Influence of genetic variants and omega-3 fatty acids on acute myocardial infarction: findings from a prospective cohort study

Epidemiological studies have indicated that elevated levels of omega-3 fatty acids may reduce the risk of acute myocardial infarction (AMI). In contrast, genetic studies and randomized controlled trials have not succeeded in corroborating this protective association. This study aims to clarify how specific genetic variants related to omega-3 fatty acids levels influence their association with incident AMI. Initially, we performed two-sample Mendelian randomization (MR) and transcriptomics MR to identify causal loci influencing omega-3 fatty acid levels and their subsequent implications on AMI. Subsequently, we applied a series of genetic analyses to uncover pleiotropic loci shared between omega-3 levels and AMI. Furthermore, we utilized the UK Biobank cohort to assess whether genetic polymorphisms impact the correlation between omega-3 fatty acid levels and AMI. MR analysis identified that increases in genetically predicted omega-3 fatty acid levels are related to an elevated risk of AMI (odds ratio = 1.11, 95% confidence interval [CI] = 1.03–1.19, P = 0.004), with four causal loci (rs7970695, rs10096633, rs12914626, and rs964184) confirmed through transcriptomics MR. Furthermore, we established a significant positive genetic correlation between omega-3 fatty acid levels and AMI (rg = 0.10, P = 0.010), along with two notable pleiotropic loci (rs10455872 and rs112875651). In the UK Biobank cohort (56.6 ± 8.0 years, 55.1% female), elevated omega-3 fatty acid levels were linked to decreased AMI risk following thorough adjustment for confounders (adjusted hazard ratio [aHR] = 0.86, 95% CI = 0.81–0.90, P < 0.001). The most significant protective effect was observed among individuals with the rs964184 [ZNF259] GG genotype (aHR = 0.62, 95% CI = 0.41–0.94, P = 0.023), whereas an attenuation was noted in those carrying the rs964184 CC genotype (aHR = 0.87, 95% CI = 0.82–0.92, P < 0.001, P-interaction = 0.008). Additional genotypic variability, including rs10455872, rs10096633, and rs261339 (proxies for rs12914626), may also influence outcomes, though without significant interactions. The ZNF259 rs964184 variant possesses the potential to reduce the protective capacity of omega-3 fatty acids against AMI. Future clinical investigations should consider genetic factors and explore the underlying mechanistic pathways.