The influence of remnant cholesterol on ischemic stroke and its subtypes

Abstract Background Established studies have firmly identified elevated low-density lipoprotein (LDL) as a key risk factor for stroke. Nevertheless, an emerging body of evidence suggests that residual stroke risk endures even with rigorous LDL control. Recent investigations propose a potential pivotal role of remnant cholesterol (RC) in this lingering risk. However, the causative relationship between RC and ischemic stroke, encompassing its subtypes, remains elusive. In this study, we employed a two-sample Mendelian Randomization (MR) analysis to delve into the causal association between RC and ischemic stroke, aiming to shed light on its various subtypes. Methods We sourced single nucleotide polymorphism (SNP) data associated with stroke and its subtypes from the MEGASTROKE consortium's comprehensive genome-wide association study (GWAS). SNPs relevant to RC were acquired from the MRC Integrative Epidemiology Unit (IEU) Open GWAS database. Our investigation involved the evaluation of the correlation between RC and ischemic stroke, encompassing 40,585 patients and 406,111 controls. Subtypes considered included large artery atherosclerosis (n=4,373), small artery occlusion (n=5,386), and cardioembolic stroke (n=7,193). A meticulous screening process was implemented to select instrumental variables (IVs) for RC, followed by five Mendelian Randomization (MR) analyses utilizing inverse-variance-weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. Rigorous sensitivity analyses, along with assessments for heterogeneity and pleiotropy, were conducted to ensure the robustness and credibility of our study results. Results Our investigation unveiled a causal relationship between RC and large artery atherosclerosis-type ischemic stroke (IVW method, OR=1.267, 95% CI: 1.017-1.578, P=0.035). This association was further substantiated through rigorous sensitivity analyses, assessments for heterogeneity, and pleiotropy tests. In contrast, no evidence supported a causal link between RC and overall ischemic stroke (IVW method, OR=1.072, 95% CI: 0.986-1.164, P=0.102), small artery occlusion-type stroke (IVW method, OR=1.127, 95% CI: 0.939-1.353, P=0.198), and cardioembolic stroke (IVW method, OR=1.083, 95% CI: 0.931-1.259, P=0.301). Conclusions Our findings robustly establish a causal connection between elevated levels of RC and the occurrence of large artery strokes. This highlights the potential efficacy of reducing RC as a preventive strategy against large artery atherosclerosis. Nevertheless, it is crucial to note that such mitigation efforts may not necessarily result in a decreased risk associated with small artery occlusion and cardioembolic strokes.