Causal statistical association between remnant cholesterol and coronary heart disease: genetic insights into the PSRC1–CELSR2–SORT1 gene cluster

Remnant cholesterol (RC) is increasingly recognized as an independent contributor to coronary heart disease (CHD) risk beyond LDL-C. However, its causal roles, genetic determinants, tissue-specific regulation, and relevance across ancestrally diverse populations remain incompletely characterized. Associations between RC and incident CHD were evaluated in the UK Biobank (UKB) employing Cox regression and restricted cubic splines models, including subgroup analyses by LDL-C levels. Causality was assessed using two-sample Mendelian randomization (MR) and colocalization using genome-wide summary statistics from UKB and FinnGen. Findings were validated in a multiancestry dataset. Genetic regulatory mechanisms were explored using tissue-specific MR integrating expression quantitative trait locus. Lipid-wide MR was used to evaluate gene effects across multiple lipid traits. Comparison between identified genes and established lipid-modifying target genes was conducted. RC showed a size-specific, LDL-C-independent association with CHD, which remained strong among individuals with normal LDL-C (