Gene Discovery for Warfarin-Related Intracerebral Hemorrhage

描述(申请人提供)：脑出血(ICH)是最致命的卒中亚型。华法林是一种广泛用于预防血栓栓塞性中风的抗凝剂，它增加了脑出血的风险和严重性。因此，即使华法林对脑出血风险的相对较小的升高也可以改变平衡，有利于停止治疗。越来越多的证据表明，家族因素对脑出血的易感性有很大影响。来自研究人员的数据表明，与华法林相关的脑出血与非华法林治疗的脑出血患者具有相同的遗传风险因素。因此，识别脑出血的遗传危险因素可能提供新的生物学见解，并通过改善慢性抗凝的风险评估提供直接的临床影响。为了发现与脑出血和华法林相关脑出血的发展相关的基因，这项计划将一个在脑出血表型和生物学方面拥有世界级专业知识的临床医生和研究人员团队，以及在全基因组数据的方法和分析方面跻身于世界杰出专家之列的遗传学家聚集在一起。将做出贡献的患者群体是现有的最彻底的脑出血病例和对照，并已专门为遗传和基因环境研究而聚集在一起。所有受试者都有关于华法林剂量的详细数据，实验室数据包括凝血参数、临床病史、神经成像和临床随访。具体目标是：1)收集和整理1,000例与华法林无关的脑出血患者和1,000例未服用华法林的匹配对照的&gt；900,000个SNP和946,000个拷贝数探针的数据；2)利用500例华法林相关性脑出血患者和1,000名服用华法林但未服用华法林的匹配对照的数据，识别与华法林相关的脑出血相关的遗传变异；3)确定影响华法林相关性脑出血500例和1,000名匹配对照的华法林剂量需求的基因变异。任何关联的复制都将在另外三个独立数据集中进行。我们的研究将彻底检验常见变异在脑出血中发挥主要作用的假设，为未来对这种疾病的遗传学研究奠定基础。该团队在脑出血的神经成像和流行病学以及人类基因变异方面的尖端研究记录，加上我们积极的数据发布政策，将确保在表型和基因分型方面的大量投资被用于为当前和未来的患者带来最大可能的好处。公共卫生相关性：脑出血(ICH)是最致命的中风亚型。华法林是一种广泛用于预防血栓栓塞性中风的抗凝剂，它增加了脑出血的风险和严重性。该项目旨在发现在服用和停用华法林的个体中导致脑出血的基因。因此，它提供了新的生物学见解的希望，以及通过改进慢性抗凝的风险评估而立即产生的临床影响。

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is the deadliest stroke subtype. Warfarin, a widely used anticoagulant for prevention of thromboembolic stroke, increases both risk and severity of ICH. Thus, even relatively minor elevations in risk for ICH on warfarin can sway the balance in favor of withholding treatment. Accumulated evidence points to a strong familial contribution to ICH susceptibility. Data from the investigators suggest warfarin-related ICH shares genetic risk factors with ICH in individuals not on warfarin. The identification of genetic risk factors for ICH may therefore offer novel biological insights, as well as provide immediate clinical impact by improving risk assessment for chronic anticoagulation. To discover genes involved in development of ICH and warfarin-related ICH, this proposal brings together a team of clinician-investigators with world-class expertise in the phenotyping and biology of ICH alongside geneticists who are among the world's preeminent experts in the methods and analysis of genome-wide data. The population of patients who will contribute are the most thoroughly characterized ICH cases and controls available, and have been assembled specifically for genetic and gene-environment studies. Subjects all have detailed data on warfarin dose, laboratory values including coagulation parameters, clinical history, neuroimaging and clinical follow-up. Specific aims are:1) To collect and curate data for >900,000 SNPs and 946,000 copy number probes in 1,000 cases with ICH unrelated to warfarin and 1,000 matched controls not taking warfarin; 2) To identify genetic variants associated with warfarin-related ICH, using data for >900,000 SNPs and 946,000 copy number probes in 500 cases of warfarin related ICH and 1,000 matched controls taking warfarin, but without ICH; 3) To identify genetic variants that influence warfarin dose requirement in the same group of 500 cases of warfarin-related ICH and 1,000 matched controls. Replication of any association will be carried out in three additional independent datasets. Our study will thoroughly test the hypothesis that common variants play a major role in ICH, setting the stage for the future genetic study of this disease. The team's track record of cutting-edge research in the neuroimaging and epidemiology of ICH as well as in human genetic variation, along with our aggressive data release policy, will ensure that the substantial investment in phenotyping and genotyping is used for the widest possible benefit for present and future patients. PUBLIC HEALTH RELEVANCE: Intracerebral hemorrhage (ICH) is the deadliest stroke subtype. Warfarin, a widely used anticoagulant for prevention of thromboembolic stroke, increases both risk and severity for ICH. This project aims to discover the genes that cause ICH in individuals on and off warfarin. It therefore offers the promise of novel biological insights, as well as immediate clinical impact through improving risk assessment for chronic antiocoagulation.