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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059727-02
Application #
7667211
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Gwinn, Katrina
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$872,002
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Marini, Sandro; Devan, William J; Radmanesh, Farid et al. (2018) 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage. Stroke 49:1618-1625
Akhter, Murtaza; Morotti, Andrea; Cohen, Abigail Sara et al. (2018) Timing of INR reversal using fresh-frozen plasma in warfarin-associated intracerebral hemorrhage. Intern Emerg Med 13:557-565
Marini, Sandro; Morotti, Andrea; Lena, Umme K et al. (2018) Men Experience Higher Risk of Pneumonia and Death After Intracerebral Hemorrhage. Neurocrit Care 28:77-82
Prins, Bram P; Mead, Timothy J; Brody, Jennifer A et al. (2018) Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biol 19:87
Biffi, Alessandro; Kuramatsu, Joji B; Leasure, Audrey et al. (2017) Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol 82:755-765
Traylor, Matthew; Malik, Rainer; Nalls, Mike A et al. (2017) Genetic variation at 16q24.2 is associated with small vessel stroke. Ann Neurol 81:383-394
Marini, Sandro; Morotti, Andrea; Ayres, Alison M et al. (2017) Sex differences in intracerebral hemorrhage expansion and mortality. J Neurol Sci 379:112-116
Grunwald, Zachary; Beslow, Lauren A; Urday, Sebastian et al. (2017) Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage. Neurocrit Care 26:205-212
Phuah, Chia-Ling; Dave, Tushar; Malik, Rainer et al. (2017) Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke. Brain 140:2663-2672
Woo, Daniel; Debette, Stephanie; Anderson, Christopher (2017) 20th Workshop of the International Stroke Genetics Consortium, November 3-4, 2016, Milan, Italy: 2016.036 ISGC research priorities. Neurol Genet 3:S12-S18

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