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

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.