Journal of the American College of Cardiology · 2026
Genetically Mediated Differences in LDL Cholesterol and Risk of Venous Thromboembolism.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Sui Yang, Kany Shinwan, Khurshid Shaan, Supriami Kelvin, Rämö Joel T, Jurgens Sean J, Enzan Nobuyuki, Choi Seung Hoan, Yu Zhi, Li Linke, Truong Buu, Chen Xingyu, Kim Min Seo, Shim Injeong, Twerenbold Raphael, Pirruccello James P, Natarajan Pradeep, Ellinor Patrick T, Fahed Akl C
Аннотация
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.
OBJECTIVES: This study sought to evaluate whether lifelong genetically mediated differences in low-density lipoprotein cholesterol (LDL-C) are associated with VTE risk.
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.
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.
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.
OBJECTIVES: This study sought to evaluate whether lifelong genetically mediated differences in low-density lipoprotein cholesterol (LDL-C) are associated with VTE risk.
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.
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.
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.