1 Nutritional Epidemiology Program, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA
2 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
3 Laboratory for Nutrition and Vision Research, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA
4 Department of Epidemiology, Harvard School of Public Health, Boston, MA
5 Department of Nutrition, Harvard School of Public Health, Boston, MA
Correspondence to Dr. Paul F. Jacques, Nutritional Epidemiology Program, US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111 (e-mail: paul.jacques{at}tufts.edu).
Received for publication June 4, 2004. Accepted for publication December 14, 2004.
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ABSTRACT |
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cataract extraction; dietary fats; fatty acids, omega-3; trans fatty acids
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INTRODUCTION |
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Cataract formation is associated with perturbation of lens membrane composition, structure, and function (710
), including changes in fatty acid composition (11
), and high intake of polyunsaturated fatty acids delays the onset of mature cataracts in animal studies (12
, 13
). Thus, differences in lens membrane fatty acid composition and function due to dietary fat intake may influence cataract formation. Because there has been little epidemiologic research on dietary fat intake and risk of cataract, we examined the association between specific types of fat and incidence of cataract extraction among participants of the Nurses' Health Study.
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MATERIALS AND METHODS |
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Assessment of dietary fat intake
In 1980, a 61-item semiquantitative food frequency questionnaire was sent to the study participants to assess dietary intake of specific fats and other nutrients. An expanded food frequency questionnaire with approximately 130 food items was sent to women in 1984, 1986, 1990, 1994, and 1998 to assess usual food intakes in the previous year. A common unit or portion size for each food was specified, and participants were asked how often, on average, they had consumed that amount of food or beverage during the previous year. There were nine possible responses for each food item, ranging from "almost never" to "6 or more times per day." For this analysis, we chose 1984 as the start of the follow-up, because the shorter food frequency questionnaire collected in 1980 did not have the detailed questions needed for calculation of intake of omega-3 fatty acids. The average daily intake of fat and other nutrients was calculated by multiplying the frequency of consumption of each item by its nutrient content per serving and totaling the nutrient intake for all food items.
The reproducibility and validity of the 1984 dietary questionnaire were assessed previously (15). The Pearson correlation coefficients for energy-adjusted total and specific types of fat assessed by two 1-week dietary records and the food frequency questionnaire range from 0.48 to 0.79, with correction for attenuation due to random error. Spearman's correlation coefficients between fat intakes calculated from the food frequency questionnaire and the fatty acid composition of subcutaneous fat aspirates also indicated that the food frequency questionnaire provided a reasonable measure of fatty acids from exogenous sources (r = 0.48 for long-chain omega-3 fatty acids, r = 0.51 for trans-fatty acid) (16
). The correlation coefficients between dietary records and the food frequency questionnaire for intake of meat and fish varied from 0.46 to 0.66 (17
). The mean total fish intake was 3.7 servings per week assessed by the food frequency questionnaire and 3.6 servings per week assessed by dietary records, with a Spearman's correlation coefficient of 0.61.
Population analyzed
We restricted the baseline population to women who were older than 45 years in 1984 and excluded those who did not complete a baseline food frequency questionnaire, who had implausible caloric intakes (<600 or >3,500 kcal/day), or who left more than 70 items blank on the food frequency questionnaire. We also excluded participants who reported a diagnosis of cataract (n = 1,892), cancer (except nonmelanoma skin cancer) (n = 4,452), or diabetes mellitus (n = 2,455) at baseline. A total of 56,864 women who were aged 45 or more years in 1984 were included in the analysis, and those who were aged less than 45 years in 1984 were entered into the analysis in the 2-year cycle after they reached the age of 45. By the end of the follow-up in June 2000, a total of 71,083 women were available for analysis.
Outcome
Starting in 1984, participants were asked on the biennial questionnaire whether they had had a cataract extraction; if so, permission was requested to obtain information from their medical records. The ophthalmologist who had performed the surgery and, when available, the patient's optometrist or another health care provider who had ophthalmologic records were contacted and asked to complete a questionnaire that inquired about the dates of initial diagnosis and extraction; cause of the cataract, if known; the participant's best-corrected visual acuity in both eyes prior to surgery; and the location of the lens opacity. Ninety percent of the ophthalmologists contacted responded to the questionnaire, and all confirmed the extraction. For subjects whose information on cataract extraction could not be obtained from the physicians, self-report was used based on the 100 percent ophthalmologist confirmation of self-report. Participants with physician- or self-confirmed cataract extractions in at least one eye were defined as cases.
We excluded those cases whose cataracts were considered to be either congenital or secondary to chronic steroid use, chronic intraocular inflammation, ocular trauma, previous intraocular surgery, or glaucoma (n = 787). These cases accrued person-time up to the date on which the cataract was initially diagnosed, determined as the earlier of the dates indicated by the participant and the ophthalmologist. We also excluded subjects who developed cancer (n = 40) or diabetes mellitus (n = 214) before cataract diagnosis; these individuals accrued person-time up to the date of cancer or diabetes diagnosis and were not counted as cases. Finally, we excluded those whose cataracts were diagnosed prior to the age of 45 years (n = 145). A total of 4,196 cataract cases were included in the analysis. Cataracts in different areas of the lens (nuclear, posterior subcapsular, or cortical) may have different etiologies (18, 19
). On the basis of information from those participants whose ophthalmologists indicated a subtype, we were able to identify cases with only one subtype and those with primarily one subtype. The primary analysis was based on the presence of any cataract, but we also considered cataract subtype: 1) primarily nuclear cataract, in either eye (if unilateral) or in both eyes (if bilateral), as determined by the participant's eye physician (n = 2,547); 2) primarily posterior subcapsular cataract (n = 995); and 3) primarily cortical cataract (n = 431). A total of 225 cases could not be classified.
Data analysis
The percentage of energy contributed by each type of fat was derived by dividing energy intake from each fat by total energy intake. Dietary variables were updated by using the information from the 1984, 1986, 1990, 1994, and 1998 dietary questionnaires to account for the long follow-up period. We calculated intake of fat as a cumulative average intake from all available dietary questionnaires up to the start of each 2-year follow-up interval. For example, the intake in 1984 was used for the 19841986 follow-up, and the average of the 1984 and 1986 intakes was used for the 19861990 follow-up. Participants were divided into categories according to quintiles of fat intake and frequency of consumption of individual fat-containing foods, which were also updated according to average frequencies of intake over the follow-up period.
Each participant's follow-up time began with the date of return of the 1984 questionnaire or the point at which the participant reached the age of 45 years, whichever was later. Since it was possible that participants could change their eating pattern after diagnosis of cataract but prior to extraction, we used the date of diagnosis as the end of follow-up for cases of cataract extraction. Because cataracts may be asymptomatic, participants who did not have eye examinations may have been less likely to have their cataracts diagnosed. Therefore, we did not accumulate follow-up time for those women who did not report having an eye examination during the previous 2-year period based on the 1990, 1992, 1994, 1996, and 1998 questionnaires (information on eye examination was not available prior to 1990). Follow-up continued until cataract diagnosis, death, cancer diagnosis, diabetes diagnosis, loss to follow-up, or end of follow-up (June 2000), whichever came first.
To determine the association between fat intake and other risk factors for cataract extraction, we used Cox proportional hazards models (PROC PHREG) for all multivariable analyses (SAS Institute, Inc., Cary, North Carolina) (20). To control for confounding by age, calendar time, and any possible two-way interactions between these two time variables, we stratified the analysis jointly by age in months at the start of follow-up and calendar year of the current questionnaire cycle. The multivariable models included potential risk factors for cataract such as total energy intake, body mass index, lutein and zeaxanthin intake, alcohol intake, physical activity (quintiles of metabolic equivalents per week), menopausal status and postmenopausal hormone use, history of hypertension, cigarette smoking, number of visits with a physician in the past year (as reported in 1978), and state of residency (in 1976). We chose pack-years of smoking (the number of years of smoking multiplied by the average number of packs of cigarettes smoked per day) as a measure of smoking status, because cataract development is more strongly related to the cumulative effect of smoking than to current smoking status (21
). We also added multivitamin supplement use and the Recommended Food Score, as adapted for use with the Nurses' Health Study food frequency questionnaire (22
), to our multivariable model to examine the potential confounding by healthy dietary behaviors and patterns. Since there were no significant associations between risk of cataract extraction and intake of either vitamin C or vitamin E in our preliminary analyses, we did not include these two variables in our multivariable model. All the dietary and nondietary covariates were updated in every 2-year period except for number of visits with a physician and state of residency. The measures of fat intake were updated in the same manner.
Relative risks were calculated as the rate of occurrence of cataract extraction in each fat category, divided by the corresponding rate in the referent category, and 95 percent confidence intervals were calculated. Tests for trend across categories of fat intake were assessed by using the median within each category as a continuous variable. Tests for trend of foods were calculated with each intake category (e.g., 1, 2, 3, etc.) as a continuous variable.
We included an interaction between age and the fat intake variables in our multivariable models to determine whether there was any effect modification by age. In addition to using cumulative updated fat intake in the primary analyses, we performed alternate analyses using baseline intake and the most recent intake.
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RESULTS |
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To evaluate further the relation between fat intake and cataract, we examined the major food sources of fat (table 6). Among these foods, intake of beef, pork, or lamb as a main dish was positively related to cataract extraction. More than one serving/day of this food item was associated with a 22 percent greater risk of cataract extraction compared with one or fewer servings/week (95 percent CI: 1.03, 1.44; ptrend = 0.01), and the trend was significant in analysis of primarily nuclear cataract. High intake of mayonnaise or other creamy salad dressings and cheese was significantly associated with increased risk of cataract extraction. Margarine and oil-and-vinegar dressing intakes were not related to risk of cataract extraction. Analyses of cataract subtype yielded similar results.
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DISCUSSION |
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The relation between dietary fat intake and risk of cataract was previously evaluated in only a few cross-sectional studies, and none considered specific fatty acids. Tavani et al. (23) observed that a high total dietary fat intake was related to greater risk of cataract extraction (odds ratio = 1.8, 95 percent CI: 1.2, 2.8), which was consistent with our findings. In the Blue Mountains Eye Study, intake of polyunsaturated fatty acid was associated with a lower prevalence of cortical cataract (odds ratio = 0.7, 95 percent CI: 0.5, 0.9) (24
). We did not observe any significant relation between polyunsaturated fatty acid intake and cataract extraction, but we had limited statistical power to examine relations with primary cortical cataract.
The long-chain omega-3 fatty acids, namely, eicosapentaenoic acid and docosahexaenoic acid, play important functional roles in animal cells. The amount of omega-3 fatty acid incorporated into the plasma membrane is partly determined by dietary intake and greatly influences membrane fluidity, the formation of receptors, binding of ligands to their receptors, and activation of intracellular signaling pathways (2528
). Many clinical, experimental, and epidemiologic studies indicate that omega-3 fatty acids exert beneficial effects on atherosclerosis and some types of cancer (29
, 30
). Higher omega-3 fat and fish intakes have been related to a reduced risk of age-related macular degeneration, another common eye disease in the elderly, in some (31
34
), but not all (35
, 36
), studies.
Although there is no known mechanism for the effects of long-chain omega-3 fatty acids on cataract formation, they may affect lens membrane composition, which could alter membrane structure and function, for example, intracellular signaling and membrane enzyme function, as has been demonstrated in other tissue cell membranes (37, 38
). Numerous studies suggest that cataractogenesis is associated with perturbation of lens membrane integrity (7
10
). In the lipid bilayer of lens fiber membranes from cataractous lenses, there is a significant increase in the level of oxidized unsaturated fatty acids with an increase in the content of palmitic acid and a decrease in the levels of docosahexaenoic acid (9
, 39
).
Theoretically, the highly unsaturated nature of long-chain omega-3 fatty acids renders them particularly vulnerable to oxidative stress, which is an important factor in cataract formation. However, experimental results that indicated no change or even decreased lipid peroxidation in non-lens tissues enriched with docosahexaenoic acid (4043
) have led to the hypothesis that docosahexaenoic acid, possibly in association with the vinyl ether linkage of plasmalogens, can combat free radicals.
Our analysis of primary nuclear subtype yielded findings similar to those for all cataracts combined. For primary posterior subcapsular cataract, we found similar relative risks as for all types combined, but associations reached statistical significance for dark-meat fish only, possibly because of a smaller number of cases of this subtype. The lack of significant findings for primary cortical cataract was probably due to the much smaller number of cases of this subtype.
The difference between the primary analyses (using cumulative updated average fat intake) and the secondary analyses (using either baseline or the most recent fat intake) may suggest that cumulative updated average intake was better representing the long-term intake than a single measure of intake.
Because of our large study population, repeated and standardized eye examinations were not possible. However, this should not present a major limitation. Detailed confirmation of cataract extraction without similar confirmation of noncases should not compromise validity. By restricting the analysis to cataract extraction, we have essentially no false positive cases (100 percent specificity in our disease definition). Although there will be subjects with cataracts not requiring extraction in our noncase group, this underascertainment of cases (i.e., low sensitivity) should not bias the relative risk in a prospective study, unless the likelihood of someone with cataract extraction's identification as a case is associated with the exposures of interest (44), in our case, fatty acid intake. This is very unlikely for a number of reasons. 1) The severity of cataract (as measured by presurgical visual acuity) is unrelated to omega-3 fatty acid intake in our study population, indicating that those with higher intakes are not having cataract extracted at an earlier stage. 2) Omega-3 fatty acid intakes were unrelated to the frequency of reported eye examinations. 3) Starting in 1990 (when the question about eye examinations was first asked), we allowed only those women who reported having undergone an eye examination during that questionnaire cycle (i.e., in the previous 2 years) to contribute person-time to that follow-up interval. We are unable to place similar limits on the follow-up time before 1990. 4) Because all participants are registered nurses, factors that are likely to influence the decision of individuals with cataract to have it extracted, such as access to medical care and threshold for surgery, are likely to be more uniform than in the general population. 5) Any bias resulting from a greater tendency for healthier behaviors to result in earlier identification of cataract and surgery for less mature cataract would tend to elevate the apparent risk of cataract extraction among those with healthier behaviors. Thus, if women who were more likely to consume fatty fish were also more likely to be screened for cataract or to have cataract extracted at an earlier stage, there would be a tendency to either underestimate the potential benefit of omega-3 intake or create a spurious positive association between omega-3 fatty acid intake and cataract risk. Such bias could not explain the observed protective association with omega-3 fatty acid intake.
Bias may be introduced through other means as well, such as assessment of fat intake or loss to follow-up. The date of initial diagnosis of cataract, rather than the date of cataract surgery, was used as the end of follow-up to minimize bias due to change in fat intake in response to diagnosis. Since fat intake was assessed before the diagnosis of disease, any misclassification of fat intake would be nondifferential and tend to bias our association toward the null. In addition, misclassification of exposure was reduced by averaging intakes during the long follow-up. Loss to follow-up as a source of bias was minimized because of the high follow-up rate in this cohort. Although we controlled for a wide range of potential confounders, some unmeasured risk factors might have confounded the associations seen. Finally, our study population was a nonrepresentative sample of women.
In summary, our findings suggest that a high intake of long-chain omega-3 fatty acid through consumption of dark-meat fish may contribute to the prevention of cataract formation. More studies, particularly in population-based samples, are needed to confirm and clarify the relation between dietary fat intake and cataract.
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ACKNOWLEDGMENTS |
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References |
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