A phenome-wide approach to identify causal risk factors for deep vein thrombosis
A phenome-wide approach to identify causal risk factors for deep vein thrombosis
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采用全表组方法来识别深静脉血栓形成的因果危险因素
DOI：
10.1101/476135
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Constantinescu A
中科院分区：
文献类型：
--
作者：
Constantinescu A
深静脉血栓（DVT）是在深静脉中形成的血块。深静脉血栓栓塞可导致静脉血栓栓塞（VTE），这是深静脉血栓栓塞和肺栓塞的综合术语，是世界范围内死亡和残疾的主要原因。尽管深静脉血栓的患病率和相关发病率，其根本原因尚不清楚。我们的目的是利用可公开获得的遗传汇总关联统计数据来确定深静脉血栓的因果危险因素。我们进行了一项孟德尔随机化全现象关联研究（MR-PheWAS），使用973例暴露和DVT的遗传汇总关联统计数据（6767例和330392例对照，来自UK Biobank）。有证据表明57种暴露对深静脉血栓风险有因果影响，包括先前报道的风险因素（如体重指数- bmi和身高）和新的风险因素（如甲状腺功能亢进和静脉曲张）。由于大多数已确定的危险因素与肥胖相关，我们通过对bmi相关循环蛋白与DVT风险的两样本MR中介分析，探索了与DVT的分子联系。我们的研究结果表明，循环神经源性基因座缺口同源蛋白1 （NOTCH1）、抑制素β C链（INHBC）和纤溶酶原激活物抑制剂1 （PAI-1）影响DVT风险，PAI-1介导BMI-DVT关系。采用全现象的方法，我们提供了甲状腺功能亢进、静脉曲张和BMI增加DVT风险的推定因果证据。此外，循环蛋白PAI-1在DVT病因学中起因果作用，并参与介导bmi与DVT的关系。
Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index—BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.
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DOI：
10.1126/science.1260793
发表时间：
2015-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Battle A;Khan Z;Wang SH;Mitrano A;Ford MJ;Pritchard JK;Gilad Y
通讯作者：
Gilad Y
影响因子：
16.6
作者：
Zaghlool SB;Sharma S;Molnar M;Matías-García PR;Elhadad MA;Waldenberger M;Peters A;Rathmann W;Graumann J;Gieger C;Grallert H;Suhre K
通讯作者：
Suhre K
合并症对肾细胞癌患者静脉血栓栓塞风险的影响。
DOI：
10.1016/j.urolonc.2013.07.008
发表时间：
2014
期刊：
Urologic oncology
影响因子：
--
作者：
Smith,AngelaB;Horvath-Puhó,Erzsébet;Nielsen,MatthewE;Lash,TimothyL;Baron,JohnA;Sørensen,HenrikT
通讯作者：
Sørensen,HenrikT
影响因子：
45.3
作者：
Maki, Robert G.
通讯作者：
Maki, Robert G.
影响因子：
5.3
作者：
Laumen, Helmut;Skurk, Thomas;Hauner, Hans
通讯作者：
Hauner, Hans