ESC Congress 2026 Abstract · Oct 26, 2026
Genetically mediated differences in LDL cholesterol were not consistently associated with venous thromboembolism: rare variant analyses in over 700,000 participants
By Sui Y, Kany S, Khurshid S et al.
Background/Introduction: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality, with substantial lifetime risk and recurrence despite anticoagulation. While low-density lipoprotein cholesterol (LDL-C) is a well-established causal factor in atherosclerotic cardiovascular disease, its role in VTE remains uncertain. Meta-analyses of lipid-lowering therapies have suggested modest reductions in incident VTE, raising the possibility that LDL lowering, or therapy-specific pleiotropic effects, may influence venous thrombosis risk. Clarifying whether LDL lowering itself modifies VTE risk has important implications for understanding the clinical relevance of lipid pathways in venous thrombosis. Purpose: To evaluate whether lifelong genetically altered LDL-C is associated with VTE risk using rare and common variants in LDLR, APOB, and PCSK9. Methods: Whole-genome sequencing data from 430,049 UK Biobank and 283,609 All of Us participants were analysed. Rare protein-truncating and damaging missense variants (minor allele frequency <0.1%) in LDLR, APOB, and PCSK9, as well as the common PCSK9 R46L variant, were examined. Associations with LDL-C were assessed using linear regression. Associations with VTE were evaluated using Firth logistic regression with adjustment for demographic and genetic covariates, followed by fixed-effect meta-analysis. Incident VTE was analysed using Cox proportional hazards models in UK Biobank. Statistical power was estimated to detect moderate effect sizes. Results: Rare functional variants were associated with substantial gene-specific differences in LDL-C. APOB variants were associated with 48–53% lower LDL-C, PCSK9 variants with 20–29% lower LDL-C, and LDLR variants with 40–53% higher LDL-C. Despite these marked lifelong differences, rare variant burdens were not consistently associated with VTE in either biobank, and prospective analyses yielded similar findings. In meta-analysis, pooled odds ratios across genes and variant classes ranged from 0.60 to 1.07. In contrast, established thrombophilia genes and variants demonstrated strong associations with VTE, supporting validity of the analytical framework. Power analyses indicated adequate power to detect moderate protective associations. Conclusions: In two large population-based cohorts comprising over 700,000 participants, genetically mediated differences in LDL-C were not consistently associated with VTE risk. These findings suggest that LDL-related pathways may not substantially influence venous thrombosis risk within the range examined.ESC_study_submit.jpgFor image description, please refer to the figure legend and surrounding text.myversion_VTE_assso_4gene_ESC.jpgFor image description, please refer to the figure legend and surrounding text.