Abstract
BACKGROUND: Emerging evidence suggests that remnant cholesterol (RC) is strongly associated with an increased incidence of cardiometabolic diseases (CMD). However, the causality have not been confirmed. We aimed to evaluate the causal associations of RC with CMD and the relative risk factors using two-sample Mendelian randomization (MR) methods. METHODS: Summary-level statistics of RC, CMD, and cardiometabolic risk factors were obtained from the published data from individuals with a predominantly European ancestry mainly from the UK Biobank and the FinnGen biobank. Univariable and multivariable MR analyses were used to evaluate the causal relationships between RC and CMD. A bidirectional MR analysis was performed to estimate the causality between RC and cardiometabolic risk factors. The main MR method was conducted using the inverse-variance weighted method. RESULTS: Univariable MR analyses showed that genetically predicted RC was causally associated with higher risk of ischemic heart disease, myocardial infarction, atrial fibrillation and flutter, peripheral artery disease, and non-rheumatic valve diseases (all P < 0.05). Multivariable MR analyses provided compelling evidence of the harmful effects of RC on the risk of ischemic heart disease (P < 0.05). Bidirectional MR analysis demonstrated that RC was bidirectionally causally linked to total cholesterol, triglycerides, low-density lipoprotein cholesterol, hypercholesterolemia (all P < 0.05). However, no genetic association was found between RC and metabolic disorders or the other cardiometabolic risk factors. CONCLUSIONS: This MR study demonstrates that genetically driven RC increases the risk of several CMD and cardiometabolic risk factors, suggesting that targeted RC-lowering therapies may be effective for the primary prevention of CMD.