APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: A genetic association study

Alessandro Biffi, Christopher D. Anderson, Jeremiasz M. Jagiella, Helena Schmidt, Brett Kissela, Björn M. Hansen, Jordi Jimenez-Conde, Caroline R. Pires, Alison M. Ayres, Kristin Schwab, Lynelle Cortellini, Joanna Pera, Andrzej Urbanik, Javier M. Romero, Natalia S. Rost, Joshua N. Goldstein, Anand Viswanathan, Alexander Pichler, Christian Enzinger, Raquel RabionetBo Norrving, David L. Tirschwell, Magdy Selim, Devin L. Brown, Scott L. Silliman, Bradford B. Worrall, James F Meschia, Chelsea S. Kidwell, Joseph P. Broderick, Steven M. Greenberg, Jaume Roquer, Arne Lindgren, Agnieszka Slowik, Reinhold Schmidt, Daniel Woo, Jonathan Rosand

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)702-709
Number of pages8
JournalThe Lancet Neurology
Volume10
Issue number8
DOIs
StatePublished - Aug 2011

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Cerebral Hemorrhage
Genetic Association Studies
Genotype
Hemorrhage
Meta-Analysis
Mortality
Hematoma
Alleles
African Americans
National Institute of Neurological Disorders and Stroke
Cerebral Amyloid Angiopathy
Genetic Research
National Institutes of Health (U.S.)
Research
Linear Models

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Biffi, A., Anderson, C. D., Jagiella, J. M., Schmidt, H., Kissela, B., Hansen, B. M., ... Rosand, J. (2011). APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: A genetic association study. The Lancet Neurology, 10(8), 702-709. https://doi.org/10.1016/S1474-4422(11)70148-X

APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage : A genetic association study. / Biffi, Alessandro; Anderson, Christopher D.; Jagiella, Jeremiasz M.; Schmidt, Helena; Kissela, Brett; Hansen, Björn M.; Jimenez-Conde, Jordi; Pires, Caroline R.; Ayres, Alison M.; Schwab, Kristin; Cortellini, Lynelle; Pera, Joanna; Urbanik, Andrzej; Romero, Javier M.; Rost, Natalia S.; Goldstein, Joshua N.; Viswanathan, Anand; Pichler, Alexander; Enzinger, Christian; Rabionet, Raquel; Norrving, Bo; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F; Kidwell, Chelsea S.; Broderick, Joseph P.; Greenberg, Steven M.; Roquer, Jaume; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Woo, Daniel; Rosand, Jonathan.

In: The Lancet Neurology, Vol. 10, No. 8, 08.2011, p. 702-709.

Research output: Contribution to journalArticle

Biffi, A, Anderson, CD, Jagiella, JM, Schmidt, H, Kissela, B, Hansen, BM, Jimenez-Conde, J, Pires, CR, Ayres, AM, Schwab, K, Cortellini, L, Pera, J, Urbanik, A, Romero, JM, Rost, NS, Goldstein, JN, Viswanathan, A, Pichler, A, Enzinger, C, Rabionet, R, Norrving, B, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Broderick, JP, Greenberg, SM, Roquer, J, Lindgren, A, Slowik, A, Schmidt, R, Woo, D & Rosand, J 2011, 'APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: A genetic association study', The Lancet Neurology, vol. 10, no. 8, pp. 702-709. https://doi.org/10.1016/S1474-4422(11)70148-X
Biffi, Alessandro ; Anderson, Christopher D. ; Jagiella, Jeremiasz M. ; Schmidt, Helena ; Kissela, Brett ; Hansen, Björn M. ; Jimenez-Conde, Jordi ; Pires, Caroline R. ; Ayres, Alison M. ; Schwab, Kristin ; Cortellini, Lynelle ; Pera, Joanna ; Urbanik, Andrzej ; Romero, Javier M. ; Rost, Natalia S. ; Goldstein, Joshua N. ; Viswanathan, Anand ; Pichler, Alexander ; Enzinger, Christian ; Rabionet, Raquel ; Norrving, Bo ; Tirschwell, David L. ; Selim, Magdy ; Brown, Devin L. ; Silliman, Scott L. ; Worrall, Bradford B. ; Meschia, James F ; Kidwell, Chelsea S. ; Broderick, Joseph P. ; Greenberg, Steven M. ; Roquer, Jaume ; Lindgren, Arne ; Slowik, Agnieszka ; Schmidt, Reinhold ; Woo, Daniel ; Rosand, Jonathan. / APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage : A genetic association study. In: The Lancet Neurology. 2011 ; Vol. 10, No. 8. pp. 702-709.
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abstract = "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.",
author = "Alessandro Biffi and Anderson, {Christopher D.} and Jagiella, {Jeremiasz M.} and Helena Schmidt and Brett Kissela and Hansen, {Bj{\"o}rn M.} and Jordi Jimenez-Conde and Pires, {Caroline R.} and Ayres, {Alison M.} and Kristin Schwab and Lynelle Cortellini and Joanna Pera and Andrzej Urbanik and Romero, {Javier M.} and Rost, {Natalia S.} and Goldstein, {Joshua N.} and Anand Viswanathan and Alexander Pichler and Christian Enzinger and Raquel Rabionet and Bo Norrving and Tirschwell, {David L.} and Magdy Selim and Brown, {Devin L.} and Silliman, {Scott L.} and Worrall, {Bradford B.} and Meschia, {James F} and Kidwell, {Chelsea S.} and Broderick, {Joseph P.} and Greenberg, {Steven M.} and Jaume Roquer and Arne Lindgren and Agnieszka Slowik and Reinhold Schmidt and Daniel Woo and Jonathan Rosand",
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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

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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