Gene Discovery for Warfarin-Related Intracerebral Hemorrhage

描述（由申请人提供）：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程度。因此，即使华法林对脑出血风险的相对较小的升高也会影响到不接受治疗的平衡。积累的证据表明，家族性对脑出血易感性有很大影响。研究人员的数据表明，与华法林相关的脑出血与未使用华法林的脑出血患者具有相同的遗传风险因素。因此，确定脑出血的遗传风险因素可能提供新的生物学见解，并通过改善慢性抗凝血风险评估提供即时的临床影响。为了发现参与脑出血和华法林相关脑出血发展的基因，该提案汇集了一个在脑出血表型和生物学方面具有世界一流专业知识的临床研究人员团队，以及在全基因组数据方法和分析方面属于世界杰出专家的遗传学家。将贡献的患者群体是最彻底的脑出血病例和对照，并已专门为遗传和基因-环境研究聚集。所有受试者都有华法林剂量、实验室值（包括凝血参数）、临床病史、神经影像学和临床随访的详细数据。具体目标是：1)收集和整理1,000例与华法林无关的ICH病例和1,000例未服用华法林的匹配对照的bb90万个snp和94.6万个拷贝数探针的数据；2)鉴定与华法林相关脑出血相关的遗传变异，使用500例华法林相关脑出血病例和1000例服用华法林但未服用脑出血的匹配对照的94.6万个拷贝数探针和90万个snp数据；3)在500例与华法林相关的脑出血患者和1000例匹配的对照组中，确定影响华法林剂量需求的遗传变异。任何关联的复制都将在另外三个独立的数据集中进行。我们的研究将彻底验证常见变异在脑出血中起主要作用的假设，为未来对这种疾病的遗传研究奠定基础。该团队在脑出血神经影像学和流行病学以及人类遗传变异方面的前沿研究记录，以及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用于为当前和未来的患者提供尽可能广泛的益处。公共卫生相关性：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程度。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，以及通过改善慢性抗凝血风险评估的直接临床影响。

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.