National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
J Hum Genet. 2023 Dec;68(12):805-812. doi: 10.1038/s10038-023-01186-6. Epub 2023 Aug 3.
Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.
全基因组关联研究（GWAS）已经确定了许多静脉血栓栓塞症（VTE）的风险位点，但解析其潜在机制具有挑战性。我们采用综合分析策略，将遗传关联转化为 VTE 的新型血浆蛋白标志物。通过基于功能汇总的推断，对全蛋白质组关联研究（PWAS）进行了测定，利用全基因组关联分析的数据（14429 例 VTE 患者，267037 例对照）、血液蛋白质组（1348 例病例）进行功能汇总推断，然后进行孟德尔随机化、贝叶斯共定位、蛋白质-蛋白质相互作用和通路富集分析。20 种受遗传调控的循环蛋白丰度（F2、F11、ABO、PLCG2、LRP4、PLEK、KLKB1、PROC、KNG1、THBS2、SERPINA1、RARRES2、CEL、GP6、SERPINE2、SERPINA10、OBP2B、EFEMP1、F5 和 MSR1）与 VTE 相关。其中 13 种蛋白的孟德尔随机化相关性得到了验证。在共定位分析中，有 6 种蛋白（F2、F11、PLEK、SERPINA1、RARRES2 和 SERPINE2）得到了强有力的支持。本研究利用多维数据，提示 PLEK、SERPINA1 和 SERPINE2 可能是有说服力的蛋白，为未来的研究以及 VTE 的可能诊断和治疗靶点提供了关键线索。
