In this study, we employed two-sample MR to explore the potential causal relationship between plasma FA concentrations and AMD risk. The results indicate that a higher omega-6 to omega-3 ratio was associated with an increased AMD risk. Conversely, higher plasma concentrations of omega-3 fatty acids were associated with a lower risk for both AMD types. However, the protective effects of omega-3 were somewhat attenuated for dry AMD after adjusting for other lipids (e.g., HDL, LDL, and triglycerides) using Multivariable Mendelian randomization. Subsequent FADS locus-specific MR analyses suggested that these relationships are likely driven by genetic variants within the FADS gene cluster, which plays a role in PUFA desaturation.
Omega-3, derived from alpha-linolenic acid, includes essential fatty acids like DHA, which humans cannot synthesize de novo. (23) These acids perform essential structural and protective functions in the retina. (6, 24) For example, DHA, highly concentrated in photoreceptors' outer segment membranes, is crucial for cell survival and maintaining retinal homeostasis.(25, 26) Additionally, DHA derivatives, such as neuroprotectins, have anti-inflammatory and anti-angiogenic properties(27–29), crucial in AMD where local antioxidant capacity is vital in the macular area.(30)
Previous research, encompassing cross-sectional, cohort studies, and meta-analyses, suggests that high omega-3 intake may reduce the risk of AMD.(6) However, systematic reviews by Cochrane, including RCTs, concluded that increasing dietary omega-3 levels does not progression significantly prevent AMD.(31, 32) Subsequent RCTs, such as the AREDS2 and NAT2 studies, investigating long-chain omega-3 oral supplementation, have produced conflicting results, influenced by factors like baseline nutritional parameters, supplementation formula, and bioavailability. (14, 33) Interestingly, wet AMD progression was prevented in NAT2 participants who maintained elevated plasma and cellular DHA levels.(34, 35) Similarly, the current MR study provides evidence that higher circulating plasma concentrations of omega-3, particularly DHA, may lower the risk of wet AMD.
Several factors must be considered to explain the inconsistencies among these findings. First, the MR study’s evidence regarding the effects of DHA or omega-3 fatty acids on AMD should be interpreted in the context of long-term or lifetime exposure.(19) For example, FADS genotypes affect children’s DHA supply during pregnancy via maternal RBC phospholipids.(36) In contrast, the impact of short-term PUFA oral supplementation in RCTs or dietary intake studies (typically 3–5 years) may not provide sufficient protective effects against AMD. This outcome may also partly depend on the overall diet composition or individual dietary habits of the participants. Second, dietary intake data of PUFA composition does not fully reflect the plasma concentrations or the lipid concentrations in photoreceptors' outer segments.(6) Other mechanisms, such as phospholipase A2 activity, oxidative stress, and local trafficking, might contribute to the contradictory data, beyond mere synthesis or intake.(27, 37–39) Third, the omega-3 supplementation formula and administration time are essential for the treatment outcome.(40, 41) Future studies, designed with a focus on causal inference, are required to optimize specific FA concentrations/formulas at different illness stages and their effects in response to treatment. The current MR results at least provide valuable insights into which supplements might be effective against AMD.
Compared with omega-3, a relatively high proportion of dietary omega-6 consumption has detrimental effects on AMD, which is supported by heterogeneous and inconsistent evidence. A few epidemiological studies have indicated that a high intake of omega-6 is significantly associated with the risk of AMD. (6, 42, 43) In contrast, an elevated plasma omega-6 to omega-3 ratio, leading to an imbalance in circulating oxidation products, was correlated with AMD risk in a Chinese cohort.(27) These contradictory results might arise because the ratio calculated from dietary intake data cannot be directly equated with values determined from plasma. Our MR analysis suggests that the omega-6 to omega-3 ratio may have a positive causal effect on wet AMD. Notably, our findings align with the NAT2 RCT cohort study, which found a higher omega-6 to omega-3 ratio in patients with AMD.(34) This supports the hypothesis that a disproportionate dietary omega-6 to omega-3 ratio (such as the 20:1–30:1 ratio common in Western diets) may contribute to AMD pathology, particularly by accelerating inflammation and oxidative stress.
In addition to individual dietary preferences for FA intake, genetic factors have been associated with the composition of circulating fatty acids, especially in plasma.(44) Genome-wide association studies have shown that variations in the FADS haplotype, which encodes the Δ-5 and Δ-6 desaturases, are linked to PUFA blood concentrations and disrupted long-chain PUFA synthesis in conditions such as cardiovascular diseases, schizophrenia, and major depressive disorder.(18, 19, 45) FADS enzymes are directly linked to both omega-3 and omega-6 long-chain PUFA metabolism and play a central role in the ratio-limiting steps of their respective pro-inflammatory and anti-inflammatory precursor lipid metabolites. (46, 47) Our MR analysis also suggests possible causal effects of omega-3, DHA, and the omega-6 to omega-3 ratio on wet AMD via the FADS gene cluster. Consequently, it is speculated that in regions with limited omega-3 availability or scarce access to seafood, FADS genetic variants may exacerbate the omega-6 to omega-3 ratio imbalance typical of modern Western diet preferences, which ultimately leads to the progressive onset of wet AMD.
Studies have also investigated the effect of these FA on dry AMD endpoints. Although previous animal or clinical RCT studies have supported this,(48, 49) the causality between omega-3 and dry AMD was attenuated after multivariant MR correction. This is partly because some FA instruments share loci also linked to lipoproteins, suggesting that we cannot propose a direct effect of omega-3 and the omega-6 to omega-3 ratio independent of HDL, LDL, and triglycerides on dry AMD.
Our study has several strengths. First, it employs the largest available GWAS samples for identifying FA instruments and evaluating causation, thereby minimizing bias from small sample sizes and traditional observational study methodologies. Second, the consistent effect power observed across heterogeneity, horizontal pleiotropy, and multivariate MR analyses reinforces the impact of omega-3 and DHA on wet AMD. Last, distinct MR approaches were utilized to validate the effects more robustly, reducing the potential influence of horizontal pleiotropy.
However, our data must be interpreted within the context of some limitations. One notable limitation is the focus on individuals of European ancestry. It is important to acknowledge that the frequencies of FADS risk alleles differs across geographic regions.(50, 51) In fact, divergent FADS haplotypes are more commonly observed in populations of non-European descent, such as African Americans.(44, 52) Consequently, the mechanistic effects proposed in our study might be more pronounced in these non-European ancestral groups. Second, our study does not provide specific insights into the optimal dosage or formula ratio of polyunsaturated fatty acids, nor does it address the ideal timing for their supplementation. Therefore, future studies should investigate the omega-6 to omega-3 ratio range associated with wet AMD risk. Thirdly, a comprehensive MR analysis would ideally include a broader range of FA. In this study, typical and significant FA metabolites were quantified. However, the quantification of other metabolites, such as arachidonic acid, was not feasible due to the limited number of available SNPs after instrument screening.
In conclusion, our MR findings support the protective role of circulating DHA and omega-3 against the risk of wet AMD. Furthermore, this study suggests a role for an increased omega-6 to omega-3 ratio in the pathophysiology of AMD. However, the causal relationship was attenuated in dry AMD samples after multivariable MR, conditioned on other lipids.