PDF(Pubmed)
Abstract：
UNASSIGNED: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed.
UNASSIGNED: To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, P = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, P = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, P = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, P = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, P = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, P = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses.
UNASSIGNED: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
UNASSIGNED: To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, P = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, P = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, P = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, P = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, P = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, P = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses.
UNASSIGNED: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
摘要：
全世界数百万患者常规使用抗凝剂来预防血栓。然而，抗凝治疗的问题仍然存在，包括长期抗凝治疗患者的持续和累积出血风险。需要新的更安全的抗凝靶点。
为了优先考虑具有最强疗效[静脉血栓栓塞（VTE）预防]和安全性（低出血风险）的抗凝目标，我们进行了双样本孟德尔随机化和遗传共定位.我们利用了三个大规模血浆蛋白数据集（deCODE作为发现数据集，Fenland和社区动脉粥样硬化风险作为复制数据集）和一个肝脏基因表达数据集（魁北克心脏病等肺炎减肥生物库），从对44例152例VTE和47例对照的新的全基因组关联分析中，评估了26种凝血级联蛋白对VTE的因果效应的证据中风亚型，出血结果,和父母寿命作为疗效/安全性比的总体衡量标准。1SD基因预测的F2血水平降低与VTE[比值比（OR）=0.44，95％置信区间（CI）=0.38-0.51，P=2.6e-28]和心源性卒中风险（OR=0.55，95％CI=0.39-0.76，P=4.2e-04）相关，但与出血无关（OR=1.13，95％CI=0.93-1.36，遗传预测的F11减少与VTE（OR=0.61，95％CI=0.58-0.64，P=4.1e-85）和心源性卒中（OR=0.77，95％CI=0.69-0.86，P=4.1e-06）的风险降低相关，但与出血无关（OR=1.01，95％CI=0.95-1.08，P=7.5e-01）。这些孟德尔随机化关联在三个血液蛋白数据集和肝基因表达数据集以及共定位分析中是一致的。
■这些结果提供了强有力的遗传证据，证明F2和F11可能是预防VTE和心源性卒中的安全有效的治疗靶点，而不会显著增加出血风险。
为了优先考虑具有最强疗效[静脉血栓栓塞（VTE）预防]和安全性（低出血风险）的抗凝目标，我们进行了双样本孟德尔随机化和遗传共定位.我们利用了三个大规模血浆蛋白数据集（deCODE作为发现数据集，Fenland和社区动脉粥样硬化风险作为复制数据集）和一个肝脏基因表达数据集（魁北克心脏病等肺炎减肥生物库），从对44例152例VTE和47例对照的新的全基因组关联分析中，评估了26种凝血级联蛋白对VTE的因果效应的证据中风亚型，出血结果,和父母寿命作为疗效/安全性比的总体衡量标准。1SD基因预测的F2血水平降低与VTE[比值比（OR）=0.44，95％置信区间（CI）=0.38-0.51，P=2.6e-28]和心源性卒中风险（OR=0.55，95％CI=0.39-0.76，P=4.2e-04）相关，但与出血无关（OR=1.13，95％CI=0.93-1.36，遗传预测的F11减少与VTE（OR=0.61，95％CI=0.58-0.64，P=4.1e-85）和心源性卒中（OR=0.77，95％CI=0.69-0.86，P=4.1e-06）的风险降低相关，但与出血无关（OR=1.01，95％CI=0.95-1.08，P=7.5e-01）。这些孟德尔随机化关联在三个血液蛋白数据集和肝基因表达数据集以及共定位分析中是一致的。
■这些结果提供了强有力的遗传证据，证明F2和F11可能是预防VTE和心源性卒中的安全有效的治疗靶点，而不会显著增加出血风险。
