We have attempted to identify possible risk factors for the presence of moderate- to large-sized drusen and pigment abnormalities, both of which are prominent features of patients with AMD,28
and two advanced forms of AMD, geographic atrophy and neovascular AMD. Drusen, in particular soft, indistinct drusen, and pigment abnormalities are considered to be high risk characteristics for the development of geographic atrophy or neovascular AMD and are often viewed as manifestations of "early" AMD.29,30
If the presence of intermediate- and large-size drusen and pigment abnormalities do represent early manifestations of AMD, one may expect many similarities in risk factor profiles for the four case groups studied here. Longitudinally collected data from AREDS will eventually provide information on how the presence, size, and extent of drusen and pigment abnormalities relate to the development of late-stage AMD and which risk factors influence the development of such macular changes.
Our finding that smoking, a modifiable exposure, was associated with the three more severe AMD groups is consistent with findings from many earlier observational studies.6-13
The mechanism of action by which smoking could affect the retina, RPE, or choroid is not known. However, the finding is consistent with the hypothesis that AMD is the result of cumulative oxidative insults to the outer retina. Smoking is known to lower levels of circulating antioxidants. Stryker et al31
reported that men who smoked one pack of cigarettes per day had only 72% of the plasma β-carotene levels of nonsmokers, even after adjusting for dietary differences between smokers and nonsmokers. This finding is consistent with the observation that smoking was associated with a decrease in luteal pigments in the human retina.32
The decreased availability of compounds with antioxidant capabilities could decrease retinal defenses against oxidative damage. The smoking finding is also consistent with an hypothesis of an underlying vascular basis for AMD,14
because smoking could damage choroidal vessels or choroidal blood flow by promoting atherosclerotic and hypoxic changes in the choroidal vessels or directly causing vasoconstriction.
The AREDS participants with large drusen or neovascular AMD were statistically significantly more likely to have systemic hypertension, defined as elevated blood pressure levels or current treatment with antihypertensive medications. This finding is consistent with an underlying vascular basis for AMD. Some,15-17
but not all,9,33-35
earlier studies of AMD have reported similar associations. As emphasized in one study16
that found an increasingly strong relationship with longer duration of hypertension, it may be important to take duration of hypertension into account when examining the relationship.
In AREDS, hyperopic refractive error was associated with both more extensive drusen and neovascular AMD. In the Eye Disease Case-Control Study,7
hyperopia that was similarly defined and adjusted for in multivariate analysis was also associated with an increased risk of neovascular macular degeneration (OR = 1.5). This association has been found in some,22,36
but not all, population-based cohorts.37,38
The underlying reason for an association of hyperopia with AMD, if it exists, is not known.
In the AREDS population, higher BMI, a measure of obesity, was associated with neovascular AMD. This is consistent with findings from the Oulu study where the investigators speculated that if not a chance finding, it may be the result of excessive caloric intake increasing the risk of ARM because of an increased risk of oxidative damage.35
Greater BMI was associated with the prevalence of early ARM but not neovascular AMD in the Beaver Dam Study.34
However, in this study there was no association between either BMI or being overweight at baseline with the 5-year incidence of early ARM or neovascular AMD.36
Most other studies have either not looked for or have not found a cross-sectional association of BMI and AMD.
The AREDS finding of an increased frequency of choroidal neovascularization in white persons compared with nonwhite persons is consistent with findings from other clinical and epidemiologic studies.39-42
Also, the finding in AREDS of a higher frequency of one or more large drusen (>125 μm) or extensive intermediate drusen in white persons than in nonwhite persons was previously noted in the Baltimore Eye Study where, after adjusting for age, large drusen (>125 μm) in persons more than 70 years of age were more common in white persons (15.2%) than in non-white persons (9.0%).40
Several studies, including AREDS, the Baltimore Eye Study, and the National Health and Nutrition Study III,39
have found little difference between white persons and nonwhite persons in the frequency of smaller-size drusen. It is unclear why smaller drusen may be equally prevalent in white persons and nonwhite persons, and large drusen, geographic atrophy, and choroidal neovascularization are more common in white persons. There could be an ascertainment bias favoring the identification of smaller drusen in nonwhite persons if smaller drusen are easier to identify against a dark background. This bias may not be present for large drusen because they may be easier to identify regardless of the background pigmentation. It may also be that small drusen are independently associated with age, whereas large drusen and focal hyperpigmentation are the risk factors for the development of geographic atrophy and choroidal neovascularization.43,44
Perhaps increased melanin in RPE cells, acting as a free radical scavenger or simply as a filter for ultraviolet radiation, protects the RPE cells and Bruch′s membrane, reducing the risk of developing large drusen and pigmentary changes and therefore reducing the risk of geographic atrophy, choroidal neovascularization, or both.
Statistically significant associations were found between any lens opacity and the presence of large drusen or the presence of neovascular disease. However, this study represents a limited spectrum of lens opacities because persons with aphakia were excluded from these analyses and persons with moderate media opacities were excluded from the study if the media were not clear enough for AMD assessment. An association between lens opacity and AMD has been inconsistently reported by others. Although a strong cross-sectional association was found between early age-related maculopathy (ARM) and nuclear opacity in the Beaver Dam Eye Study (OR, 1.96; 95% confidence interval, 1.28-3.01), nuclear opacity was not associated with the presence of late ARM at baseline or the 5-year incidence of early or late ARM or progression of ARM in that study.45
In Chesapeake Bay watermen, after controlling for age and other factors, there were significantly higher odds of AMD in the presence of nuclear opacity (OR, 2.50; 95% confidence interval, 1.31-4.80) but not of cortical opacity.46
In the National Health and Nutrition Survey I, there was an increased frequency of AMD in the presence of nuclear or cortical opacity.47
However, no associations were found between cataract type and ARM in the Blue Mountains Eye Study,48
and in the Framingham Eye Study49
there was a decreased frequency of age-related macular changes in the presence of nuclear sclerosis and increased frequency in the presence of cortical lens changes
Education was inversely related to the presence of one or more large drusen or extensive intermediate drusen, geographic atrophy, and choroidal neovascularization in AREDS. This is consistent with the finding in the Eye Disease Case-Control Study where, after adjusting for other risk factors, those who completed 12 years of school or more were 30% less likely to have neovascular age-related macular degeneration compared with those who completed less than 12 years of school (OR, 0.7; 95% confidence interval, 0.5-1.1). A similar inverse relationship of education was found in the National Health and Nutrition Examination Survey I. However, no relationship was found in the case-control study of Hyman et al,9
the Framingham Eye Study,15
the Beaver Dam Eye Study,2
and National Health and Nutrition Examination Survey III,39
all studies with few cases of neovascular AMD. The reasons for the differences among studies are not known. It is possible that selection bias in AREDS resulting from the higher participation of more educated persons in the control group and intermediate drusen group contributed to this finding. It is also possible that participation bias and low frequency of advanced disease prevented recognition of this relationship in other studies.
Chance, bias, and unadjusted confounding must be considered when interpreting our findings. We have studied a large number of possible risk factors and conducted multiple tests of significance. Therefore, some of our "significant" findings may be the result of chance alone. This possibility is of particular concern for associations that are seen in only one case group, that are relatively modest in strength, or that have not been reported previously, such as those for arthritis and angina and for antacid, thyroid hormone, or hydrochlorothiazide usage. Chance may be a less likely explanation for the findings on education, refractive error, gender, BMI, and smoking because they had been suggested as possible risk factors by earlier studies, although the possibility of consistent bias across studies cannot be ruled out. In any case, education itself is unlikely to be a direct risk factor, but rather a surrogate for other factors.
Conversely, some of our "nonsignificant" findings may be true associations that were missed because of low power. For example, association with sunlight exposure is in the direction of being a risk factor but is not statistically significant, especially when included in models with other important covariates. The AREDS assessment of sun exposure by use of a questionnaire dependent on participant recall is imprecise, and we can not rule out a true association.
Selection bias is a special concern in clinic-based, case-control studies, and ours is no exception. The control group (group 1) and persons with intermediate size drusen or extensive small drusen (group 2) were substantially more likely to have been volunteers from nonmedical sources. It has been shown that volunteers for prevention studies have more formal education, are more health conscious, and are more often employed in professional and skilled positions,50,51
and that smoking is inversely associated with educational achievement.52
Indeed, persons with no drusen to intermediate drusen at time of enrollment had greater educational achievement and smoked less than persons with large drusen, geographic atrophy, or choroidal neovascularization. However, the fact that the overall risk factor profile for participants with intermediate drusen, who were drawn from similar sources as the control group, is more like that of the more advanced AMD groups () lessens concern about selection bias as an explanation for the AMD findings.
We attempted to minimize the possibility of unadjusted confounding by including in the study nearly all variables that had been previously suggested as possible risk factors and by using multivariate analytic techniques. However, confounding by factors not included in these analyses may exist. For example, it is possible that nutritional factors may modify the association found between AMD and factors such as smoking or education.
In summary, we have noted associations between AMD and multiple risk factors, several of which are modifiable factors. Avoidance of smoking and control of hypertension have benefits beyond potentially reducing the risk of AMD. Perhaps for some patients, prevention of vision impairment can be used as a motivating factor to help them modify these risk factors. Incident cases of geographic atrophy and choroidal neovascularization are developing throughout the AREDS follow-up period. Analyses using these incident cases will provide additional information to investigate which risk factors are associated with the development of AMD.