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. 2025 May;132(5):598-609.
doi: 10.1016/j.ophtha.2024.12.005. Epub 2024 Dec 9.

Omega-3 Fatty Acids as Protective Factors for Age-Related Macular Degeneration: Prospective Cohort and Mendelian Randomization Analyses

Can Can Xue  1 , Hengtong Li  2 , Marco Yu  1 , Crystal Chun Yuen Chong  1 , Qiao Fan  3 , Yih-Chung Tham  4 , Chui Ming Gemmy Cheung  5 , Tien Yin Wong  6 , Emily Y Chew  7 , Ching-Yu Cheng  8
Affiliations

Omega-3 Fatty Acids as Protective Factors for Age-Related Macular Degeneration: Prospective Cohort and Mendelian Randomization Analyses

Can Can Xue et al. Ophthalmology. 2025 May.

Abstract

Purpose: Epidemiologic studies and clinical trials have reported inconsistent findings regarding omega-3 fatty acids' protective role in age-related macular degeneration (AMD). We investigated their association in a prospective cohort and examined causality using Mendelian randomization (MR) analyses.

Design: Prospective cohort study and 2-sample MR analyses.

Participants: The cohort included 258 350 AMD-free individuals of European descent from the UK Biobank. Mendelian randomization analyses used genome-wide association study data on plasma omega-3 and docosahexaenoic acid (DHA) (UK Biobank, n = 115 006) and AMD (dry, wet, and any; FinnGen, n = 208 690-209 122).

Methods: Cox regression assessed the association between plasma omega-3 and DHA levels and AMD incidence, adjusting for systemic covariates and AMD polygenetic risk score (PRS). Interaction effects of AMD genetic risk (PRS, complement factor H and age-related maculopathy susceptibility 2 genotypes), and plasma omega-3 and DHA levels were tested. For MR analyses, we used random-effect inverse-variance weighted model as primary, with 5 sensitivity models. Causality was considered significant if P < 0.05 in the primary model and at least 2 sensitivity models.

Main outcome measures: Risk of AMD.

Results: Over 12.9 years, 5068 people (1.9%) demonstrated AMD. Higher plasma levels (in millimoles per liter) of omega-3 (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72-0.95; P = 0.006) and DHA (HR, 0.65; 95% CI, 0.44-0.96; P = 0.029) were associated with lower risk of receiving an AMD diagnosis. Mendelian randomization showed genetic predisposition to higher plasma omega-3 levels reduced the risk of dry AMD (odds ratio [OR], 0.83; 95% CI, 0.73-0.96; P = 0.010), wet AMD (OR, 0.76; 95% CI, 0.65-0.88; P < 0.001), and any AMD (OR, 0.82; 95% CI, 0.74-0.92; P < 0.001). Similar results were found for plasma DHA levels (wet AMD:OR, 0.79; 95% CI, 0.65-0.96; P = 0.017; any AMD: OR, 0.84; 95% CI, 0.72-0.98; P = 0.030). No significant interaction was found between omega-3 and DHA levels and AMD genetic risk (all P > 0.05).

Conclusions: Both the prospective and MR analyses suggest omega-3 and DHA may protect against AMD, supporting the need for further clinical trials to test their effectiveness in AMD prevention and treatment.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Age-related macular degeneration; Docosahexaenoic acid; Mendelian randomization; Omega-3; UK Biobank.

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Conflict of interest statement

Chui Ming Gemmy Cheung receives grants from Bayer, Novartis, Roche, Boehringer Ingelheim, Zeiss, and Topcon; consultancy fees from Janssen, Roche, and Boehringer Ingelheim; and payment for lectures from Bayer, Novartis, Roche, Boehringer Ingelheim, Topcon, and Zeiss. She receives support for attending meetings from Roche and Bayer. She also participates on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim. For all the above-mentioned activities, payments were made to her institution. She also owns stocks in Avirmax. Tien Yin Wong is a consultant for Abbvie Pte Ltd, Aldropika Therapeutics, Bayer, Boehringer Ingelheim, Carl Zeiss, Genentech, Iveric Bio, Novartis, Opthea Limited, Plano, Quaerite Biopharm Research Ltd, Roche, Sanofi, and Shanghai Henlius. He is also a co-founder of the start-up companies EyRiS and Visre. Emily Y. Chew participates on a Data Safety Monitoring Board or Advisory Board for NBM Bio DSMC, Genentech, and 4DMT, but no funds are involved in these activities. All other authors declare no competing interests.

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