Mendelian Randomization Indicates Enhanced Lipid Control is Essential for Omega-3's Cardiovascular Protection

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.