| Title: | Genetically Mediated Differences in LDL Cholesterol and Risk of Venous Thromboembolism |
| Journal: | Journal of the American College of Cardiology |
| Published: | 4 Aug 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42663354/ |
| DOI: | https://doi.org/10.1016/j.jacc.2026.06.026 |
Publication 21212
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Abstract
BACKGROUND: Venous thromboembolism (VTE) is a common and clinically significant cardiovascular condition. Although low-density lipoprotein (LDL) cholesterol is causally linked to atherosclerotic disease, its role in VTE remains unclear. Meta-analyses of randomized trials have suggested modest reductions in VTE with lipid-lowering therapy, but whether these effects are LDL mediated is uncertain.</p>
OBJECTIVES: This study sought to evaluate whether lifelong genetically mediated differences in low-density lipoprotein cholesterol (LDL-C) are associated with VTE risk.</p>
METHODS: Whole-genome sequencing data from 430,049 UK Biobank and 283,609 All of Us participants were analyzed. Rare protein-truncating and AlphaMissense-predicted damaging missense variants (minor allele frequency <0.1%) in LDLR, APOB, and PCSK9, as well as the common PCSK9 R46L variant, were evaluated. Associations with LDL-C were assessed using linear regression, and VTE associations using Firth logistic regression with fixed-effect meta-analysis. Incident VTE was evaluated using Cox models.</p>
RESULTS: Rare functional variants in LDLR, APOB, and PCSK9 produced substantial gene-specific differences in LDL-C (up to ∼50% differences). Despite these marked lifelong differences, rare variant burdens were not consistently associated with VTE across cohorts, although smaller effect sizes could not be excluded. Meta-analyzed ORs ranged from 0.60 to 1.07. Sensitivity and prospective analyses yielded similar findings. Complementary common variant and multivariable Mendelian randomization analyses suggested that previously reported LDL-C associations with VTE may partly reflect broader metabolic and obesity-related pathways. Positive control analyses of established thrombophilia variants demonstrated expected associations.</p>
CONCLUSIONS: Across 2 large biobanks, genetically mediated differences in LDL-C were not consistently associated with VTE risk, suggesting that genetically mediated differences in LDL-C are unlikely to exert a large effect on venous thrombosis risk, although small effects cannot be excluded. Complementary common variant analyses further suggest that previously reported LDL-C associations with VTE may partly reflect broader metabolic and obesity-related pathways rather than LDL-C itself.</p>
19 Authors
- Yang Sui
- Shinwan Kany
- Shaan Khurshid
- Kelvin Supriami
- Joel T Rämö
- Sean J Jurgens
- Nobuyuki Enzan
- Seung Hoan Choi
- Zhi Yu
- Linke Li
- Buu Truong
- Xingyu Chen
- Min Seo Kim
- Injeong Shim
- Raphael Twerenbold
- James P Pirruccello
- Pradeep Natarajan
- Patrick T Ellinor
- Akl C Fahed
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
Enabling scientific discoveries that improve human health