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Observational Study
. 2025 Aug 26;23(1):495.
doi: 10.1186/s12916-025-04329-y.

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

Chenhao Lin #  1   2 , Haolong Wen #  1 , Mengyao Yu #  3 , Qingxia Huang  1 , Qi Wang  1 , Jinran Lin  1 , Wenjun Yang  1   4 , Jennifer Ming Jen Wong  5 , Mingfeng Xia  6   7 , Huiru Tang  1 , Li Jin  1 , Sijia Wang  8 , Xiaofeng Wang  1   9 , Yuxiang Dai  10 , Guo-Chong Chen  11 , Yan Zheng  12   13
Affiliations
Observational Study

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

Chenhao Lin et al. BMC Med. .

Abstract

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.

Keywords: Cardiovascular diseases; Genome-wide association study; Mendelian randomization; Remnant cholesterol.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The National Survey of Physical Traits is the subproject of the National Science & Technology Basic Research Project which was approved by the Ethics Committee of Human Genetic Resources of the School of Life Sciences, Fudan University (14117). The Shanghai Changfeng study was approved by the Ethical Committee of Zhongshan Hospital, Fudan University (2013–132). The Rugao Longevity and Aging study was approved by the Human Ethics Committee of the School of Life Sciences, Fudan University (BE1815). The GRAND study was approved by the central Ethics Committee at Zhongshan Hospital, Fudan University (B2017-051). All participants or their legal representatives provided informed consent before joining the study. Consent for publication: All authors have consent for publication. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The analysis workflow of the study
Fig. 2
Fig. 2
Results of the meta-analysis of GWAS for remnant cholesterol (RC) levels in 14,939 Han Chinese. The Manhattan plot showed seven significantly associated loci for RC levels. Variants in the seven loci were highlighted in red. The genome-wide threshold for significant (P = 5.0 × 10−8) associations was indicated by the horizontal dashed line
Fig. 3
Fig. 3
Causal effects of genetically predicted circulating levels of remnant cholesterol on cardiovascular diseases using univariate Mendelian randomization in a population of A East-Asian ancestry and B European ancestry. The inverse variance weighted method was considered the primary result. Sensitivity analyses were conducted using the MR-Egger method, weighted median method, weighted mode method, and MR-PRESSO method. The X-axes are shown on a log-transformed scale
Fig. 4
Fig. 4
Causal effects of genetically predicted circulating remnant cholesterol levels on cardiovascular diseases in populations of A East Asian ancestry and B European ancestry, using univariable and multivariable Mendelian randomization (MR). The primary results were derived using the inverse variance weighted (IVW) method under the univariable MR framework. Sensitivity analyses were performed using multivariable MR with Model 1: total cholesterol (TC); Model 2: low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c); Model 3: apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB). X-axes are shown on a log-transformed scale
Fig. 5
Fig. 5
Causal effects of genetically predicted cardiovascular diseases on circulating remnant cholesterol levels in East Asian ancestry individuals (inner circle) and European ancestry individuals (outer circle). The potential causal association was evaluated using two-sample MR analyses with the IVW method. Sensitivity analyses were conducted using the MR-Egger method, weighted median method, weighted mode method, and MR-PRESSO method. The results are presented as causal estimates with Beta (SE) for each disease status
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