Gene Discovery for Warfarin-Related Intracerebral Hemorrhage

华法林相关脑出血的基因发现

• 批准号: 8306884
• 负责人: JONATHAN ROSAND
• 金额: $ 81.4万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306884
• 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; Methods; Minor; National Institute of Neurological Disorders and Stroke; 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; genome-wide analysis; improved; insight; neuroimaging; novel; patient population

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. 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. 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 anticoagulation.

脑出血（ICH）是最致命的中风亚型。Warfare是一种广泛使用的 预防血栓栓塞性卒中的抗凝剂，增加了 ICH。因此，即使华法林导致ICH风险相对较小的升高也会动摇平衡 赞成停止治疗越来越多的证据表明 对ICH易感性的贡献。研究者的数据表明华法林相关ICH 在未服用华法林的个体中，与ICH具有相同的遗传风险因素。的识别 因此，ICH的遗传风险因素可能提供新的生物学见解， 通过改善长期抗凝治疗的风险评估，立即产生临床影响。 为了发现与脑出血和华法林相关脑出血发生有关的基因， 该提案汇集了一个具有世界一流专业知识的临床研究人员团队， 表型和生物学的ICH与遗传学家谁是世界上 全基因组数据方法和分析方面的杰出专家。的人口 参与研究的患者是最彻底表征的ICH病例和对照组 这些基因组是专门为遗传和基因环境研究而组装的。 所有受试者都有华法林剂量、实验室检查值（包括凝血）的详细数据 参数、临床病史、神经影像学和临床随访。 具体目标是：1）收集和管理> 900，000个SNP和946，000个拷贝的数据 1，000例与华法林无关的ICH病例和1，000例匹配对照的数字探针 不服用华法林; 2）鉴定与华法林相关ICH相关的遗传变异， 使用500例华法林病例中> 900，000个SNP和946，000个拷贝数探针的数据， 相关ICH和1，000名服用华法林但未发生ICH的匹配对照; 3） 在同一组500例患者中影响华法林剂量需求的遗传变异 华法林相关ICH和1,000名匹配对照。任何关联的复制都将 在另外三个独立的数据集中进行。 我们的研究将彻底检验这一假设，即常见的变异在 ICH，为这种疾病的未来遗传学研究奠定了基础。该团队的跟踪记录 脑出血的神经影像学和流行病学以及人类 遗传变异，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获得尽可能广泛的益处 现在和未来的患者。脑出血（ICH）是最致命的中风亚型。Warfare是一种广泛使用的 用于预防血栓栓塞性中风的抗凝剂会增加血栓栓塞性中风的风险和严重程度 ICH。这个项目的目的是发现基因，导致脑出血的个人和关闭 华法林因此，它提供了新的生物学见解的承诺，以及立即 通过改善慢性抗凝治疗的风险评估来实现临床影响。

项目成果

Leukocyte Count and Intracerebral Hemorrhage Expansion.

• DOI: 10.1161/strokeaha.116.013176
• 发表时间: 2016-06
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Morotti A;Phuah CL;Anderson CD;Jessel MJ;Schwab K;Ayres AM;Pezzini A;Padovani A;Gurol ME;Viswanathan A;Greenberg SM;Goldstein JN;Rosand J
• 通讯作者: Rosand J

Process improvement methods increase the efficiency, accuracy, and utility of a neurocritical care research repository.

• DOI: 10.1007/s12028-012-9689-x
• 发表时间: 2012-08
• 期刊: NEUROCRITICAL CARE
• 影响因子: 3.5
• 作者: O'Connor, Sydney;Ayres, Alison;Cortellini, Lynelle;Rosand, Jonathan;Rosenthal, Eric;Kimberly, W. Taylor
• 通讯作者: Kimberly, W. Taylor

Lymphopenia, Infectious Complications, and Outcome in Spontaneous Intracerebral Hemorrhage.

• DOI: 10.1007/s12028-016-0367-2
• 发表时间: 2017-04
• 期刊: Neurocritical care
• 影响因子: 3.5
• 作者: Morotti A;Marini S;Jessel MJ;Schwab K;Kourkoulis C;Ayres AM;Gurol ME;Viswanathan A;Greenberg SM;Anderson CD;Goldstein JN;Rosand J
• 通讯作者: Rosand J

Significance of admission hypoalbuminemia in acute intracerebral hemorrhage.

• DOI: 10.1007/s00415-017-8451-x
• 发表时间: 2017-05
• 期刊: Journal of neurology
• 影响因子: 6
• 作者: Morotti A;Marini S;Lena UK;Crawford K;Schwab K;Kourkoulis C;Ayres AM;Edip Gurol M;Viswanathan A;Greenberg SM;Anderson CD;Rosand J;Goldstein JN
• 通讯作者: Goldstein JN

Personalized approaches to clopidogrel therapy: are we there yet?

氯吡格雷疗法的个性化方法：我们在那里吗？

• DOI: 10.1161/strokeaha.110.594069
• 发表时间: 2010-12
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Anderson CD;Biffi A;Greenberg SM;Rosand J
• 通讯作者: Rosand J