Importance: Omega-3 fatty acids are widely regarded as beneficial supplementation for preventing cardiovascular disease. However, the definitive role of omega-3 fatty acid in reducing cardiovascular risk remains inconclusive. It is crucial to elucidate their relationship for informed clinical guidance. Objective: This study aims to examine the causal relationship between omega-3 fatty acids and cardiovascular disease. Design: We employed five well-established mendelian randomization (MR) methods to investigate the causal association between omega-3 and cardiovascular events. Two large independent omega-3 GWAS (>110,000 participants each) were analyzed across 14 cardiovascular and metabolic phenotypes (>50,000 participants each). To understand the direct effect of omega-3 on coronary artery disease (CAD), multivariable MR (MVMR) model and mediation analysis were conducted. Summary-data-based MR (SMR) was further applied to identify circulating proteins associated with omega-3 levels. Results: Genetically elevated omega-3 levels were found associated with increased cardiovascular risk across all MR methods, particularly for CAD (Pmedian = 2.65E-04), myocardial infarction (Pmedian = 1.03E-07) and heart failure (Pmedian = 4.84E-03). Higher genetically predicted omega-3 were significantly linked to elevated LDL-C (Pmedian = 2.50E-33) and its key component apolipoprotein B (Pmedian = 5.60E-08), while significantly reducing triglyceride levels (Pmedian = 4.16E-03). Notably, after adjusting for the genetic effect of LDL-C, omega-3 exhibited a protective effect on CAD (βcombined = -0.025, Pcombined = 0.022), which was strengthened by adjusting for both LDL-C and triglycerides. Mediation analysis suggests that omega-3 is likely to increase CAD risk through raising LDL-C (P median = 2.40E-12). Revisiting data from the STRENGTH and REDUCE-IT trials indicated that the cardiovascular benefits of omega-3 were closely related to the intensity of LDL-C lowering. Circulating proteins regulating lipid homeostasis, such as ANGPTL3 (Psmr = 1.22E-27) and PCSK9 (Psmr = 1.15E-21), were also found positively associated with omega-3 levels. Conclusion and Relevance: Our results suggest that the cardiovascular benefits of omega-3 fatty acids are context-dependent, showing protective effects when lipids, particularly LDL-C, are well controlled. We hypothesize that combining omega-3 supplementation with effective lipid-lowering therapy, such as those targeting ANGPTL3 or PCSK9, may enhance the cardiovascular benefits.

The authors have declared no competing interest.

We gratefully acknowledge funding supports from the Shenzhen-Hong Kong Jointly Funded Project (Category A; SGDX20230116093201002) and the Stability Support for Higher Education from Shenzhen Science and Technology Program, the Guangdong Natural Science Foundation Youth Enhancement Project (2024A1515030287), 1+1+1 CUHK-CUHK(SZ)-GDSTC Joint Collaboration Fund (GRDP2025-056 and YSP05) and the National Natural Science Foundation of China (82471825). We also extend our thanks to the faculty development grant (Project number: H800005) from the Hang Seng University of Hong Kong and the Warshel Institute for Computational Biology and their funding support from Shenzhen City and Longgang District (LGKCSDPT2024001). The authors thank the anonymous reviewers for their constructive comments and valuable suggestions that helped to improve the quality of the manuscript.

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https://www.ebi.ac.uk/gwas/studies/GCST90301959 https://www.ebi.ac.uk/gwas/studies/GCST90092931 https://www.ebi.ac.uk/gwas/studies/GCST90092816 https://www.ebi.ac.uk/gwas/studies/GCST90132314 https://www.ebi.ac.uk/gwas/studies/GCST005194 https://www.ebi.ac.uk/gwas/studies/GCST011365 https://www.ebi.ac.uk/gwas/studies/GCST009541 https://www.ebi.ac.uk/gwas/studies/GCST006061 https://www.ebi.ac.uk/gwas/studies/GCST006906 https://www.ebi.ac.uk/gwas/studies/GCST006908 https://cnsgenomics.com/content/data https://www.ebi.ac.uk/gwas/studies/GCST90013791 https://www.ebi.ac.uk/gwas/studies/GCST90239676 https://www.ebi.ac.uk/gwas/studies/GCST90239658 https://www.ebi.ac.uk/gwas/studies/GCST90239649 https://www.ebi.ac.uk/gwas/studies/GCST90239664 https://www.ebi.ac.uk/gwas/studies/GCST90179149 https://www.ebi.ac.uk/gwas/studies/GCST90301946 https://www.ebi.ac.uk/gwas/studies/GCST90019495 https://www.ebi.ac.uk/gwas/studies/GCST90086092