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

AbstractO_ST_ABSBackgroundC_ST_ABSThe association between omega-3 fatty acids and cardiovascular disease has been examined in populations with established disease. However, the definitive role of omega-3 fatty acids in cardiovascular risk remains inconclusive, and evidence from general populations is still limited. This study aims to examine the causal relationship between omega-3 and cardiovascular disease using large-scale genetic data. MethodsWe 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) from general populations 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 applied to identify circulating proteins associated with omega-3 levels. ResultsGenetically 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 linked to elevated LDL-C (Pmedian = 2.50E-33) and its key component apolipoprotein B (Pmedian = 5.60E-08), while reducing triglyceride levels (Pmedian = 4.16E-03). Notably, after adjusting for the genetic effect of LDL-C, omega-3 demonstrated a protective effect on CAD ({beta}combined = -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 elevating LDL-C (P median = 2.40E-12), highlighting the need for effective LDL-C management to maximize the cardiovascular benefits of omega-3. Circulating proteins, such as ANGPTL3 (Psmr = 1.22E-27) and PCSK9 (Psmr = 1.15E-21), were also found positively associated with omega-3 levels. A reanalysis of clinical trial data confirmed that the cardiovascular benefits of omega-3 were closely related to the intensity of LDL-C lowering therapy. ConclusionsOur results suggest that the cardiovascular benefits of omega-3 fatty acids may depend on effective lipid management, particularly LDL-C control. Combining omega-3 supplementation with advanced lipid-lowering therapy may be critical for maximizing their protective impact on cardiovascular health.