In this large prospective cohort study of female health professionals, regular consumption of DHA and EPA and fish was associated with a 35%–45% lower risk of visually-significant AMD during 10 years of follow-up. This inverse association was independent of other AMD risk factors, and was not materially altered after adjustment for saturated, monounsaturated, and trans unsaturated fat intake. The study population was comprised of women without a prior diagnosis of AMD, and the large majority of cases documented during follow-up were characterized by some combination of drusen and RPE changes signifying an early stage of disease development. Thus, these findings suggest that dietary intake of DHA and EPA and fish may be beneficial in the primary prevention of AMD.
Previous observational studies (44
), including 5 prospective studies (48
), are suggestive of an inverse association between fish and ω-3 long chain fatty acid intake and risks of advanced AMD (ie. neovascular AMD or central geographic atrophy). For example, recent prospective data from AREDS indicated that those with the highest consumption of DHA and EPA, compared to the lowest, had an approximate 30% lower risk of progression to advanced AMD that was apparent even after 12 years of follow-up (56
). However, the data for early AMD are more limited and inconsistent. Of 5 cross-sectional studies that included cases of early AMD, 3 reported an inverse relation with advanced AMD only (45
), and 2 reported no association with either early or advanced AMD (44
). Interestingly, recent cross-sectional data from the Carotenoids in Age-Related Eye Disease Study indicated an increased risk of intermediate AMD for those with high intake of DHA and EPA (58
). Data from three previous prospective studies provide only modest support for an inverse link between early AMD and fish and ω-3 long chain fatty acid intake. A report based on 567 cases of visually-significant (20/30 or worse) AMD identified during 10 to 12 years of follow-up of 42,000 women in the Nurses Health Study (NHS) and 30,000 men in the Health Professionals Follow-up Study (HPFS), aged 50 years and older, found that higher intake of DHA was associated with a 30% lower risk of AMD (multivariable RR [high vs. low quintile]; 0.70, CI, 0.52–0.93) (59
). However, the RR was attenuated and no longer significant after further adjustment for other fats. A similar non significant inverse relation was observed for EPA in that study, while intake of ALA was directly related to risks of AMD in a fully adjusted model (RR, 1.41; CI, 1.00–1.98). That study also found that men and women who reported eating fish 4 or more times per week, compared to those who ate fish less than 4 times a month, had a 35% lower risk of AMD (RR, 0.65; CI, 0.46–0.91). This lower risk appeared to be due largely to intake of canned tuna fish (RR, 0.61; CI, 0.45–0.83); no association was observed for intake of dark- or white-meat fish in that study (59
). In the Blue Mountains Eye Study, a repeat eye exam at 5 years for 2,335 men and women aged 49 years and older documented 130 new cases of early AMD and 22 cases of late AMD (49
). Participants in the highest quintile of intake for ω-3 long chain fatty acids (DHA, DPA, EPA), compared to the lowest quintile, had a significantly lower risk of early AMD (OR, 0.41; CI, 0.22–0.75). Consumption of fish was also associated with significantly lower risks of early AMD (and late AMD) at the 5 year follow-up (49
). However, at 10 years, the inverse relation between early AMD and intake of ω-3 long chain fatty acids (DHA, DPA, EPA) and fish was attenuated and no longer significant (55
). In a third study, conducted among 846 men and women in Reykjavik, Iceland, aged 50 years and older, a repeat eye exam at 5 years of follow-up documented 126 new cases of early AMD. Those who reported eating herring 2 times per week or more, versus less than once a month, had a 39% lower risk of early AMD (RR, 0.61, CI, 0.37–1.00) (60
). Our data, based on 10 years of follow-up of a large cohort of female health professionals, are broadly consistent with these earlier findings, and appear to be the strongest observational evidence to date in support of a possible role for intake of ω-3 long chain fatty acids and fish in the primary prevention of AMD. Moreover, because early AMD is associated with an increased risk of developing advanced AMD (eg. one study showed that eyes with soft indistinct drusen or RPE abnormalities were approximately 20 to 40 times more likely to develop late AMD than were eyes without these lesions ), our data further suggest that dietary intake of ω-3 long chain fatty acids and fish by persons at usual risk may ultimately reduce the number of persons who suffer from advanced AMD.
There is strong biologic plausibility for an association of DHA and EPA intake with AMD, and multiple mechanisms have been described (61
). DHA and EPA could affect AMD occurrence by modulating inflammatory and immune processes thought to play a role in AMD pathogenesis (62
). ω-3 and ω-6 fatty acids compete both for enzymes that convert essential fatty acids ALA and LA to longer chain DHA, EPA, and AA (64
), and for enzymes that initiate conversion of these long-chain fatty acids to eicosanoids, locally-acting lipids more immediately involved in the control of inflammatory and immune processes (65
). Higher intake of ω-3 fatty acids reduces production of AA-derived eicosanoids which are generally proinflammatory, and increases levels of EPA-derived eicosanoids which are 10–100 fold less active (68
). Our observation in the present study that the ratio of ω-6 to ω-3 fatty acids (DHA plus EPA) was strongly predictive of early AMD is consistent with similar findings for advanced AMD in prior studies (47
), and supports the conclusion that both the level of ω-3 fatty acids and its ratio to ω-6 fatty acids are important in determining risks of AMD (70
). We also observed that the inverse relation of DHA and EPA with AMD was more apparent in participants reporting higher levels of ω-6 fatty acid intake although tests of interaction were not significant. This finding appears consistent with subgroup findings for LA intake in the AREDS population (51
), but seems to conflict with two previous reports indicating a benefit primarily among participants with the lowest levels of LA intake (47
). The reasons for these somewhat different findings are unclear and require further investigation. Other mechanisms through which DHA and EPA may contribute to a reduced risk of AMD include enhanced production of resolvins and neuroprotectins, which are thought to dampen and resolve inflammatory responses (71
), and the modulation of expression of signal transduction genes and genes for proinflammatory cytokines (74
The study had several strengths and limitations that need to be considered. The prospective design of the study precluded the possibility of recall bias, and the high follow-up rate minimized the possibility of selection bias. The nutritional estimates were derived from a validated food frequency questionnaire which has been shown to reflect long-term dietary intake (77
). Moreover, because women with a previous history of coronary heart disease, cerebrovascular disease, cancer (except nonmelanoma skin cancer), or other major chronic illnesses were excluded, misclassification due to recent changes in dietary intake prior to baseline was less likely in this population. Nonetheless, estimates of nutrient intake from dietary self-reports are prone to measurement error which would tend to underestimate any association of diet with risk of AMD. In addition, any changes in dietary intake during follow-up, which would likely be nondifferential with respect to the AMD endpoint, would also attenuate the true associations. We collected information on a range of known or potential risk factors for AMD at baseline and this enabled adjustment for these variables in the analyses. However, residual or unmeasured confounding remains a possibility in our analyses. It seems unlikely though that residual or unmeasured confounding had a major effect on these analyses since observed associations were not materially changed after adjustment for a range of measured confounders. With respect to the generalizability of our findings, participants are female health professionals, thus the findings may not be generalizable to other populations. It is also important to consider limitations of our methodology of disease ascertainment. Our study endpoint was based on participant self report, thus, some degree of underascertainment of AMD is plausible. Random misclassification of AMD, which would tend to shift the RR estimate toward the null, was reduced by the use of medical records to confirm the self reports, and by the use of strict diagnostic criteria that included reduction in best-corrected visual acuity to 20/30 or worse due to AMD. Surveillance bias was a possibility since women who reported higher intake of ω-3 fatty acids were more likely to report an eye exam in the past 2 years, and thus may have been more likely to have existing AMD diagnosed. However, the likely effect of such bias would be to underestimate any reduction in risk of AMD associated with ω-3 fatty acid intake. We controlled for possible surveillance bias by including a term for a baseline report of an eye exam in the past 2 years in multivariate analyses. Finally, it should be noted that this methodology has identified important risk factors for AMD such as cigarette smoking (14
), body weight (78
), and genetic variants (79
), associations also demonstrated in examined populations with fundus photographs, providing reassuring evidence for the construct validity of this methodology.
In summary, these prospective data from a large population of women with no prior diagnosis of AMD indicate that regular consumption of DHA and EPA and fish significantly reduced the risk of incident AMD. These data appear to be the strongest evidence to date to support a role for ω-3 long chain fatty acids in the primary prevention of AMD, and perhaps a reduction in the number of persons who ultimately suffer from advanced AMD, and need to be confirmed in randomized trials.