Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

Authors

  • Alessandro Biffi MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge MA
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  • Akshata Sonni BS,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge MA
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  • Christopher D. Anderson MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge MA
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  • Brett Kissela MD, MSc,

    1. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Jeremiasz M. Jagiella MD, PhD,

    1. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
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  • Helena Schmidt MD,

    1. Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Austria
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  • Jordi Jimenez-Conde MD, PhD,

    1. Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
    2. Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
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  • Björn M. Hansen BS,

    1. Department of Clinical Sciences Lund Neurology, Lund University, Lund, Sweden
    2. Department of Neurology, Skåne University Hospital, Lund, Sweden
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  • Israel Fernandez-Cadenas PhD,

    1. Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Lynelle Cortellini MSc,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge MA
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  • Alison Ayres BA,

    1. Department of Neurology, Massachusetts General Hospital, Boston MA
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  • Kristin Schwab BA,

    1. Department of Neurology, Massachusetts General Hospital, Boston MA
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  • Karol Juchniewicz PhD,

    1. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
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  • Andrzej Urbanik MD, PhD,

    1. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
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  • Natalia S. Rost MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge MA
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  • Anand Viswanathan MD, PhD,

    1. Department of Neurology, Massachusetts General Hospital, Boston MA
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  • Thomas Seifert-Held MD,

    1. Department of Neurology, Medical University Graz, Austria
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  • Eva-Maria Stoegerer MD,

    1. Department of Neurology, Medical University Graz, Austria
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  • Marta Tomás MD, PhD,

    1. Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
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  • Raquel Rabionet PhD,

    1. Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
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  • Xavier Estivill MD, PhD,

    1. Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
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  • Devin L. Brown MD, MSc,

    1. Stroke Program, Department of Neurology, University of Michigan Health System, Ann Harbor, MI
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  • Scott L. Silliman MD,

    1. Department of Neurology, University of Florida College of Medicine, Jacksonville, FL
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  • Magdy Selim MD,

    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
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  • Bradford B. Worrall MD, MSc,

    1. Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA
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  • James F. Meschia MD,

    1. Department of Neurology, Mayo Clinic, Jacksonville, FL
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  • Joan Montaner MD, PhD,

    1. Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Arne Lindgren MD, PhD,

    1. Department of Clinical Sciences Lund Neurology, Lund University, Lund, Sweden
    2. Department of Neurology, Skåne University Hospital, Lund, Sweden
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  • Jaume Roquer MD,

    1. Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
    2. Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
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  • Reinhold Schmidt MD,

    1. Department of Neurology, Medical University Graz, Austria
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  • Steven M. Greenberg MD, PhD,

    1. Department of Neurology, Massachusetts General Hospital, Boston MA
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  • Agnieszka Slowik MD, PhD,

    1. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
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  • Joseph P. Broderick MD,

    1. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Daniel Woo MD, MSc,

    1. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Jonathan Rosand MD, MSc,

    Corresponding author
    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge MA
    • Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN-6818, Boston, MA 02114
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  • on behalf of the International Stroke Genetics Consortium


Abstract

Objective

Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied.

Methods

We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification.

Results

Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50–2.23, p = 6.6 × 10−10; and OR = 2.20, 95%CI = 1.85–2.63, p = 2.4 × 10−11, respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08–1.36, p = 2.6 × 10−4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes.

Interpretation

APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010

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