Genetic and Clinical Predictors of Response to Warfarin and Novel Anticoagulants

摘要： 尽管口服抗凝剂(OAC)治疗可显著降低房颤患者的卒中风险 纤颤(AF)，它被广泛地利用不足，出血是一种主要的威慑。OAC相关性出血 占美国不良药物相关住院的33.3%，是建立 心理治疗。 这一修订后的应用建立在我们成功的识别基因对华法林剂量影响的项目基础上， 抗凝控制和出血(n=1310，43%为黑色)。我们扩大努力，将新的 OAC确定达比加特兰(DBG；n=500)和华法林(n=1000；590)出血的预测因素 应计)通过四个特定目标治疗房颤患者。 目的1阐明常见和罕见的基因变异对华法林相关出血风险的影响。 使用全基因组的方法。这些发现工作将以700例与华法林有关的出血为基础 在1000名接受华法林治疗的房颤患者的独立前瞻性队列中进行复制的病例对照配对。 目的2将阐明种族、肾损害和同时接受抗血小板治疗对糖尿病风险的影响。 1000名接受华法林治疗的房颤患者的前瞻性队列中与华法林相关的出血。 目的3将阐明肾损害和同时接受抗血小板治疗对华法林风险的影响。 500名接受DBG治疗的房颤患者的前瞻性队列中的相关出血。 AIM 4将结合患者特定的遗传和临床因素来提炼(用于华法林)和建立(用于 临床预测规则(CPR)，以个性化预测出血。 房颤患者队列将为未来的努力提供坚实的基础，这些努力将纳入其他新的OAC 即利伐沙班和阿皮沙班。对自动对焦的关注为未来的现实世界比较奠定了基础- 对具有临床实践代表性的人群进行效果评估。

ABSTRACT: Although oral anticoagulant (OAC) therapy provides superior stroke risk reduction in patients with Atrial Fibrillation (AF), it is widely underutilized with hemorrhage being a major deterrent. OAC related hemorrhage accounts for 33.3% of adverse-drug- related hospitalizations in the US and is a critical barrier to institution of therapy. This revised application builds on our successful project identifying the influence of genes on warfarin dose, anticoagulation control, and hemorrhage (n=1310; 43% Black). We expand our efforts to incorporate new OACs to identify predictors of hemorrhage in Dabigatran (DBG; n=500) and warfarin (n=1000; 590 accrued) treated AF patients through four specific aims. Aim 1 will elucidate the influence of common and rare genetic variation on risk of warfarin-related hemorrhage using a genome-wide approach. The discovery efforts will be grounded in 700 warfarin-related hemorrhage case-control pairs with replication in an independent prospective cohort of 1000 warfarin-treated AF patients. Aim 2 will elucidate the influence of race, kidney impairment and concurrent antiplatelet therapy on risk of warfarin-related hemorrhage in the prospective cohort of 1000 warfarin-treated AF patients. Aim 3 will elucidate the influence of kidney impairment and concurrent antiplatelet therapy on risk of warfarin- related hemorrhage in the prospective cohort of 500 DBG-treated AF patients. Aim 4 will incorporate patient-specific genetic and clinical factors into refining (for warfarin) and building (for DBG) clinical prediction rules (CPRs) to personalize the prediction of hemorrhage. The AF patient-cohort will provide a robust foundation for future efforts that will incorporate other new OACs namely rivaroxaban and apixaban. The focus on AF lays the foundation for future "real-world" comparative- effectiveness evaluation in a population representative of clinical practice.