Mendelian randomization analysis of over 220,000 participants reveals a paradoxical finding: genetically elevated omega-3 levels increase cardiovascular disease risk, particularly for coronary artery disease (P=2.65E-04) and myocardial infarction (P=1.03E-07). The mechanism appears to involve omega-3's effect on raising LDL cholesterol and apolipoprotein B while lowering triglycerides. However, when researchers adjusted for LDL-C levels, omega-3 demonstrated protective cardiovascular effects, suggesting the fatty acids are beneficial only when cholesterol is simultaneously controlled. This finding challenges the widespread assumption that omega-3 supplements are universally cardioprotective. The research identifies key proteins like ANGPTL3 and PCSK9 as mediators in this pathway, offering potential therapeutic targets. For the millions taking omega-3 supplements, this suggests benefits may require concurrent statin therapy or other cholesterol management. The study's genetic approach provides stronger causal evidence than previous observational studies, though as a preprint awaiting peer review, these results require validation. This represents a potentially paradigm-shifting finding that could reshape omega-3 supplementation guidelines and explain inconsistent results in previous cardiovascular trials.