Marini, Sandro, Crawford, Katherine, Morotti, Andrea, Lee, Myung, Pezzini, Alessandro, Moomaw, Charles, Flaherty, Matthew, Montaner, Joan, Roquer, Jaume, Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano-Tarraga, Carolina, Słowik, Agnieszka, Jagiełła, Jeremiasz, Pera, Joanna, Urbanik, Andrzej, Pichler, Alexander, Hansen, Bjorn, McCauley, Jacob, Tirschwell, David, Selim, Magdy, Brown, Devin, Silliman, Scott, Worrall, Bradford, Meschia, James, Kidwell, Chelsea, Testai, Fernando, Kittner, Steven, Schmidt, Helena, Enzinger, Christian, Deary, Ian, Rannikmae, Kristiina, Samarasekera, Neshika, Al-Shahi Salman, Rustam, Sudlow, Catherine, Klijn, Catharina, van Nieuwenhuizen, Koen, Fernandez-Cadenas, Israel, Delgado, Pilar, Norrving, Bo, Lindgren, Arne, Goldstein, Joshua, Viswanathan, Anand, Greenberg, Steven, Falcone, Guido, Biffi, Alessandro, Langefeld, Carl, Woo, Daniel, Rosand, Jonathan, Anderson, Christopher, National Institute of Neurological Disorders and Stroke (US), Neurocritical Care Society (US), American Heart Association, Medical Research Council (UK), Age UK, Centre for Cognitive Ageing and Cognitive Epidemiology (UK), Wellcome Trust, Binks Trust, Scottish Funding Council, Chief Scientist Office (UK), Swedish Heart-Lung Foundation, Skåne Regional Council, Skåne University Hospital, The Grand Lodge of Sweden, King Gustaf V and Queen Victoria's Foundation, Lund University, Foundation of Färs & Frosta, Swedish Stroke Association, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Instituto de Salud Carlos III, and European Commission
[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, [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., This study was funded by grants K23NS086873, R01NS103924, U01NS069763, R01NS093870, R01AG047975, R01AG026484, P50AG005134, and K23AG02872605 from the NIH National Institute of Neurological Disorders and Stroke; a Yale Pepper Scholar Award (P30AG021342) and the Neurocritical Care Society Research Fellowship (Dr Falcone); an American Heart Association fellowship (18POST34080063) (Dr Marini); and a United Kingdom Medical Research Council/Stroke Association Clinical Research Training Fellowship and a United Kingdom Medical Research Council Senior Clinical Fellowship. The Lothian Birth Cohort 1936 is supported by Age UK (The Disconnected Mind project), the Medical Research Council (MR/M01311/1), and the Centre for Cognitive Ageing and Cognitive Epidemiology (which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council [MR/K026992/1]). The Edinburgh Stroke Study was supported by the Wellcome Trust and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility and part of the Scottish Imaging Network–A Platform for Scientific Excellence collaboration (funded by the Scottish Funding Council and the Chief Scientist Office). Lund Stroke Register is supported by the Swedish Heart and Lung Foundation, Region Skåne, Skåne University Hospital, the Freemasons Lodge of Instruction EOS in Lund, King Gustaf V and Queen Victoria’s Foundation, Lund University, the Foundation of Färs & Frosta (one of Sparbanken Skåne’s ownership Foundations), and the Swedish Stroke Association. ICH case and control recruitment from Spain has been supported by the Spain Ministry of Health Instituto de Salud Carlos III FEDER RD16/0019/0002.INVICTUS-PLUS.