Causal Mediation of Immune Cells and Fatty Acids in Coronary Atherosclerosis: Insights From Mendelian Randomization Analysis

Observational studies have suggested a link between total fatty acid levels and the development of coronary atherosclerosis. While the involvement of immune cells in the pathogenesis of this condition is well‐established, the precise causal mechanisms by which fatty acids influence immune cell function and subsequently affect coronary atherosclerosis remain unclear. To address this, we systematically assessed the causal relationships among 731 immune cell traits, circulating fatty acid levels, and coronary atherosclerosis using a two‐sample Mendelian randomization (MR) approach. Multivariable Mendelian randomization (MVMR) was further employed to investigate the potential mediating role of dendritic cells in the pathway linking fatty acids to coronary atherosclerosis. Our analysis identified significant causal associations between 30 immune cell traits and coronary atherosclerosis. Furthermore, circulating fatty acid levels were causally linked to an increased risk of coronary atherosclerosis. MVMR analysis revealed that dendritic cells, specifically the CD62L− CD86+ myeloid subset, partially mediate the causal effect of fatty acid levels on coronary atherosclerosis. This study provides genetic evidence supporting the causal roles of multiple immune cell traits and fatty acid levels in coronary atherosclerosis. Importantly, dendritic cells were identified as a key mediator in the pathway through which fatty acids influence disease risk. These findings offer new insights into the interplay between nutrition and immunity in atherosclerosis and highlight potential targets for future therapeutic and preventive strategies.