Causal Effects of Lipoproteins and Lipids on Atrial Fibrillation: A Mendelian Randomization Study

Background and AimsThe relationship between blood lipids and atrial fibrillation (AF) remains unclear. Nuclear magnetic resonance (NMR) spectroscopy enables the profiling of size‐defined lipoproteins and their contained lipid components. This study aimed to analyze the genetic causal relationships between lipoproteins, NMR‐measured lipids, and AF, providing insights into the prediction and treatment of AF. Methods and Results. Summary‐level data on lipoprotein and lipid concentrations measured by NMR were obtained from the UK Biobank. Summary‐level data on AF were sourced from the FinnGen project. Mendelian Randomization (MR) analysis using inverse‐variance weighting was employed as the primary analytical method. Genetically predicted elevated low‐density lipoprotein (LDL) cholesterol, LDL free cholesterol, LDL phospholipids, and LDL total lipids measured by NMR were associated with an increased risk of AF. MR analyses did not identify robust causal associations between lipids contained in high‐density lipoproteins (HDL), intermediate‐density lipoproteins (IDL), or very‐low‐density lipoproteins (VLDL) and AF. Among size‐defined LDL particles, elevated lipids of large LDL (L‐LDL) were strongly associated with increased risk of AF. Hypertension and coronary heart disease mediated these effects. Genetic variation alleles at ABCG5 , LDLR , and PCSK9 genes, which reduce lipid levels, were associated with lower risk of AF. Conclusions Increased lipids contained in LDL were associated with elevated risk of AF. L‐LDL particles exhibited a clear association with increased AF risk. LDL is identified as a critical lipoprotein for predicting and treating AF.