TY - JOUR
T1 - APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage
T2 - A genetic association study
AU - Biffi, Alessandro
AU - Anderson, Christopher D.
AU - Jagiella, Jeremiasz M.
AU - Schmidt, Helena
AU - Kissela, Brett
AU - Hansen, Björn M.
AU - Jimenez-Conde, Jordi
AU - Pires, Caroline R.
AU - Ayres, Alison M.
AU - Schwab, Kristin
AU - Cortellini, Lynelle
AU - Pera, Joanna
AU - Urbanik, Andrzej
AU - Romero, Javier M.
AU - Rost, Natalia S.
AU - Goldstein, Joshua N.
AU - Viswanathan, Anand
AU - Pichler, Alexander
AU - Enzinger, Christian
AU - Rabionet, Raquel
AU - Norrving, Bo
AU - Tirschwell, David L.
AU - Selim, Magdy
AU - Brown, Devin L.
AU - Silliman, Scott L.
AU - Worrall, Bradford B.
AU - Meschia, James F.
AU - Kidwell, Chelsea S.
AU - Broderick, Joseph P.
AU - Greenberg, Steven M.
AU - Roquer, Jaume
AU - Lindgren, Arne
AU - Slowik, Agnieszka
AU - Schmidt, Reinhold
AU - Woo, Daniel
AU - Rosand, Jonathan
N1 - Funding Information:
We thank Tammy Gillis and Marcy MacDonald for technical assistance in genotyping of APOE samples in the Genetics of Cerebral Hemorrhage on Anticoagulation (GOCHA) study. 9 The Differences in the Imaging of Primary Hemorrhage based on Ethnicity or Race (DECIPHER) project was supported by Award Number U54NS057405 from the National Institute of Neurological Disorders And Stroke (NINDS) and National Institute on Minority Health and Health Disparities (NIMHD) ( U54NS057405 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health (DECIPHER). The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study was supported by NIH grants NS36695 ( Genetic and Environmental Risk Factors for Hemorrhagic Stroke ) and NS30678 (Hemorrhagic and Ischemic Stroke among Blacks and Whites), and by the Greater Cincinnati Foundation Grant (Cincinnati Control Cohort). The GOCHA study was funded by NIH-NINDS grants K23NS042695, 5K23NS059774, R01NS059727 , and 5R01NS042147 , the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, by the University of Michigan General Clinical Research Center ( M01 RR000042 ), and by a grant from the National Center for Research Resources. AB and CDA were supported in part by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research ( 0775010N ). The Hospital del Mar ICH (HM-ICH) study was funded by the Ministerio de Sanidad y Consumo de España, Instituto de Salud Carlos III with the grants “ Registro BASICMAR ” Funding for Research in Health ( PI051737 ), Contract for Research Training for Professionals with Specialty ( CM06100067 ), “Ramon y Cajal” Postdoctoral Contract, and Spanish Research Networks “Red HERACLES” ( RD06/0009 ). The Jagiellonian University Hemorrhagic Stroke Study (JUHSS) was supported by a grant funded by the Polish Ministry of Education ( N N402 083934 ). The Lund Stroke Register (LSR) was funded by Lund University, Region Skåne and the Swedish Medical Research Council ( K2007-61X-20378-01-3 ). Biobank services and genotyping were done at Region Skåne Competence Centre (RSKC Malmö), Skäne University Hospital, Malmö, Sweden. Controls from the Medical University of Gratz ICH (MUG-ICH) study were from the Austrian Stroke Prevention Study, which is a population-based study funded by the Austrian Science Fond grant numbers P20545-P05 and P13180 ; The Medical University of Graz supports the databank of the Austrian Stroke Prevention Study.
PY - 2011/8
Y1 - 2011/8
N2 - Carriers of APOE e{open}2 and e{open}4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. Methods: We investigated the association of APOE e{open}2 and e{open}4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE e{open}4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. Findings: For patients with lobar ICH, carriers of the APOE e{open}2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10-5), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10-8). In the meta-analysis, each copy of APOE e{open}2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE e{open}2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10-5) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10-5) compared with non-carriers after lobar ICH. APOE e{open}4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Interpretation: Vasculopathic changes associated with the APOE e{open}2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the e{open}2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. Funding: US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.
AB - Carriers of APOE e{open}2 and e{open}4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. Methods: We investigated the association of APOE e{open}2 and e{open}4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE e{open}4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. Findings: For patients with lobar ICH, carriers of the APOE e{open}2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10-5), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10-8). In the meta-analysis, each copy of APOE e{open}2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE e{open}2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10-5) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10-5) compared with non-carriers after lobar ICH. APOE e{open}4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Interpretation: Vasculopathic changes associated with the APOE e{open}2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the e{open}2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. Funding: US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.
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U2 - 10.1016/S1474-4422(11)70148-X
DO - 10.1016/S1474-4422(11)70148-X
M3 - Article
C2 - 21741316
AN - SCOPUS:79960341939
SN - 1474-4422
VL - 10
SP - 702
EP - 709
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 8
ER -