnesota, Minneapolis; Robert Brunner, University of Nevada, Reno; Gerardo Heiss, University of North Carolina, Chapel Hill; Lewis Kuller, University of Pittsburgh, Pittsburgh, Pennsylvania; Karen C. Johnson, University of Tennessee, Memphis;Robert Brzyski, University of Texas Health Science Center, San Antonio; Gloria E. Sarto, University of Wisconsin, Madison; Denise Bonds, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Susan Hendrix, Hutzel Hospital, Wayne State University School of Medicine, Detroit, Michigan.
Correspondence: Julie A. Mares, PhD, Department of Ophthalmology and Visual Sciences, University of Wisconsin, 610 N Walnut St, 1063 WARF Bldg, Madison, WI 53726-2336 (firstname.lastname@example.org).
Submitted for Publication: July 14, 2006;final revision received June 7, 2007; accepted June 25, 2007.
CAREDS Investigators: Catherine Allen, PhD, Barbara A. Blodi, MD, Matthew Davis, MD, Larry Hubbard, MAT, Tara LaRowe, PhD, Niyati Parekh, RD, PhD, University of Wisconsin, Madison;Karen M. Gehrs, MD, Robert Wallace, MD, University of Iowa Hospital and Clinics, Iowa City; Elizabeth J. Johnson, PhD, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts;Michael L. Klein, MD, Casey Eye Institute, Oregon Health and Science University, Portland; Cheryl Ritenbaugh, PhD, MPH, University of Arizona, Tucson; D. Max Snodderly, PhD, Medical College of Georgia, Augusta;Amy Millen, PhD, State University of New York, Buffalo; Bill Wooten, PhD, Brown University, Providence, Rhode Island.
CAREDS Staff: Paula Smith, BS, Susan K. Nolte, BS, Debora Vahrenwald, BS, Portland, Oregon; Kelly O’Berry, BS, Heather Stockman, BS, Steven Wallace, BS, Lindsey Fuhrmeister, BS, Iowa City, Iowa; Jane Armstrong, BS, Michael Neider, BS, Hugh Wabers, BS, Janet Rowley, BS, Tanya Judge, BS, Lisa Oxton, BS, Rickie Voland, BS, Gail Ostrowski, BS, Scott Burfield, BS, Julie Ewing, BS, Tracy Perkins, BS, Madison, Wisconsin.
Financial Disclosure: None reported.
Funding/Support: This research was supported by grants EY13018 and DK 07665 from the National Institutes of Health and by Research to Prevent Blindness, and it was part of the CAREDS, an ancillary study of the WHI. The National Eye Institute funded the CAREDS, and the National Heart, Lung, and Blood Institute, National Institutes of Health funded the WHI program.
Additional Contributions: The Scientific Advisory Board, including Natalie Kurinji, PhD, National Eye Institute, Bethesda, Maryland; Sheila West, PhD (chair), Neil Bressler, MD, Johns Hopkins University, Baltimore, Maryland; Anne Lindblad, PhD, The EMMES Corp, Rockville, Maryland; and Susan Mayne, PhD, Yale University, New Haven, Connecticut, provided useful discussions and critical reading of the manuscript. The WHI investigators, staff, and participants provided time and effort in obtaining the WHI data that were presented in this article.