This report extends the findings of AREDS report No. 1917
to include ω-3 LCPUFA and ω-3 LCPUFA–rich food-based factors. To our knowledge, this work is the first to report separate outcomes on progression to NV AMD and CGA as they may relate to ω-3 LCPUFA intake. Associations of nutrients and AMD attained statistical significance for CGA only. The ω-3 LCPUFAs and their metabolites show cytoprotective effects under conditions of oxidant stress in primary cell cultures of rat photoreceptors25,26
and human retinal pigment epithelial cells27
through their effect on the expression of apoptotic regulatory proteins. Studies of ω-3 LCPUFA feeding in young rodents resulted in a decreased volume of abnormal neovascular retinal28
growth in response to angiogenic stimuli via modulation of inflammatory factors and processes. Our null results on NV AMD are unexpected in the context of emerging evidence, and we believe it is best to obtain confirmation from independent samples before applying strong inference. AREDS2 (http://www.areds2.org
) is a 4000-person randomized clinical trial designed to examine the efficacy of ω-3 LCPUFA supplementation on prevention of progression to CGA and NV AMD and should offer information on issues discussed in this report.
We acknowledge a number of cautions concerning the validity of inference in our study. These include differential and random misclassification of nutrient intake based on disease status and psychometric factors (FFQ measurement and interpretation issues). A healthy diet usually reflects a healthy lifestyle; this is a factor that may confound our inferences. We did not have measures of physical activity to aid in the assessment of this possibility. These concerns for validity are to be considered with the pertinent strengths of the AREDS research design. Strengths include the standardized methods of exposure and outcome ascertainment, an extensive set of directly measured health-related variables, annual ophthalmic examinations with fundus photographs applied for outcome classification, and low participant attrition rates. Because dietary intake data were obtained before the development of NV AMD or CGA, it is unlikely that AMD status systematically biased reporting. If misclassification (in this case, inaccuracy) of nutrient intake existed, it was most probably random in nature, thus affecting all participants and attenuating measures of association. Because relationships of CGA with EPA, DHA, or EPA+DHA were always strongest in comparison of extreme exposure categories (quintile 1 vs quintile 5 or quintile 4), the strength of associations was not changed appreciably after adjustment for age, sex, smoking, and other covariates. We acknowledge that unmeasured factors may have operated differentially within the participants who experienced progression to CGA, and we are unable to conclusively refute the idea that a factor or a process strongly associated with ω-3 LCPUFA intake may have confounded our inferences. To have an appreciable effect on our results, the actions of this factor or process would need to vary with both ω-3 LCPUFA intake and AMD. The ORs suggest a potential relationship between tuna intake and NV AMD, but the lack of a strong finding for relationships of EPA and DHA with NV AMD may indicate that fish intake is a proxy for a healthy lifestyle. Although concentrations of DHA and EPA vary with the type and habitat of fish, the structure of AREDS FFQ items did not provide information on these factors.
Emerging evidence suggests that ω-3 LCPUFA intake may reduce the likelihood of progression to CGA or NV AMD. Seddon et al14
applied a prospective design to report a 60% reduced risk of progression to advanced AMD (defined as NV AMD or GA) among people who reported the highest fish consumption (≥2 times vs <1 time per week) and low linoleic acid intake (relative risk, 0.36; 95% CI, 0.14-0.95). We did not observe any effect modification of linoleic acid on ω-3 LCPUFA levels for either outcome. A 5-year prospective sample from the Blue Mountains Eye Study8
(with the end point defined as NV AMD or GA) yielded ORs of 0.18 (95% CI, 0.02-1.38) for comparison of the highest quintile vs quintiles 2, 3, and 4 and 0.25 (95% CI, 0.06-1.00) for the highest quintile vs the lowest quintile of fish consumption. Neither work reported separate findings for NV AMD or GA.
Results from participants who reported caloric intake values between the 5th and 95th percentiles from the CSFII are found in eTable 2
); these AREDS participants were most likely to report dietary intake accurately. In this cohort, association of CGA with the highest level of DHA intake emerged (OR, 0.45; 95% CI, 0.21-0.95), and the reduced likelihood of progression to CGA remained at 60% (OR, 0.41; 95% CI, 0.20-0.85) for EPA and EPA+DHA.