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Original Investigation
February 6, 2019

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis

Sandro Marini, MD1; Katherine Crawford, BS1; Andrea Morotti, MD2; et al Myung J. Lee, BA3; Alessandro Pezzini, MD4; Charles J. Moomaw, PhD5; Matthew L. Flaherty, MD5; Joan Montaner, MD, PhD6,7,8; Jaume Roquer, MD, PhD9; Jordi Jimenez-Conde, MD, PhD9; Eva Giralt-Steinhauer, MD, PhD9; Roberto Elosua, MD, PhD9; Elisa Cuadrado-Godia, MD, PhD9; Carolina Soriano-Tarraga, PhD, BSc9; Agnieszka Slowik, MD, PhD10; Jeremiasz M. Jagiella, MD, PhD10; Joanna Pera, MD10; Andrzej Urbanik, MD, PhD10; Alexander Pichler, MD10; Björn M. Hansen, MD11,12; Jacob L. McCauley, PhD13; David L. Tirschwell, MD, MSc14; Magdy Selim, MD, PhD15; Devin L. Brown, MD, MS16; Scott L. Silliman, MD17; Bradford B. Worrall, MD, MSc18; James F. Meschia, MD19; Chelsea S. Kidwell, MD20; Fernando D. Testai, MD21; Steven J. Kittner, MD, MPH22; Helena Schmidt, MD23; Christian Enzinger, MD23; Ian J. Deary, FBA, FRSE, FMedSci24; Kristiina Rannikmae, MD, PhD25; Neshika Samarasekera, PhD, MRCP25; Rustam Al-Shahi Salman, MA, PhD, FRCP25; Catherine L. Sudlow, BMBCh, MSc, DPhil, FRCPE26; Catharina J. M. Klijn, MD, PhD27,28; Koen M. van Nieuwenhuizen, MD27,28; Israel Fernandez-Cadenas, PhD6,29; Pilar Delgado, MD, PhD6; Bo Norrving, MD11,12; Arne Lindgren, MD11,12; Joshua N. Goldstein, MD, PhD3; Anand Viswanathan, MD, PhD3; Steven M. Greenberg, MD, PhD3; Guido J. Falcone, MD, ScD, MPH30,31; Alessandro Biffi, MD32; Carl D. Langefeld, PhD33; Daniel Woo, MD5; Jonathan Rosand, MD, MSc1,3,34; Christopher D. Anderson, MD, MMSc1,3,34; for the International Stroke Genetics Consortium
Author Affiliations
  • 1Center for Genomic Medicine, Massachusetts General Hospital, Boston
  • 2Stroke Unit, IRCCS Mondino Foundation, Pavia, Italy
  • 3Department of Neurology, Massachusetts General Hospital, Boston
  • 4Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy
  • 5Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 6Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
  • 7Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain
  • 8Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain
  • 9Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d’Investigacions Mèdiques, Universitat Autonoma de Barcelona, Barcelona, Spain
  • 10Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
  • 11Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
  • 12Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
  • 13John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami
  • 14Stroke Center, Harborview Medical Center, University of Washington, Seattle
  • 15Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 16Cardiovascular Center, University of Michigan, Ann Arbor
  • 17Department of Neurology, University of Florida College of Medicine, Jacksonville
  • 18Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville
  • 19Department of Neurology, Mayo Clinic, Jacksonville, Florida
  • 20Department of Neurology, University of Arizona, Tucson
  • 21Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago
  • 22Department of Neurology, Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore
  • 23Department of Neurology, Medical University of Graz, Graz, Austria
  • 24Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
  • 25Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
  • 26Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
  • 27Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
  • 28Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
  • 29Stroke Pharmacogenomics and Genetics, Sant Pau Institute of Research, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • 30Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
  • 31Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, New Haven, Connecticut
  • 32Division of Behavioral Neurology, Massachusetts General Hospital, Boston
  • 33Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, North Carolina
  • 34Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
JAMA Neurol. Published online February 6, 2019. doi:10.1001/jamaneurol.2018.4519
Key Points

Question  Is history of hypertension and apolipoprotein E (APOE) associated with intracerebral hemorrhage risk in participants stratified by self-reported race/ethnicity?

Findings  In this case-control study of 13 124 adults, having a copy of APOE ε4 alleles increased the risk for lobar intracerebral hemorrhage only in white individuals, but after propensity score matching for hypertension burden, Hispanic individuals showed the same risk of APOE ε4.

Meaning  APOE ε4 appears to be confirmed as a risk factor for lobar intracerebral hemorrhage in nonwhite populations but is masked by differential hypertension burden in Hispanic individuals; further studies are needed to explore the interactions between APOE alleles and environmental exposures.


Importance  Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.

Objective  To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH.

Design, Setting, and Participants  This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study.

Main Outcomes and Measures  Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies.

Results  In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity.

Conclusions and Relevance  APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score–matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.