The causal effects of remnant cholesterol on increased risk of cardiovascular diseases in East Asians.

Background: Remnant cholesterol (RC) has been implicated in cardiovascular diseases (CVDs) in populations of European ancestry, yet its causal role remains underexplored in populations of East Asian ancestry, which are underrepresented in genetic studies. We sought to investigate the causal association between circulating RC levels and CVD risk in East Asian populations.

Methods: We first conducted observational analyses of RC and multiple CVD outcomes in Chinese populations. We then conducted genome-wide association studies (GWAS) of RC in 14,939 Chinese individuals and assessed its causal associations with CVD risk using two-sample Mendelian randomization (MR) with Biobank Japan data. Replication analyses in European ancestry populations utilized summary statistics from the UK Biobank and FinnGen.

Results: Circulating RC levels were significantly associated with multiple CVD outcomes in Chinese individuals. Our GWAS identified seven significant loci associated with circulating RC levels in the Chinese population. In the MR analyses, we found that genetically predicted higher RC levels were significantly associated with increased risks of aortic aneurysm (odds ratio per standard deviation increase, 1.82; 95% CI, 1.53-2.17; P = 1.17 × 10^-11) and ischemic heart diseases, such as myocardial infarction (1.22, 1.13-1.32; P = 1.81 × 10^-7) and stable angina pectoris (1.17, 1.11-1.23; P = 1.18 × 10^-8). Notably, these associations persisted after adjustment for total cholesterol, low-density and high-density lipoprotein cholesterols, Apolipoprotein A1 and Apolipoprotein B, respectively. Replication in European ancestry populations confirmed consistent causal effects for aortic aneurysm and ischemic heart diseases. A suggestive East Asian-specific association was identified between genetically predicted higher RC levels and an increased risk of peripheral artery disease, whereas a suggestive association with a higher risk of atrial flutter/fibrillation and ventricular arrhythmia was only observed in populations of European ancestry.

Conclusions: Our findings establish RC as an independent causal CVD risk factor in East Asian ancestry individuals and highlight population-specific differences in CVD risk profiles, emphasizing the need for ethnicity-tailored prevention strategies.