Gene Discovery for Warfarin-Related Intracerebral Hemorrhage

华法林相关脑出血的基因发现

• 批准号: 7899883
• 负责人: JONATHAN ROSAND
• 金额: $ 84.21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899883
• 关键词: Anticoagulants; Anticoagulation; Area; Biological; Biology; Cerebral hemisphere hemorrhage; Chronic; Clinical; Clinical Trials; Coagulation Process; Code; Data; Data Set; Development; Disease; Dose; Ensure; Environment; Epidemiology; Equilibrium; Funding; Future; Genes; Genetic; Genetic Variation; Genotype; Haplotypes; Human Genetics; Human Genome; Individual; International; Investments; Knowledge; Laboratories; Left; Methods; Minor; Pathway interactions; Patients; Phenotype; Play; Policies; Population Genetics; Predisposition; Prevention; Recording of previous events; Research; Research Personnel; Risk; Risk Assessment; Role; Sampling; Sampling Studies; Severities; Single Nucleotide Polymorphism; Staging; Stroke; Survivors; Technology; Testing; Variant; Warfarin; Withholding Treatment; base; case control; clinical decision-making; disability; experience; follow-up; gene discovery; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide analysis; improved; insight; neuroimaging; novel; patient population; public health relevance

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.

描述（由申请人提供）：脑内出血（ICH）是最致命的中风子类型。华法林是一种广泛使用的抗凝剂，用于预防血栓栓塞中风，可增加ICH的风险和严重性。因此，即使是在华法林上ICH的风险相对较小的海拔，也可以利用平衡，有利于预扣治疗。积累的证据表明，对ICH易感性做出了强有力的家族贡献。研究人员的数据表明，与华法林的ICH共享与华法林的个体中的ICH共享遗传危险因素。因此，ICH遗传危险因素的鉴定可能会提供新的生物学见解，并通过改善慢性抗凝风险评估来立即产生临床影响。为了发现与ICH和WARFARIN相关ICH开发的基因，该提案汇集了一组临床医生评估者的团​​队，在ICH的表型和生物学方面具有世界一流的专业知识，以及在全球范围内基因组数据方面和分析中均出色的遗传学家。将贡献的患者人数是最彻底的ICH病例和对照，并且已专门用于遗传和基因环境研究。受试者都有有关华法林剂量的详细数据，包括凝血参数，临床病史，神经影像和临床随访的实验室价值的详细数据。具体目的是：1）在1,000个情况下收集和策划> 900,000个SNP和946,000份副本编号探针，而ICH与Warfarin无关，而1,000个不服用华法林的匹配的控件； 2）使用> 900,000个SNP和946,000份的遗传变异，在500例华法林相关的ICH中，使用> 900,000 SNP和946,000份拷贝数探针，并使用1,000匹配的对照组，以华法林的速度进行了。 3）确定在500例与华法林相关的ICH和1,000个匹配的对照组中，在同一组中影响华法林剂量需求的遗传变异。任何关联的复制将在三个其他独立数据集中进行。我们的研究将彻底检验以下假设：普通变体在ICH中起主要作用，为该疾病的未来遗传研究奠定了基础。该团队在ICH以及人类遗传变异的神经影像学和流行病学方面的尖端研究的记录以及我们的积极数据发布政策，将确保对表型和基因分型的大量投资用于当前和未来患者的最广泛的可能益处。公共卫生相关性：脑内出血（ICH）是最致命的中风子类型。华法林是一种广泛使用的抗凝剂，用于预防血栓栓塞中风，可增加ICH的风险和严重性。该项目旨在发现在华法林（Warfarin）内外引起ICH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癌风险评估的直接临床影响。