Variants At APOE Influence Risk Of Deep And Lobar Intracerebral Hemorrhage.
Alessandro Biffi, Akshata Sonni, C D Anderson, Brett M. Kissela, Jeremiasz Jagiełła, Helena X. Schmidt, Jordi Jiménez‐Conde, Björn M. Hansen, I. Fernández-Cadenas, Lynelle Cortellini, A Ayres, Kristin E Schwab, Karol Józef Juchniewicz, Andrzej Urbanik, Natalia S. Rost, Anand Viswanathan, Thomas Seifert-Held, Eva-Maria Stoegerer, Marta Gillué Tomás, Raquel Rabionet, Xavier Estivill, Devin L Brown, Scott Silliman, Magdy Selim, Bradford B. Worrall, James F Meschia, J Montaner, Arne Lindgren, Jaume Roquer, Reinhold Schmidt, Steven M. Greenberg, Agnieszka Słowik, J P Broderick, Daniel Woo, Jonathan Rosand
Published 2010 · Medicine
Download PDFAnalyze on Scholarcy
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.
This paper references
Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working G
J P Broderick (2007)
Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke
D Woo (2011)
Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe−/− Mice: Isoform-Specific Effects on Neurodegeneration
Manuel Buttini (1999)
Prediction of death in patients with primary intracerebral hemorrhage: a prospective study of a defined population.
Ola G. Nilsson (2002)
Lack of Association of Lobar Intracerebral Hemorrhage with Apolipoprotein E Genotype in an Unselected Population
Thomas J. Seifert (2006)
Apolipoprotein E (ApoE) Isoform-dependent Lipid Release from Astrocytes Prepared from Human ApoE3 and ApoE4 Knock-in Mice*
Jian-Sheng Gong (2002)
Genetic and Environmental Risk Factors for Intracerebral Hemorrhage: Preliminary Results of a Population-Based Study
Daniel Woo (2002)
Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease
Eric M. Reiman (2001)
Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria
Katherine A Knudsen (2001)
Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype.
Gary E Gibson (2000)
Spontaneous intracerebral hemorrhage.
Raul G. Nogueira (1992)
Genetic variation and neuroimaging measures in Alzheimer’s disease
A Biffi (2010)
ACE variants and risk of intracerebral hemorrhage recurrence in amyloid angiopathy
Sophie Domingues-Montanari (2011)
Diagnosis of cerebral amyloid angiopathy: sensitivity and specificity of cortical biopsy.
W I Rosenblum (1997)
Stable Expression and Secretion of Apolipoproteins E3 and E4 in Mouse Neuroblastoma Cells Produces Differential Effects on Neurite Outgrowth (*)
Stefano Bellosta (1995)
APOE genotype, ethnicity, and the risk of cerebral hemorrhage
Christophe Tzourio (2008)
APOLIPOPROTEIN E POLYMORPHISM AND STROKE IN A POPULATION FROM EASTERN TURKEY
Selma Duzenli (2004)
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Eric M. Reiman (2003)
Apolipoprotein E genetic polymorphism and stroke subtypes in a Bangladeshi hospital-based study.
A H Chowdhury (2001)
Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy.
Steven M. Greenberg (1995)
The Genetics of Primary Haemorrhagic Stroke, Subarachnoid Haemorrhage and Ruptured Intracranial Aneurysms in Adults
George Peck (2008)
Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage.
Mark O McCarron (2000)
Clinical diagnosis of cerebral amyloid angiopathy : validation of the Boston crite
SM Greenberg (2001)
Genetic variation and neuroimaging measures in Alzheimer disease.
Alessandro Biffi (2010)
APOE in Deep and Lobar ICH December
Apolipoprotein E polymorphism in cerebrovascular disease.
Andrew J. Catto (2000)
Hemorrhage Burden Predicts Recurrent Intracerebral Hemorrhage After Lobar Hemorrhage
Steven M. Greenberg (2004)
Glutathione Peroxidase 1 C593T Polymorphism Is Associated with Lobar Intracerebral Hemorrhage
Joanna Pera (2008)
Unique Lipoproteins Secreted by Primary Astrocytes From Wild Type, apoE (−/−), and Human apoE Transgenic Mice*
Anne M. Fagan (1999)
ApoE isoform affects LTP in human targeted replacement mice
Barbara L. Trommer (2004)
Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database
Lars Bertram (2007)
Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease.
Gary W. Small (1995)
Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro.
Britto P. Nathan (1994)
Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy
Steven M. Greenberg (1995)
Exploiting common genetic variation to make anticoagulation safer.
Genome-wide significance for dense SNP and resequencing data.
Clive J. Hoggart (2008)
Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls.
C. Sudlow (2006)
ANNALS of Neurology
Outcome of intracerebral haemorrhage patients pre-treated with statins.
M. J. Serralta Gomis (2010)
The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.
Jonathan Rosand (2004)
APOE distribution in world populations with new data from India and the UK
P P Singh (2006)
Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.
Robert W. Mahley (2006)
This paper is referenced by
Generation and Applicability of Genetic Risk Scores (GRS) in Stroke
Natalia Cullell (2020)
Risk factors for intracerebral hemorrhage differ according to hemorrhage location
S Martini (2012)
Vitamin K antagonist-associated intracerebral hemorrhage: lessons from a devastating disease in the dawn of the new oral anticoagulants.
Marta Suárez-Pinilla (2014)
Genetics of Small Vessel Disease
Rainer Malik (2017)
Rare Coding Variation and Risk of Intracerebral Hemorrhage
Farid Radmanesh (2015)
Cerebral microbleeds の成因と臨床
俊雄 今泉 (2013)
Treatment of intracerebral hemorrhage associated with new oral anticoagulant use: the neurologist's view.
Roland Veltkamp (2014)
β-amyloid wall deposit of temporal artery in subjects with spontaneous intracerebral haemorrhage
Antonino Tuttolomondo (2018)
Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy
Y Inoue (2017)
Superficial siderosis is a warning sign for future intracranial hemorrhage
Jennifer Linn (2012)
Advances in genetics 2010.
James F Meschia (2011)
Restarting antiplatelet therapy after intracerebral haemorrhage
Wendy C. Ziai (2019)
A New Sign of Intracerebral Hematoma Expansion.
Zhenzhi Xia (2017)
Lipoprotein Phospholipase A2 and Cerebral Microbleeds in the Framingham Heart Study
José Rafael Romero (2012)
Cerebral amyloid angiopathy in the elderly.
Anand Viswanathan (2011)
Genetic Risk Factors for Ischemic and Hemorrhagic Stroke
Ganesh Chauhan (2016)
Astrocytes and the Warning Signs of Intracerebral Hemorrhagic Stroke
Annalisa Scimemi (2018)
Intracerebral Hemorrhage in the Neurocritical Care Unit
Xuemei Cai (2019)
Apolipoprotein E Genotype Predicts Hematoma Expansion in Lobar Intracerebral Hemorrhage
H B Brouwers (2012)
Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association
Emelia J. Benjamin (2017)
Genetics of Sporadic Cerebral Amyloid Angiopathy
Kristiina Rannikmae (2014)
Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery
Zane Jaunmuktane (2018)
Intracerebral hemorrhage: an update on diagnosis and treatment
Isabel Charlotte Hostettler (2019)
Genetics of intracerebral haemorrhage: a tsunami effect of APOE ɛ2 genotype on brain bleeding size?
J Montaner (2011)
Neuropathology and Pathophysiology of Stroke
Konstantin Alexander Hossmann (2014)
Recurrent intracerebral haemorrhage after coitus: a case report of sporadic cerebral amyloid angiopathy in a younger patient.
Rainer Ehling (2012)
Apolipoprotein E polymorphism and hippocampal atrophy across the spectrum of Alzheimer’s disease and dementia with Lewy bodies
Usman Saeed (2018)
Racial/ethnic disparities in the risk of intracerebral hemorrhage recurrence
Audrey C Leasure (2020)
Emerging insights from the genetics of cerebral small-vessel disease.
Loes C A Rutten-Jacobs (2019)
Non-Caucasian Stroke Genetics
Stacie L. Demel (2017)
Risk of intracranial hemorrhage with protease-activated receptor-1 antagonists.
Guido J. Falcone (2012)
Applied clinical neuroimaging in cerebral amyloid angiopathy and spontaneous intracerebral haemorrhage
Andreas Charidimou (2015)See more