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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059727-05
Application #
8306884
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Gwinn, Katrina
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$814,013
Indirect Cost
$321,042
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Hwang, David Y; Dell, Cameron A; Sparks, Mary J et al. (2016) Clinician judgment vs formal scales for predicting intracerebral hemorrhage outcomes. Neurology 86:126-33
Morotti, Andrea; Phuah, Chia-Ling; Anderson, Christopher D et al. (2016) Leukocyte Count and Intracerebral Hemorrhage Expansion. Stroke 47:1473-8
Anderson, Christopher D; Falcone, Guido J; Phuah, Chia-Ling et al. (2016) Genetic variants in CETP increase risk of intracerebral hemorrhage. Ann Neurol 80:730-740
Gesierich, Benno; Opherk, Christian; Rosand, Jonathan et al. (2016) APOE ɛ2 is associated with white matter hyperintensity volume in CADASIL. J Cereb Blood Flow Metab 36:199-203
Morotti, Andrea; Jessel, Michael J; Brouwers, H Bart et al. (2016) CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage. Neurocrit Care 25:79-85
Zhang, Cathy R; Cloonan, Lisa; Fitzpatrick, Kaitlin M et al. (2015) Determinants of white matter hyperintensity burden differ at the extremes of ages of ischemic stroke onset. J Stroke Cerebrovasc Dis 24:649-54
Raffeld, Miriam R; Biffi, Alessandro; Battey, Thomas W K et al. (2015) APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage. Neurology 85:349-56
Brouwers, H Bart; Battey, Thomas W K; Musial, Hayley H et al. (2015) Rate of Contrast Extravasation on Computed Tomographic Angiography Predicts Hematoma Expansion and Mortality in Primary Intracerebral Hemorrhage. Stroke 46:2498-503
Radmanesh, Farid; Falcone, Guido J; Anderson, Christopher D et al. (2015) Rare Coding Variation and Risk of Intracerebral Hemorrhage. Stroke 46:2299-301
Rannikmäe, Kristiina; Davies, Gail; Thomson, Pippa A et al. (2015) Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology 84:918-26

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