Causal association between remnant cholesterol level and risk of cardiovascular diseases: a bidirectional two sample...

Serum lipids have been associated with an increased risk of various cardiovascular diseases (CVDs) in several observational studies, but the causal inference between the remnant cholesterol (RC) levels and several CVDs risk has not been established. The purpose of this study was to investigate whether there is a causal relationship between RC levels and risk of developing CVDs by a bidirectional two-sample Mendelian randomization (TSMR) analysis. One TSMR analysis was performed using the publicly released large-scale genome-wide association study (GWAS) data. Inverse variance weighted (IVW) method was chosen as the main analysis method, and MR-Egger, weighted median, simple mode, and weighted mode were used as supplementary methods. We conducted a series of sensitivity analyses to assess the robustness of the main results, including the Cochran's Q test, MR-Egger intercept test, leave-one-out sensitivity analysis, and funnel plot. The main IVW method revealed that genetically predicted serum level of RC is significantly associated with an increased risk of developing ischemic heart disease (OR = 1.409, 95%CI = 1.284-1.546, P value = 4.753E-13), unstable angina pectoris (OR = 1.621, 95%CI = 1.398-1.880, P value = 1.672E-10), myocardial infarction (OR = 1.526, 95%CI = 1.337-1.741, P value = 3.771E-10), cardiac arrest (OR = 1.595, 95%CI = 1.322-1.924, P value = 1.076E-06), heart failure (OR = 1.086, 95%CI = 1.009-1.169, P value = 0.028), hypertension (OR = 1.089, 95%CI = 1.043-1.136, P value = 9.458E-05), major coronary heart disease (CHD) events (OR = 1.515, 95%CI = 1.376-1.669, P value = 3.217E-17), coronary atherosclerosis (OR = 1.388, 95%CI = 1.231-1.564, P value = 7.739E-08), cardiac arrhythmias (OR = 1.067, 95%CI = 1.008-1.130, P value = 0.025), and atrial fibrillation and flutter (OR = 1.122, 95%CI = 1.039-1.211, P value = 0.003). Additionally, the causal associations between the RC levels and these CVDs remained significant after correcting for the false discovery rate (all P value < 0.05). However, this study did not find any significant association of RC with cardiomyopathy and pericarditis (both P value > 0.05). Heterogeneity existed in the IVs of RC and ischemic heart disease, unstable angina pectoris, myocardial infarction, heart failure, hypertension, major CHD events, cardiomyopathy, coronary atherosclerosis, cardiac arrhythmias and atrial fibrillation and flutter using the Cochran's Q test (all P value < 0.05). Moreover, there was no horizontal pleiotropy in this study (all P value > 0.05). The leave-one-out sensitivity analyses showed that the causal effects between RC level and CVDs (except for heart failure, cardiomyopathy, pericarditis and cardiac arrhythmias) are not driven by a single SNP. The funnel plots showed that there is no obvious potential bias in our study. In the replication analysis, the genetically predicted RC levels were positively associated with a 43.12% higher risk of coronary artery disease. This present study supported the causal link between RC and heightened the risk of CVDs, indicating that RC-lowering treatment might be effective in preventing CVDs.