Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis
Open accessAbstract
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.
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APOE is the most potent risk factor for sporadic CAA and AD onset.
“Furthermore, APOE is the most potent risk factor for sporadic CAA and AD onset [611, 612].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [611]
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- Authors
- Marini, S., Crawford, K., Morotti, A., Lee, M. J., Pezzini, A., Moomaw, C. J., Flaherty, M. L., Montaner, J., Roquer, J., Jimenez-Conde, J., Giralt-Steinhauer, E., Elosua, R., Cuadrado-Godia, E., Soriano-Tarraga, C., Slowik, A., Jagiella, J. M., Pera, J., Urbanik, A., Pichler, A., Hansen, B. M., McCauley, J. L., Tirschwell, D. L., Selim, M., Brown, D. L., Silliman, S. L., Worrall, B. B., Meschia, J. F., Kidwell, C. S., Testai, F. D., Kittner, S. J., Schmidt, H., Enzinger, C., Deary, I. J., Rannikmae, K., Samarasekera, N., Salman, R. A.-S., Sudlow, C. L., Klijn, C. J. M., van Nieuwenhuizen, K. M., Fernandez-Cadenas, I., Delgado, P., Norrving, B., Lindgren, A., Goldstein, J. N., Viswanathan, A., Greenberg, S. M., Falcone, G. J., Biffi, A., Langefeld, C. D., Woo, D., Rosand, J., Anderson, C. D., & for the International Stroke Genetics Consortium
- Affiliations
- Massachusetts General Hospital (US)
- Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
- University of Brescia (IT)
- University of Cincinnati (US)
- Universitat Autònoma de Barcelona (ES)
- Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d’Investigacions Mèdiques, Universitat Autonoma de Barcelona, Barcelona, Spain
- Jagiellonian University (PL)
- Lund University (SE)
- University of Miami (US)
- University of Washington (US)
- Beth Israel Deaconess Medical Center (US)
- University of Michigan (US)
- University of Florida (US)
- University of Virginia Health System (US)
- Mayo Clinic (US)
- University of Arizona (US)
- University of Illinois Chicago (US)
- University of Maryland, Baltimore (US)
- Medical University of Graz (AT)
- University of Edinburgh (GB)
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
- Radboud University Nijmegen (NL)
- Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
- Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
- Yale University (US)
- Wake Forest University (US)
- Broad Institute (US)
- Corresponding author
- Anderson, Christopher D.
- ORCID
- Marini, Sandro
- Pezzini, Alessandro
- Moomaw, Charles J.
- Flaherty, Matthew L.
- Montaner, Joan
- Roquer, Jaume
- McCauley, Jacob L.
- Tirschwell, David L.
- Worrall, Bradford B.
- Meschia, James F.
- Testai, Fernando D.
- Enzinger, Christian
- Deary, Ian J.
- Samarasekera, Neshika
- Salman, Rustam Al-Shahi
- Klijn, Catharina J. M.
- Delgado, Pilar
- Viswanathan, Anand
- Greenberg, Steven M.
- Langefeld, Carl D.
- Woo, Daniel
- Rosand, Jonathan
- Anderson, Christopher D.
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-04-01
- Volume
- 76
- Issue
- 4
- Pages
- 480
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6459133
- OpenAlex
- W2911419914
- Cited by
- 68
- References
- 56
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 13 · 2023: 4 · 2022: 11 · 2021: 12 · 2020: 7 · 2019: 5 · 2018: 1
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
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- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Lirias (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- American Heart Association (R01NS103924, 18POST34080063)
- Massachusetts General Hospital
- Yale University (P30AG021342)
- University of Miami
- Wake Forest University
- University of Cincinnati
- McMaster University
- Wellcome Trust
- Broad Institute
- Neurocritical Care Society
- Parkinson's UK (G-0907)
- Scottish Funding Council
- Age UK (MR/M01311/1, MR/K026992/1)
- University College London
- Rosetrees Trust
- Singapore General Hospital
- Radboud Universiteit
- Soongsil University
- Lunds Universitet
- Taipei Medical University
- Chinese University of Hong Kong
- Sahlgrenska Universitetssjukhuset
- STROKE-Riksförbundet
- Karl-Franzens-Universität Graz
- Region Skåne
- Southern Medical University
- Taichung Veterans General Hospital
- Medizinische Universität Graz
- Nanfang Hospital
- Skånes universitetssjukhus
- Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1)
- National Institutes of Health (K23 AG02872605, UL1TR001863)
- Health Science Center, University of Tennessee
- University of California, Irvine
- Leonard M. Miller School of Medicine
- Medical Research Council (MR/K026992/1, MR/K01417X/1, MR/L501542/1, MR/M01311/1, MR/M013111/1, MR/N026004/1, MR/S004130/1)
- Biotechnology and Biological Sciences Research Council (MR/K026992/1, BB/F019394/1)
- Instituto de Salud Carlos III (RD 16/0019)
- National Institute on Aging (R01AG026484, P50AG005134, R01AG047975, P30AG021342)
- National Institute of Neurological Disorders and Stroke (U01NS069763, R01NS103924, U01NS036695, K23AG02872605, R01NS093870, K23NS086873)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Keywords
- intracerebral hemorrhage, apolipoprotein E, APOE ε4, APOE ε2, genetic risk factors, racial and ethnic differences, Hispanic population, Black population, lobar intracerebral hemorrhage, stroke genetics
- MeSH terms
- Aged, Aged, 80 and over, Apolipoproteins E, Black or African American, Cerebral Hemorrhage, Female, Hispanic or Latino, Humans, Hypertension, Male, Middle Aged, Risk Factors, United States, Case-Control Studies, Genetic Predisposition to Disease, White People
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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