Gene Discovery for Warfarin-Related Intracerebral Hemorrhage

描述（由申请人提供）：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卒中的抗凝剂，可增加ICH的风险和严重程度。因此，即使华法林导致ICH风险相对较小的升高也会影响平衡，有利于停止治疗。累积的证据表明，家族对ICH易感性有很强的贡献。来自研究者的数据表明，华法林相关的ICH与未服用华法林的个体的ICH具有相同的遗传风险因素。因此，ICH遗传风险因素的识别可能提供新的生物学见解，并通过改善长期抗凝治疗的风险评估提供直接的临床影响。为了发现参与ICH和华法林相关ICH发展的基因，该提案汇集了一个在ICH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世界杰出专家的遗传学家。参与研究的患者人群是最全面表征的ICH病例和对照，并且专门为遗传和基因-环境研究而收集。所有受试者都有关于华法林剂量、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中> 900，000个SNP和946，000个拷贝数探针的数据; 2）使用500例华法林相关ICH病例和1,000例服用华法林但未服用ICH的匹配对照中> 900，000个SNP和946，000个拷贝数探针的数据，鉴定与华法林相关ICH相关的遗传变异; 3）在同一组500例华法林相关ICH病例和1,000例匹配对照中，确定影响华法林剂量需求的遗传变异。任何关联的复制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ICH中起主要作用的假设，为未来这种疾病的遗传学研究奠定基础。该团队在ICH的神经影像学和流行病学以及人类遗传变异方面的尖端研究的跟踪记录，沿着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现在和未来的患者提供最广泛的利益。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卒中的抗凝剂，可增加ICH的风险和严重程度。该项目旨在发现个体服用和不服用华法林导致ICH的基因。因此，它提供了新的生物学见解的承诺，以及通过改善慢性抗凝的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.