Causal Effects of N-6 Polyunsaturated Fatty Acids on Age-related Macular Degeneration: A Mendelian Randomization...

Although the role of n-6 polyunsaturated fatty acids (PUFAs) in age-related macular degeneration (AMD) has been studied in previous observational studies, the precise manner in which 1 or more n-6 PUFAs account for this relationship remains unclear.

Using genetic instruments for n-6 PUFAs traits implemented through mendelian randomization (MR), we aimed to study possible causal associations between n-6 PUFAs and AMD.

The 2-sample MR method was used to obtain unconfounded causal estimates. We selected genetic variants strongly associated (P < 5 × 10-8) with circulating linoleic acid (LA) and arachidonic acid (AA) from a study involving 8 631 individuals and applied to an AMD case-control study (33 526 participants and 16 144 cases). The weighted median and MR Egger methods were used for the sensitivity analysis.

Our MR analysis suggested that circulating LA was a causal protective factor for AMD, with an odds ratio (OR) estimate of 0.967 (95% CI 0.945 to 0.990; P = .005) per percentage in total fatty acid increase in LA. In contrast, higher genetically predicted circulating AA causally increased the AMD risk (OR = 1.034; 95% CI 1.012 to 1.056; P = .002). Sensitivity analysis provided no indication of unknown pleiotropy. The findings from different single-nucleotide polymorphism selections and analytic methods were consistent, suggesting the robustness of the causal associations.

Our study provided genetic evidence that circulating LA accounted for protective effects of n-6 PUFAs against the risk of AMD, whereas AA was responsible for deleterious effects on higher AMD risk.