Glycomics of Heart and Lung Disease in the Genomic Era

描述(申请人提供)：近期全基因组关联研究的一个惊人发现是ABO糖转移酶基因座在全基因组范围内与心脏和血液表型的一致性和多样性的显着关联。这些包括急性心肌梗死(AMI)、冠状动脉疾病、静脉血栓栓塞症以及多种心肺生物标志物特征，如循环中的VonWillebrand因子(VWF)、因子VIII、可溶性ICAM-1、可溶性E-选择素和低密度脂蛋白胆固醇。我们扩展了这些发现，以显示ABO基因座与急性肺损伤(ALI)和阻塞性睡眠呼吸暂停并发症的名义关联。这些数据表明ABO糖转移酶活性和细胞特异性和循环ABO糖蛋白修饰在心肺疾病中发挥了重要的机制作用，同时也强调了复杂碳水化合物修饰在不同的心、肺、血液和睡眠(HLBS)疾病中的作用被低估。利用无偏倚的质谱学方法，我们建议定义疾病(急性心肌梗死和ALI)和细胞(血小板和内皮)特异的ABO糖蛋白，以开发HLBS疾病风险的糖肽标记和HLBS的跨器官、基于机制的表型。相关性(见说明)：最近的基因组研究揭示了编码糖转移酶的ABO基因座与心脏和血液表型的不同关联。这些包括心肌梗死、冠状动脉疾病和多个心肺生物标志物的特征。我们建议定义疾病和细胞特异性的ABO糖蛋白，以开发跨几种心肺疾病特征的糖蛋白质组分类和预测。(摘要结束)

DESCRIPTION (provided by applicant): A striking finding of recent genome wide association studies (GWAS) is the consistent and diverse genome- wide significant associations of the ABO glycotransferase locus with heart and blood phenotypes. These include acute myocardial infarction (AMI), coronary artery disease, venous thrombo-embolism, as well as multiple cardiopulmonary biomarkers traits such as circulating levels of VonWillebrand factor (VWF), Factor VIII, soluble ICAM-1, soluble E-selectin, and LDL cholesterol. We have extended these findings to show nominal associations of the ABO locus with acute lung injury (ALI) and complications of obstructive sleep apnea. These data indicate an important mechanistic role for ABO glycotransferase activity and cell-specific and circulating ABO glycoprotein modifications in cardiopulmonary diseases while also underscoring an underappreciated role for complex carbohydrate modifications in diverse heart, lung, blood and sleep (HLBS) disorders. Using unbiased mass-spectrometry approaches, we propose to define, disease (AMI and ALI) and cell (platelets and endothelium) specific ABO glycoproteomes in order to develop glycopeptide markers of HLBS disease risk and cross-organ, mechanism-based phenotypes in HLBS. RELEVANCE (See Instructions): Recent genomic studies reveal diverse associations of the ABO locus, encoding a glycotransferase, with heart and blood phenotypes. These include myocardial infarction, coronary artery disease and multiple cardiopulmonary biomarkers traits. We propose to define disease and cell-specific ABO glycoproteins in order to develop glycoproteomic classification and prediction across several cardiopulmonary disease traits. (End of Abstract)