Associated Risk Factors
As expected, the odds ratio for age was large. The age effect was more marked for nuclear than cortical cataracts. For example, for moderate nuclear cataract the OR for persons over age 70 compared with persons under age 66 was 12.7. The corresponding OR for moderate cortical cataract was 5.96. It remains a challenge for epidemiologic and laboratory studies to explain the rapid and large increase in cataract risk with advancing age. Studies of genetic factors that affect aging, and the interaction of such factors with environmental insults, may help explain the strong influence of age on cataract risk.
The cumulative evidence from many studies suggests a slight excess risk of cataract for women.6,7,20,33-36
In AREDS the excess risk was only for nuclear cataract. Clinic-based case-control studies7,33
and a general population survey36
have reported a statistically significant excess risk of cortical opacities for women. However, three population-based surveys20,34,35
found a higher prevalence of both cortical and nuclear opacities in women. Although the finding of an excess risk of cataract for women seems consistent across studies, it is less clear whether this pertains to all cataract types or only some types. Hormonal influences or differential environmental exposures for men and women may explain the small, but apparently real, gender difference in cataract risk.
We found a higher risk of nuclear cataracts in nonwhites, who in AREDS are mostly African Americans. No association was noted between race and moderate cortical opacities. The finding that nonwhites were at decreased risk of mild cortical opacities was unexpected and perhaps spurious. Three population-based studies6,35,37
have reported an increased risk of cortical cataract in blacks. Compared with whites, participants of African descent in the Barbados Eye Study had a higher overall prevalence of lens opacities and cortical opacities. Black race was also associated with cortical opacities in the Lens Opacities Case-Control Study.7
Racial differences in cataract risk may be related to genetic factors or differences in exposures to cataract risk factors. The apparent greater risk of cataract in blacks, although not the major explanation, may contribute to the much higher rates of blindness caused by unoperated cataracts in blacks compared with whites.38
The association between educational achievement and cataract has been one of the most consistently reported observations in epidemiologic studies of cataract.6-9
In our study, as in other studies, the relationship persists even after adjustment for potential confounders, factors such as smoking, alcohol use, and diabetes, which have been associated with both educational status and cataract. These results suggest that there are unknown confounding factors associated with both educational level and lens opacity severity. Identification of these factors could lead to the development of interventions designed to reduce the risk of development of lens opacities.
There is a growing consensus that smoking increases the risk of nuclear cataract; no association has been reported for cortical cataract.7,9-12
In AREDS the ORs for nuclear cataract associated with current smoking were 1.96 and 1.44 for moderate and mild nuclear opacities, respectively. No association was noted for cortical cataracts. Associations between cigarette smoking and nuclear cataract have been reported in case-control,7
and prospective studies of lens opacities,12,41
as well as in studies of incident cataracts42
and extracted cataracts.43
The consistency of this finding across studies and in diverse populations, combined with reports of a dose-response relationship,10,41
suggests that smoking is one of the relatively few known modifiable factors associated with cataract. Suggested mechanisms by which smoking might damage the lens include an increase in oxidative stress caused by a lowering of circulating nutrients with antioxidant capabilities42,43
or lens damage from by-products of smoke, such as cadmium44
Ecologic studies have reported a higher prevalence of cataract in areas of greater sunlight and/or UV light exposure.6,9,18
Data from the first Health and Nutrition Examination Survey showed a higher prevalence of cataract, in particular cortical cataract, in areas with higher UV light exposure.6
Subsequent studies that have attempted to quantify individual cumulative lifetime exposure to UV-B radiation have provided evidence in support of the UV light/cataract hypothesis.16,17,19
In a study of Chesapeake watermen that estimated individual annual exposure to UV-B radiation after age 15, men in the upper 25% of exposure had a more than threefold increase in risk of cortical cataract compared with men in the lowest 25%.16
In AREDS, where we used an instrument similar to that in the Chesapeake watermen study to quantify individual exposure, we found a higher risk of cortical cataract in persons with higher lifetime average annual ocular UV-B exposure, although the finding for moderate cortical opacities was at a borderline level of significance. Differences in significance levels for mild and moderate cortical opacities may have resulted from the smaller number of participants with moderate opacities and the resultant decrease in statistical power. Although the totality of evidence from epidemio-logic studies suggests that cortical cataract is associated with UV light exposure, the relative contribution of such exposure to overall risk of visually significant cataract in the general population remains unclear.
We examined the relationship between cataract and those medications that were being used by at least 5% of the participants at baseline. Risk of cataract was assessed for 5 or more years of use compared with less or no use of the medication. Use of nonsteroidal antiinflammatory drugs (e.g., aspirin, ibuprofen, naproxen, piroxicam) was associated with a decreased risk of nuclear cataract. No associations were noted when aspirin use was examined separately. Our data do not permit us to examine whether the findings for the antiinflammatory drugs reflect a possible protective effect of the drugs or of the underlying conditions being treated with the drugs. We found no association between cataract and self-reported arthritis, a condition that is commonly treated with nonsteroidal analgesics. However, the finding for arthritis could be biased by unreliable self-reporting of the diagnosis of arthritis. A protective effect for aspirin-like analgesics was previously reported in a case-control study that included persons scheduled for cataract surgery as cases.46
However, in a large prospective study of women, there was no evidence of a beneficial effect of nonsteroidal analgesics on rates of cataract extraction.21
A possible protective effect for aspirin itself has been suggested by Cotlier.47
Data from The Physicians' Health Study, a randomized trial of aspirin and β-carotene among U.S. male physicians, tended to exclude a large benefit from 5 years of low-dose aspirin therapy on cataract development and extraction, but data from that study were compatible with a modest benefit on cataract extraction with this duration of aspirin treatment.48
Most other studies have noted no beneficial effect of aspirin on cataract.7,9,33,49-51
Users of thyroid hormones seemed to be at greater risk of cortical cataract in AREDS. We could not determine whether this finding is explained by an association with the underlying diseases being treated or the drugs themselves. Further substantiation is needed before concluding that use of thyroid hormones increases the risk of cataract.
Persons who had gained 53 or more pounds compared with those who had gained 10 or fewer pounds since age 20 were at increased risk of moderate cortical cataract. Higher body mass index (BMI: mass index = weight in kilograms divided by the square of height in meters) was associated with moderate cortical cataract in the AREDS age-gender adjusted analyses but not in the fully adjusted model. Epidemiologic studies that have examined the relationship between weight-related variables such as BMI and risk of specific cataract types have not produced consistent results.7,21-23,52-54
Prospectively collected data from the Framingham Heart and Eye Studies reported an increased risk of cortical cataract with higher average BMI and increasing BMI over time, but no association with fluctuations in BMI.23
The Salisbury Eye Evaluation Project also found that the risk of cortical opacification was greater in persons with higher BMIs.54
Studies of nuclear opacities have produced mixed results, with some7,54
reporting a decreased risk of nuclear opacification with higher BMI levels and another22
reporting an increased risk of nuclear cataracts and cataract extraction with higher BMI levels. No association between BMI and risk of cataract surgery was noted in the Beaver Dam Eye Study.53
The inconsistency of findings across studies makes it difficult to evaluate the relationship between weight-related characteristics and risk of cataract.
We found that darker iris color was associated with cortical cataract and mild nuclear cataract. Other studies have noted associations between darker iris color and nuclear cataract,20,33
but a biologic explanation for this finding has not been identified.
In what was probably a spurious finding, myopia was inversely associated with mild nuclear cataract. The finding of a direct association between myopia and moderate nuclear cataract, although at a borderline level of significance, was more expected. The myopic shift that is often seen clinically as nuclear cataract develops is the likely explanation for the latter finding.
In AREDS, statistically significant associations were found for cortical cataract and more advanced forms of drusen (large drusen or extensive intermediate size drusen). This finding must be interpreted cautiously because of the possibility of selection bias. For entry into AREDS, patients with no or minimal maculopathy (no drusen, small drusen, or intermediate drusen) were required to have media that were sufficiently clear to discern potential small (<63μm in diameter), punctate, or hard drusen on photographs. For patients with more advanced macular changes, such as large drusen or advanced AMD, the media had to be only sufficiently clear to discern these more advanced lesions on photographs. Thus, the eligibility criteria could have led to the selective enrollment of patients with both more severe lens opacities and more advanced AMD. It should be noted, however, that an association was noted only for cortical cataract and intermediate or large drusen but not for the most advanced forms of AMD— geographic atrophy and neovascular AMD. Results from other studies have not been consistent, and comparisons across studies are complicated by differing definitions of macular degeneration and cataract. Cross-sectional data from the Beaver Dam study found an association between "early age-related maculopathy" and nuclear cataract, but prospective data from that study reported no relationship between nuclear opacities and either "early" or "late" AMD.55
In a study of Chesapeake Bay watermen, there was significantly greater risk of AMD in the presence of nuclear opacities,56
and in the National Health and Nutrition Examination Survey there was an increased frequency of AMD in the presence of nuclear or cortical opacities.57
However, the Blue Mountains Eye Study reported no associations between cataract types and age-related maculopathy.58
On the basis of the data accumulated to date, it is not clear whether eyes with AMD are at greater risk of cataract.
Some risk factors that have previously been reported were not significantly associated with cataract in our fully adjusted model.
Diabetes has been one of the more consistently reported risk factors for cataract, particularly among persons less than age 70.7,9,13
Most studies have reported an excess risk of cortical7
and PSC cataracts6,7,14
in persons with diabetes. We found no association between diabetes and cortical cataract and were unable to study the relationship with PSC cataracts, because too few participants in AREDS had this form of cataract. Like the Lens Opacities Case-Control Study, we observed an inverse association between diabetes and nuclear cataract.7
It is possible that our ability to examine the relationship between diabetes and cataract may have been hampered by the eligibility criteria of AREDS, which called for the exclusion of persons with diabetes with more than minimal diabetic retinopathy. To the extent that increasing diabetic retinopathy is positively associated with cataract risk, those persons at the highest risk for cataract may have been systematically excluded, biasing the findings. Also, the older age of the cohort (median age, 69 years) may have restricted our evaluation of diabetes as a risk factor, because, when found, the diabetes/cataract association has been generally noted in persons less than age 70.13
The increased prevalence of cataract in postmenopausal women compared with men has suggested a possible relationship between estrogen and the development of cataract. In our study, women who were current users of estrogen replacement therapy and who had more than 5 lifetime years of regular use of such medication were significantly less likely to have nuclear and cortical opacities in the age-gender adjusted model but not in the fully adjusted model. In additional analyses (not shown), when we changed the definition of estrogen use to "ever" versus "never" use, the ORs were little changed in the full model, but the finding was then significantly protective for both moderate and mild nuclear cataract (OR = 0.71 and 0.82, respectively). Three earlier studies have noted an association between postmenopausal estrogen use and lens opacities. Two of the studies have suggested a protective effect for nuclear sclerosis.24,26
The third reported reduced risk of cortical opacities among estrogen users older than age 65 years.25
The cumulative evidence from the several studies that have examined the effect of estrogen use raises the possibility that reduction in the risk of cataract may be an additional benefit of post-menopausal estrogen use.
Many of the findings in AREDS reinforce results from earlier studies. Similarity of findings for gender, educational status, sunlight exposure, and smoking across studies with different selection criteria, definitions of cataract, methods of ascertaining risk factor data, and analytic approaches makes it more likely that reported associations are real.