Exploring the Causal Relationships between Lipid Biomarkers and Anti-VEGF Treatment Response in Patients with Neovascular Age-related Macular Degeneration

Purpose: To identify the connections between lipid biomarkers and the anti-VEGF therapy response in patients with neovascular age-related macular degeneration (nAMD). Design: A bidirectional and multivariable Mendelian randomization study. Participants: The summary statistics for anti-VEGF nAMD treatment response included a total of 128 responders, 51 nonresponders, and 6 908 005 genetic variants available for analysis. The sample size of lipid biomarkers is 441 016 and 12 321 875 genetic variants available for analysis. Methods: Two-sample Mendelian randomization (MR) method was conducted to exhaustively appraise the causalities among 13 lipid biomarkers and the risk of different anti-VEGF treatment responses (including visual acuity [VA] and central retinal thickness [CRT]) for nAMD subtypes. Main Outcome Measures: Thirteen lipid biomarkers, VA, and CRT. Results: A positive causal relationship was identified between triglycerides (TGs), apolipoproteins (Apos) E2, ApoE3, total cholesterol (TC), and VA response to anti-VEGF therapy in patients with nAMD, as confirmed by MR-Egger, weighted median, and weighted mode models. The MR-Egger model yielded statistically significant results for TC, ApoA-I, ApoB, and ApoA-V in relation to the CRT response to anti-VEGF treatment in patients with nAMD. In the reverse (LDL-c), ApoE3, and ApoF and the VA response. However, this was not the case in the weighted median and weighted mode models. In the MR-Egger model, ApoB, LDL-c, ApoE3, and ApoM were identified as significantly influencing the CRT response. In the multisample MR analysis, TC, high-density lipoprotein cholesterol, LDL-c, and TG were found to be causally related to VA response, and TC was also identified as being causally related to the CRT response to anti-VEGF Conclusions: This MR study suggests unidirectional causality between TG and ApoE3 and the response to antiVEGF treatment in patients with nAMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology Science 2025;5:100711 (c) 2025 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).