Research JAMA Neurology | Original Investigation Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis Sandro Marini, MD; Katherine Crawford, BS; Andrea Morotti, MD; Myung J. Lee, BA; Alessandro Pezzini, MD; Charles J. Moomaw, PhD; Matthew L. Flaherty, MD; Joan Montaner, MD, PhD; Jaume Roquer, MD, PhD; Jordi Jimenez-Conde, MD, PhD; Eva Giralt-Steinhauer, MD, PhD; Roberto Elosua, MD, PhD; Elisa Cuadrado-Godia, MD, PhD; Carolina Soriano-Tarraga, PhD, BSc; Agnieszka Slowik, MD, PhD; Jeremiasz M. Jagiella, MD, PhD; Joanna Pera, MD; Andrzej Urbanik, MD, PhD; Alexander Pichler, MD; Björn M. Hansen, MD; Jacob L. McCauley, PhD; David L. Tirschwell, MD, MSc; Magdy Selim, MD, PhD; Devin L. Brown, MD, MS; Scott L. Silliman, MD; Bradford B. Worrall, MD, MSc; James F. Meschia, MD; Chelsea S. Kidwell, MD; Fernando D. Testai, MD; Steven J. Kittner, MD, MPH; Helena Schmidt, MD; Christian Enzinger, MD; Ian J. Deary, FBA, FRSE, FMedSci; Kristiina Rannikmae, MD, PhD; Neshika Samarasekera, PhD, MRCP; Rustam Al-Shahi Salman, MA, PhD, FRCP; Catherine L. Sudlow, BMBCh, MSc, DPhil, FRCPE; Catharina J. M. Klijn, MD, PhD; Koen M. van Nieuwenhuizen, MD; Israel Fernandez-Cadenas, PhD; Pilar Delgado, MD, PhD; Bo Norrving, MD; Arne Lindgren, MD; Joshua N. Goldstein, MD, PhD; Anand Viswanathan, MD, PhD; Steven M. Greenberg, MD, PhD; Guido J. Falcone, MD, ScD, MPH; Alessandro Biffi, MD; Carl D. Langefeld, PhD; Daniel Woo, MD; Jonathan Rosand, MD, MSc; Christopher D. Anderson, MD, MMSc; for the International Stroke Genetics Consortium Supplemental content 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 Author Affiliations: Author an association with nonlobar ICH risk in any race/ethnicity. affiliations are listed at the end of this article. CONCLUSIONS AND RELEVANCE APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by Group Information: The race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic International Stroke Genetics Consortium members are listed at the individuals only when the excess burden of hypertension is propensity score–matched; further end of this article. studies are needed to explore the interactions between APOE alleles and environmental Corresponding Author: Christopher exposures that vary by race/ethnicity in representative populations at risk for ICH. D. Anderson MD, MMSc, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge JAMA Neurol. 2019;76(4):480-491. doi:10.1001/jamaneurol.2018.4519 Street CPZN 6818, Boston, MA 02114 Published online February 6, 2019. (cdanderson@partners.org). 480 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 01/29/2021 Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Original Investigation Research S pontaneous intracerebral hemorrhage (ICH) is the most severe form of stroke. In the United States, 160 000 people Key Points experience an ICH each year with a case fatality rate of Question Is history of hypertension and apolipoprotein E (APOE) 54% at 1 year.1 The prevalence of ICH has increased 47% associated with intracerebral hemorrhage risk in participants between 1990 and 2010,2 and ICH risk appears to vary among stratified by self-reported race/ethnicity? white, black and Hispanic populations.3-6 Compared with white Findings In this case-control study of 13 124 adults, having a copy individuals, young and middle-aged black individuals have of APOE ε4 alleles increased the risk for lobar intracerebral an almost 2-fold increased risk for ICH.3,4 Similarly, Hispanic hemorrhage only in white individuals, but after propensity score individuals have a relative risk increase that ranges from 1.4 matching for hypertension burden, Hispanic individuals showed for lobar ICH to 3.7 for nonlobar ICH.5 Moreover, not only is the same risk of APOE ε4. hypertension prevalence among older adults lower among Meaning APOE ε4 appears to be confirmed as a risk factor for non-Hispanic white groups (76.3%) than among non-Hispanic lobar intracerebral hemorrhage in nonwhite populations but is black (82.5%) and Hispanic (79.2%) groups, but the risk of ICH masked by differential hypertension burden in Hispanic in the presence of hypertension increases more than 50% from individuals; further studies are needed to explore the interactions white to Hispanic groups.7-9 The associations of genetic and between APOE alleles and environmental exposures. acquired ICH risk factors with these observed risk differences are poorly understood. Previous studies conducted in predominantly European- 1999, to December 31, 2017. Institutional review board ancestry populations have demonstrated that apolipoprotein approval was obtained from all participating centers, and E (APOE [OMIM 107741]) ε2 and ε4 alleles potently increase informed consent was obtained from all participants or their risk of lobar ICH.10 In Alzheimer disease, another disorder as- legally authorized representative. sociated with APOE ε allele status, the degree of risk contrib- The ICH cases from population-based cohorts were not in- uted by APOE genotype varies substantially by the ancestry cluded because of potential imbalances in lethal case recruit- of the population studied. Among non-Hispanic white people, ment between the 2 sampling approaches.16 Studies included homozygous carriers of APOE ε4 exhibit up to a 12-fold higher the Genetics of Cerebral Hemorrhage with Anticoagulation risk of Alzheimer disease, but this same haplotype exerts little (GOCHA) study,17 the Genetic and Environmental Risk Factors or no risk for black or Hispanic people.11-13 for Hemorrhagic Stroke (GERFHS) study,18 the Ethnic/Racial Understanding how genetic risk factors vary across race/ Variations of Intracerebral Hemorrhage (ERICH) study,19 the ethnicity may highlight novel underlying disease mecha- Hospital del Mar and Vall d’Hebron Hospital ICH studies,20,21 the nisms and identify populations who may be particularly re- Jagiellonian University Hemorrhagic Stroke Study,22 the Lund sponsive to specific prevention strategies, as has previously Stroke Register study, 23 the Edinburgh Stroke Study and been shown in treatment response for heart failure by LINCHPIN,24 the UMC Utrecht ICH study, and the Brescia Stroke race/ethnicity.14 Unfortunately, with individuals of African Registry.25 Because of variable sample sizes from contributing American and Hispanic ancestry representing less than 4% of centers, data from European studies were analyzed together for all samples in genome-wide association studies, only re- association testing in a meta-analysis (International Stroke cently has it become possible to study genetic risk of com- Genetics Consortium Europe), as done previously.26,27 mon disease across representative US populations.15 Participants with secondary causes of ICH were excluded We tested the associations of APOE ε alleles with risk of from enrollment. More specific inclusion and exclusion crite- lobar and nonlobar ICH among white, black, and Hispanic ria for each of the included studies are reported in eTable 1 individuals, using direct genotyping data supplemented by in the Supplement. Demographic variables, including self- genome-wide genotyping as available in cases and controls from identified race/ethnicity,8 were systematically obtained from the International Stroke Genetics Consortium. Because these structured patient and family member interviews within each analyses revealed substantial heterogeneity by race/ethnicity, site,19,28 along with additional covariates.29 Computed tomo- we further explored the degree to which the differential graphic images on admission were analyzed at each partici- burden of hypertension across populations is associated with pating site for classification as lobar (involving predomi- the variability in observed APOE risks. nantly the cortex and underlying white matter) and nonlobar (involving predominately the basal ganglia, periventricular white matter, or internal capsule) according to prespecified criteria.26,27 The APOE genotype was centrally determined Methods according to standard procedures.30 Genomewide data were Participating Studies and Data Collection available for a subgroup of participants. Genetic and bioinfor- Case and control participants included in the study were matic analysis followed standardized prespecified quality- gathered from 3 multicenter studies in the United States and control procedures31 (eMethods in the Supplement). from 8 European sites participating in the International Stroke Genetics Consortium, according to availability of Population Stratification directly ascertained APOE ε genotypes and a harmonized Fifteen ancestry informative markers were selected from par- local acute case recruitment scheme. These participants ticipants with direct or genomewide genotyping and sub- were enrolled in the aforementioned studies from January 1, jected to principal component (PC) analysis in accordance with jamaneurology.com (Reprinted) JAMA Neurology April 2019 Volume 76, Number 4 481 Downloaded From: https://jamanetwork.com/ on 01/29/2021 Research Original Investigation Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity previously published methods.32-35 The first 4 PCs were in- sex, and self-identified race/ethnicity. The second PS analy- cluded in regression models to adjust for population stratifi- sis, leveraging data only available in the ERICH study, con- cation in this subgroup. This PC analysis was not used to re- tained the same variables as the first PS analysis, in addition classify participants, as self-identified race/ethnicity may to the number of medications prescribed to treat hyperten- capture exposures that transcend genetic ancestry and could sion as well as systolic and diastolic blood pressure readings help explain the stratification among different populations. at ICH presentation. Propensity score results were used in a A complete description of the genetic analysis, the partici- logistic regression model for ICH risk identical to model 1, as pants genotyped, and the markers selected is available in described. In a sensitivity analysis, the same PS procedure eTable 2 in the Supplement. was tested against age (older or younger than 65 years), sex, and hypercholesterolemia to increase the confidence that Statistical Analysis the PS findings were specific for hypertension. Categorical variables were expressed as count (%), and con- tinuous variables were expressed as median (interquartile Power Calculation range [IQR]) or mean (SD), as appropriate. Categorical Using empirical data from our analyses, we performed a post variables were compared using the 2-tailed χ2 test, whereas hoc calculation of the statistical power to detect an associa- continuous variables were compared with unpaired Mann- tion of APOE ε alleles with lobar ICH risk in black and Whitney tests. The threshold for statistical significance Hispanic participants, commensurate with the effect size was set at P = .05. detected in white participants. Type I error rate of 0.05, log We tested APOE allele association with ICH risk using 3 additive inheritance mode, and 0.01 of population risk were logistic regression models. Model 1 was adjusted for age, sex, assumed, with analyses performed using Quanto software, and history of hypertension. Model 2 included variables version 1.2.4 (University of Southern California).41 from model 1 in addition to history of hypercholesterolemia; history of ischemic stroke; warfarin, statin and antiplatelet use; smoking; and alcohol use. Model 3 also included vari- ables from model 1 with the addition of the first 4 principal Results components derived from ancestry-informative genotypes. In total, 13 124 individuals (47.2% cases) were included from APOE risk allele status was modeled as 2 variables, ε2 and the participating studies. Among this sample, 7153 (54.5%) ε4, coded for allele counts (0, 1, or 2 for each) in an additive were male, with a median (IQR) age of 66 (56-76) years and model referent to the wildtype ε3 allele.17 Analyses were per- with 8334 white (63.5%), 2272 black (17.3%), 1781 Hispanic formed in lobar and nonlobar ICH, given the known differ- (13.6%), and 736 other (5.6%) race/ethnicity (Table). The lat- ences in underlying biology between the 2 ICH locations.36 ter group was excluded from the primary analyses given its All statistical analyses were performed using Stata, version low statistical power. Rates of APOE ε4 homozygosity in 13.0 (Stata Corp LLC), and R statistical software (R Founda- cases were 128 (3.6%) in white, 62 (5.3%) in black, and 22 tion for Statistical Computing). (1.8%) in Hispanic participants, and the rates of APOE ε2 homozygosity in cases were 36 (1.0%) in white, 14 (1.2%) in Transethnic Meta-analysis black, and 5 (0.4%) in Hispanic participants. Among partici- We applied a 2-stage clustering approach for meta-analysis, pants, 56.8% (4069 cases and 3379 controls of 13 124 partici- based on race/ethnicity and stratified by study.37 Cases and pants) had genomewide or direct genotyping data on ances- controls in each study were divided into black, white, and try informative markers for PC analysis (eTable 3 in the Hispanic groups, based on self-identified race/ethnicity. Supplement). Self-identified race/ethnicity showed overall Each race/ethnicity group within each study was allocated to strong concordance with PC-based ancestry (eFigure in the the same cluster and tested using the regression models Supplement). Additional clinical covariates were available described above. Individual cluster results were presented for a subset of participants (eTable 4 in the Supplement). graphically by plotting OR estimates on a forest plot to visu- ally assess heterogeneity. The effect sizes obtained were Lobar ICH then used for a DerSimonian-Laird random-effects, inverse- We analyzed 2305 lobar ICH cases from all studies. Model 1 con- weighted nonparametric meta-analysis.38 Cochran Q and I2 firmed the previously reported association of APOE ε2 (pooled tests were used to quantify heterogeneity. OR, 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (pooled OR, 1.51; 95% CI, 1.23-1.85; P < .001) with ICH risk; however, Propensity Score Modeling of APOE and Hypertension within self-identified Hispanic and black groups, no associa- To address imbalances in the burden of hypertension across tions were found (Figure 1). Model 2 was used to interrogate ICH populations, and associated imbalances of baseline the independent association of APOE alleles with ICH, con- characteristics among participants with and without hyper- trolled for established ICH factors (Figure 2). Here, APOE ε2 tension, 2 propensity score (PS) analyses were performed and ε4 alleles retained an association with lobar ICH. As with using the nearest neighbor matching method to compare model 1, this association was observed in the white group, but participants of similar underlying hypertensive pathophysi- not in black or Hispanic groups (for APOE ε2 OR, 1.45 [95% ologic burden.39,40 The first PS analysis was constructed CI, 1.04-2.03; P = .03]; for APOE ε4 OR, 1.51 [95% CI, 1.14- using history of hypertension and included variables of age, 1.99; P = .004]). Model 3 considered population stratification 482 JAMA Neurology April 2019 Volume 76, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 01/29/2021 Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Original Investigation Research Table. Demographic Characteristics and Clinical and APOE Allele Frequencies Across Participating Studies No. (%) ERICH GOCHA ISGC Europe GERFHS Source (n = 5017) (n = 2297) (n = 3471) (n = 2339) Male sex 2866 (57.1) 1266 (55.1) 1891 (54.6) 1130 (48.3) Age, median (IQR) 61 (52-72) 73 (65-80) 70 (61-77) 65 (51-75) Cases 2880 (57.4) 1322 (57.6) 1281 (36.9) 811 (34.7) Lobar ICH 882 (30.6) 613 (47.8) 493 (40.2) 316 (39.0) Nonlobar ICH 1998 (69.4) 670 (52.2) 734 (59.8) 495 (61.0) Hypertension 3364/4976 (67.6) 1667/2275 (73.3) 1673/2893 (57.8) 1264/2337 (54.1) Self-reported race/ethnicity White 1739 (34.7) 2024 (88.1) 2622 (75.5) 1949 (83.3) Black 1751 (34.9) 131 (5.7) NA 390 (16.7) Hispanic 1527 (30.4) 60 (2.6) 194 (5.6) NA Other/missing NA 82 (3.6) 654 (18.8) NA APOE ε4 allele count Abbreviations: APOE, apolipoprotein E; ERICH, Ethnic/Racial Variations of 0 3553 (70.8) 1664 (71.8) 2789 (80.4) 1664 (71.1) Intracerebral Hemorrhage; 1 1298 (25.9) 570 (24.8) 637 (18.4) 601 (25.7) GERFHS, Genetic and Environmental 2 166 (3.3) 77 (3.4) 45 (1.3) 74 (3.2) Risk Factors for Hemorrhagic Stroke; GOCHA, Genetics of Cerebral APOE ε2 allele count Hemorrhage with Anticoagulation; 0 4262 (85.0) 1916 (83.4) 3034 (87.4) 1881 (80.4) ICH, intracerebral hemorrhage; 1 710 (14.2) 363 (15.8) 413 (11.9) 431(18.4) IQR, interquartile range; ISGC, International Stroke Genetics 2 45 (0.9) 18 (0.8) 24 (0.7) 27 (1.2) Consortium; NA, not applicable. (Figure 3). In the white group, both APOE ε2 (OR, 1.81; 95% (OR, 1.43). Our analyses of APOE ε4 association in Hispanic CI, 1.33-2.45; P < .001) and APOE ε4 (OR, 1.80; 95% CI, 1.33- participants were similarly powered at 90%. Furthermore, 2.44; P < .001) conferred higher risk for lobar ICH. For APOE the APOE ε2 frequency in black participants (19.9%) at the ε4 alone, we found a similar association in the Hispanic group, reported sample sizes would provide 93.8% power to detect suggesting that population stratification may have played some the lower bound of the association seen in white participants role in the lack of ε4 association found in models 1 and 2, par- (OR, 1.38). For Hispanic participants, given the lower APOE ticularly for the large and ethnically diverse Hispanic popula- ε2 frequency (0.8%), 80% power would be achieved at a tion recruited through the ERICH study. In contrast, for the slightly higher effect size (OR, 1.60) but still would be below black population, neither APOE ε2 nor APOE ε4 conferred a that found in white participants. statistically significant risk for lobar ICH after controlling for population structure. Propensity Score Modeling for Hypertension We used a PS analysis to attempt to isolate the association of Nonlobar ICH APOE against the imbalanced burden of hypertension across We analyzed 3897 nonlobar ICH cases (Figure 1). In model 1, race/ethnicity. In the first PS, we selected case and control APOE ε2 and ε4 did not show an association with nonlobar ICH participants with a balanced hypertension burden to form a risk, across any of the self-identified race/ethnicity groups. group comprising individuals of white, black, or Hispanic When comparing nonlobar ICH cases with controls, we found ancestry. In this matched and homogeneous group, we were that the APOE ε4 P values were all P > .10. For model 2 and able to detect an association of APOE ε4 with lobar ICH risk model 3 in nonlobar ICH, again neither APOE ε2 nor APOE ε4 among Hispanic participants (OR, 1.14; 95% CI, 1.03-1.28; showed an association with disease risk across all the studies P = .01) but not in black participants (OR, 1.02; 95% CI, 0.98- and racial/ethnic groups (Figure 2 and Figure 3). 1.07; P = .25). Results were confirmed in the second PS analysis performed only in the ERICH data set, which Power Calculation (Lobar ICH) included hypertension diagnosis as well as additional hyper- Given the differences in sample sizes between white, black, tension severity variables, including number of medications and Hispanic groups, we performed post hoc power calcula- used to treat hypertension and systolic and diastolic blood tions to determine whether the study was powered to detect pressure readings (Figure 4). a comparable APOE association in the smaller populations of blacks and Hispanics. Given the frequency of APOE ε4 in black participants (ε4 frequency 37.7%), the sample size (assuming an unmatched case-control ratio of 1:1) would Discussion provide 99% power to detect an ε4 association similar to the Although APOE associations with ICH risk have been charac- lower bound of the 95% CI seen in white participants terized in multiple previous studies and meta-analyses for jamaneurology.com (Reprinted) JAMA Neurology April 2019 Volume 76, Number 4 483 Downloaded From: https://jamanetwork.com/ on 01/29/2021 Research Original Investigation Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Figure 1. Forest Plots of Meta-analysis of Apolipoprotein E (APOE) in Lobar and Nonlobar Intracerebral Hemorrhage Cases and Controls in Model 1, Stratified Across Participating Studies and Race/Ethnicity A Lobar, APOE ε4 B Lobar, APOE ε2 Participants, Decreasing Increasing Weight, Participants, Decreasing Increasing Weight, Study No. OR (95% CI) Risk Risk % Study No. OR (95% CI) Risk Risk % White participants White participants GOCHA 1369 1.67 (1.34-2.07) 15.85 GOCHA 1369 2.08 (1.57-2.75) 17.74 ERICH 1184 2.07 (1.64-2.62) 15.36 ERICH 1184 1.45 (1.08-1.94) 17.16 GERFHS 1333 2.06 (1.62-2.62) 15.16 GERFHS 1333 1.80 (1.32-2.42) 16.59 ISGC 2089 1.27 (0.95-1.69) 13.86 ISGC 2089 1.39 (1.01-1.89) 16.02 Europe Europe Subtotal Subtotal (I2 = 65%; P = .04) 1.75 (1.43-2.15) 60.24 (I2 = 37.3%; P = .20) 1.67 (1.38-2.01) 67.51 Black participants Black participants GOCHA 83 1.83 (0.85-4.10) 4.94 GOCHA 85 1.16 (0.41-3.30) 2.84 ERICH 1007 1.10 (0.84-1.43) 14.60 ERICH 1007 1.04 (0.73-1.45) 14.78 GERFHS 306 0.79 (0.39-1.49) 6.11 GERFHS 306 1.79 (0.91-3.38) 6.22 Subtotal Subtotal (I = 20.1%; P = .30) 2 1.11 (0.81-1.53) 25.65 (I = 3.4%; P = .36) 2 1.17 (0.87-1.59) 23.84 Hispanic participants Hispanic participants GOCHA 66 4.10 (0.55-99.77) 0.58 ERICH 811 1.14 (0.67-1.92) 8.65 ERICH 811 1.32 (0.98-1.79) 13.52 Subtotal 1.14 (0.67-1.94) 8.65 Subtotal (I2 = 0%; P = .40) 1.34 (1.00-1.81) 14.11 Overall Overall (I2 = 45.4%; P = .08) 1.49 (1.24-1.80) 100 (I2 = 68.5%; P = .001) 1.51 (1.23-1.85) 100 0.3 1 10 0.3 1 10 OR (95% CI) OR (95% CI) C Nonlobar, APOE ε4 D Nonlobar, APOE ε2 Participants, Decreasing Increasing Weight, Participants, Decreasing Increasing Weight, Study No. OR (95% CI) Risk Risk % Study No. OR (95% CI) Risk Risk % White participants White participants GOCHA 1383 1.09 (0.87-1.37) 16.96 GOCHA 1383 1.16 (0.85-1.57) 14.66 ERICH 1340 1.08 (0.85-1.38) 15.33 ERICH 1340 0.74 (0.55-0.99) 15.58 GERFHS 1464 1.25 (0.94-1.65) 11.56 GERFHS 1464 1.12 (0.88-1.43) 19.47 ISGC 2262 0.93 (0.70-1.22) 11.84 ISGC 2262 0.78 (0.56-1.08) 13.43 Europe Europe Subtotal Subtotal (I2 = 0.0%; P = .54) 1.08 (0.95-1.23) 55.69 (I2 = 60.1%; P = .06) 0.94 (0.74-1.18) 63.14 Black participants Black participants GOCHA 85 1.12 (0.53-2.39) 1.59 GOCHA 85 1.23 (0.48-3.20) 2.26 ERICH 1508 1.13 (0.94-1.36) 25.70 ERICH 1508 1.05 (0.82-1.34) 19.22 GERFHS 354 1.09 (0.69-1.71) 4.29 GERFHS 354 1.19 (0.69-2.00) 6.46 Subtotal Subtotal (I = 0.0%; P = .99) 2 1.12 (0.95-1.33) 31.59 (I = 0.0%; P = .88) 2 1.08 (0.87-1.34) 27.94 Hispanic participants Hispanic participants GOCHA 38 1.32 (0.04-76.09) 0.06 ERICH 1256 0.74 (0.48-1.15) 8.92 ERICH 1256 0.88 (0.67-1.15) 12.67 Subtotal Subtotal 0.74 (0.48-1.15) 8.92 (I2 = 0.0%; P = .83) 0.88 (0.67-1.15) 12.73 Overall Overall (I2 = 31.5%; P = .18) 0.96 (0.83-1.11) 100 (I2 = 0.0%; P = .80) 1.07 (0.97-1.17) 100 0.5 1 10 0.4 1 10 OR (95% CI) OR (95% CI) ERICH indicates Ethnic/Racial Variations of Intracerebral Hemorrhage; GERFHS, Genetic and Environmental Risk Factors for Hemorrhagic Stroke; GOCHA, Genetics of Cerebral Hemorrhage with Anticoagulation; ISGC, International Stroke Genetics Consortium; OR, odds ratio. Weights are from random-effects analysis. populations with European, and more recently Asian, ances- groups and to explore the degree to which differences in ge- tries, there have been fewer opportunities for examination of netic risk are attributable to comorbid exposures. Our results US minority populations at disproportionate risk for ICH. demonstrate an association of APOE ε4 and ε2 alleles with Supplemented by data from the ERICH study, we are now able lobar ICH led primarily by white individuals and confirmed to confirm variability in associations between APOE ε geno- by additional models adjusting for known covariates.29 When types and lobar ICH risk across white, black, and Hispanic the association of hypertension is propensity matched across 484 JAMA Neurology April 2019 Volume 76, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 01/29/2021 Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Original Investigation Research Figure 2. Forest Plots of Meta-analysis of Apolipoprotein E (APOE) in Lobar and Nonlobar Intracerebral Hemorrhage Cases and Controls in Model 2, Stratified Across Participating Studies and Race/Ethnicity A Lobar, APOE ε4 B Lobar, APOE ε2 Participants, Decreasing Increasing Weight, Participants, Decreasing Increasing Weight, Study No. OR (95% CI) Risk Risk % Study No. OR (95% CI) Risk Risk % White participants White participants GOCHA 420 1.85 (1.20-2.86) 17.70 GOCHA 420 2.21 (1.30-3.77) 18.50 ERICH 1156 2.06 (1.62-2.64) 25.35 ERICH 1156 1.44 (1.05-1.96) 26.75 ISGC 595 1.32 (0.64-2.57) 10.61 ISGC 595 2.66 (1.27-5.49) 13.06 Europe Europe Subtotal Subtotal (I2 = 0.0%; P = .48) 1.94 (1.58-2.38) 53.66 (I2 = 42.7%; P = .18) 1.85 (1.27-2.69) 58.31 Black participants Black participants ERICH 891 1.11 (0.84-1.47) 23.92 ERICH 891 1.01 (0.69-1.44) 24.31 Subtotal 1.11 (0.84-1.47) 23.92 Subtotal 1.01 (0.69-1.46) 24.31 Hispanic participants Hispanic participants ERICH 786 1.33 (0.96-1.81) 22.41 ERICH 786 1.01 (0.56-1.75) 17.38 Subtotal 1.33 (0.97-1.82) 22.41 Subtotal 1.01 (0.57-1.77) 17.38 Overall Overall (I2 = 67.6%; P = .02) 1.51 (1.14-1.99) 100 (I2 = 60.6%; P = .04) 1.45 (1.04-2.03) 100 0.5 1 10 0.4 1 10 OR (95% CI) OR (95% CI) C Nonlobar, APOE ε4 D Nonlobar, APOE ε2 Participants, Decreasing Increasing Weight, Participants, Decreasing Increasing Weight, Study No. OR (95% CI) Risk Risk % Study No. OR (95% CI) Risk Risk % White participants White participants GOCHA 446 1.42 (0.91-2.22) 8.48 GOCHA 446 1.70 (0.99-2.94) 18.31 ERICH 1308 1.07 (0.83-1.39) 25.28 ERICH 1308 0.63 (0.45-0.86) 25.10 ISGC 648 1.01 (0.52-1.90) 3.96 ISGC 648 0.62 (0.22-1.52) 9.77 Europe Europe Subtotal Subtotal (I2 = 0.0%; P = .52) 1.14 (0.92-1.40) 37.72 (I2 = 79.6%; P = .01) 0.89 (0.43-1.82) 53.18 Black participants Black participants ERICH 1443 1.16 (0.95-1.42) 41.29 ERICH 1443 0.99 (0.76-1.28) 26.86 Subtotal 1.16 (0.95-1.42) 41.29 Subtotal 0.99 (0.76-1.29) 26.86 Hispanic participants Hispanic participants ERICH 1201 0.88 (0.67-1.17) 20.99 ERICH 1201 0.59 (0.36-0.96) 19.96 Subtotal 0.88 (0.67-1.17) 20.99 Subtotal 0.59 (0.36-0.96) 19.96 Overall Overall (I2 = 0.0%; P = .41) 1.09 (0.96-1.24) 100 (I2 = 70.0%; P = .01) 0.84 (0.59-1.21) 100 0.4 1 10 0.2 1 10 OR (95% CI) OR (95% CI) ERICH indicates Ethnic/Racial Variations of Intracerebral Hemorrhage; GERFHS, Genetic and Environmental Risk Factors for Hemorrhagic Stroke; GOCHA, Genetics of Cerebral Hemorrhage with Anticoagulation; ISGC, International Stroke Genetics Consortium; OR, odds ratio. Weights are from random-effects analysis. race/ethnicity, APOE ε4 emerges as a risk factor for lobar ICH ERICH study, the present analysis has the advantage of a larger among self-identified Hispanic individuals. sample size via formal transethnic meta-analysis as well as a These results highlight the challenges of generalizing PS matching approach that helps to illustrate the potential genetic risk factors across ancestries, where nongenetic mechanisms underlying the observed variability of APOE exposures are known to vary by race/ethnicity. In Alzheimer ε alleles on lobar ICH risk across populations. disease, the relative risks for Hispanic or black individuals as- The observed differences in association between APOE sociated with an APOE ε 4 allele become progressively weaker ε alleles and lobar ICH risk do not provide direct evidence that or disappear entirely in comparison with white individuals.42-46 the biological risks of the APOE gene or associations with In ICH, APOE ε alleles have already been shown to exert higher underlying cerebral amyloid angiopathy (CAA, a major cause risks in East Asian individuals when compared with those of of lobar ICH) are necessarily different across racial/ethnic European ancestry.47 Although recent analyses by Sawyer boundaries. It would seem more likely that genetic and/or et al48 demonstrate the association of hypertension and APOE environmental risk exposures covarying with race/ethnicity ε allele status with ICH risk across race/ethnicity specific to the exert a role in modifying or mitigating the underlying APOE jamaneurology.com (Reprinted) JAMA Neurology April 2019 Volume 76, Number 4 485 Downloaded From: https://jamanetwork.com/ on 01/29/2021 Research Original Investigation Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Figure 3. Forest Plots of Meta-analysis of Apolipoprotein E (APOE) in Lobar and Nonlobar Intracerebral Hemorrhage Cases and Controls in Model 3, Stratified Across Participating Studies and Race/Ethnicity A Lobar, APOE ε4 B Lobar, APOE ε2 Participants, Decreasing Increasing Weight, Participants, Decreasing Increasing Weight, Study No. OR (95% CI) Risk Risk % Study No. OR (95% CI) Risk Risk % White participants White participants GOCHA 507 1.06 (0.63-1.74) 14.36 GOCHA 507 2.81 (1.60-4.90) 14.35 ERICH 1178 2.09 (1.65-2.65) 22.12 ERICH 1178 1.46 (1.09-1.95) 24.29 GERFHS 1333 2.06 (1.62-2.62) 21.95 GERFHS 1333 1.80 (1.32-2.42) 24.02 Subtotal Subtotal (I2 = 66.8%; P = .05) 1.80 (1.33-2.44) 58.43 (I2 = 52.9%; P = .12) 1.81 (1.33-2.45) 62.86 Black participants Black participants GOCHA 29 4.33 (0.03-23 804.82) 0.18 GOCHA 29 1.27 (0.00-175.16) 0.17 ERICH 998 1.09 (0.83-1.41) 21.21 ERICH 998 1.01 (0.70-1.42) 21.94 Subtotal Subtotal (I2 = 0.0%; P = .69) 1.09 (0.83-1.42) 21.40 (I2 = 0.0%; P = .95) 1.01 (0.71-1.43) 22.11 Hispanic participants Hispanic participants 1.27 (0.00-175.16) ERICH 805 1.36 (1.00-1.84) 20.17 ERICH 805 1.22 (0.71-2.07) 15.04 Subtotal 1.36 (1.01-1.85) 20.17 Subtotal 1.22 (0.71-2.09) 15.04 Overall (I2 = 76.1%; Overall (I2 = 57.4%; P = .001) 1.51 (1.13-2.02) 100 P = .04) 1.51 (1.14-2.00) 100 0.4 1 10 0.5 1 10 OR (95% CI) OR (95% CI) C Nonlobar, APOE ε4 D Nonlobar, APOE ε2 Participants, Decreasing Increasing Weight, Participants, Decreasing Increasing Weight, Study No. OR (95% CI) Risk Risk % Study No. OR (95% CI) Risk Risk % White participants White participants GOCHA 503 0.60 (0.32-1.05) 5.71 GOCHA 503 1.15 (0.60-2.09) 9.28 ERICH 1336 1.10 (0.87-1.41) 22.41 ERICH 1336 0.74 (0.55-0.99) 23.39 GERFHS 1464 1.12 (0.88-1.43) 22.42 GERFHS 1464 1.25 (0.94-1.65) 24.83 Subtotal Subtotal (I2 = 48.5%; P = .14) 1.02 (0.79-1.31) 50.55 (I2 = 69.6%; P = .04) 1.00 (0.68-1.47) 57.51 Black participants Black participants ERICH 1498 1.13 (0.94-1.37) 29.63 ERICH 1498 1.04 (0.81-1.33) 27.26 Subtotal 1.13 (0.94-1.37) 29.63 Subtotal 1.04 (0.81-1.33) 27.26 Hispanic participants Hispanic participants ERICH 1244 0.88 (0.67-1.15) 19.82 ERICH 1244 0.78 (0.50-1.21) 15.24 Subtotal 0.88 (0.67-1.15) 19.82 Subtotal 0.78 (0.50-1.21) 15.24 Overall (I2 = 36.1%; Overall (I2 = 49.3%; P = .18) 1.03 (0.89-1.19) 100 P = .10) 0.97 (0.78-1.20) 100 0.2 1 10 0.3 1 10 OR (95% CI) OR (95% CI) ERICH indicates Ethnic/Racial Variations of Intracerebral Hemorrhage; GERFHS, Genetic and Environmental Risk Factors for Hemorrhagic Stroke; GOCHA, Genetics of Cerebral Hemorrhage with Anticoagulation; ISGC, International Stroke Genetics Consortium; OR, odds ratio. Weights are from random-effects analysis. genetic risks. The PS analysis supports this conjecture, dem- to no association in black participants. APOE interaction stud- onstrating that hypertension, the most important known risk ies and transethnic genome-wide association studies for ICH factor for ICH, may simply obscure the APOE risks that may will likely provide insights on these hypotheses. Similarly, be common across ancestries. Aside from variation in envi- analyses of CAA in nonwhite populations will also clarify the ronmental risk exposures, variants in a modifier gene (or genes) association of race/ethnicity with this pathologic pathway. that differ across populations may alter the biological risk of In this study, we have not attempted to stratify subsets of APOE and consequently vary ICH risk, as has been hypoth- participants by probable CAA status using magnetic reso- esized for Alzheimer disease. 49,50 Furthermore, genetic nance imaging data as has been done in previous meta- variants that are racially stratified and not associated with APOE analyses. Most studies linking lobar hemorrhage locations to may directly modify the risk of ICH. This hypothesis repre- the pathologic diagnosis of CAA were performed in largely sents an alternative explanation for why the PS matching for white populations.51 As such, widely accepted criteria for hypertension only partially remediated the association of classifying probable and possible CAA using hemorrhage APOE ε4 with ICH risk in Hispanic participants and had little location and microbleed counts have not been validated in 486 JAMA Neurology April 2019 Volume 76, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 01/29/2021 Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Original Investigation Research nonwhite populations.52 Validating CAA burdens across mul- Figure 4. Risk of Apolipoprotein E (APOE) ε4 Allele for Lobar Intracerebral tiethnic populations will require concomitant neuroimaging Hemorrhage Across Race/Ethnicity After Propensity Score Matching and/or tissue pathologic data in genotyped individuals of many Based on Hypertension Burden races/ethnicities to ensure patients are not misassigned. Previously demonstrated associations between APOE ε4 Race/ Participants, Decreasing Increasing Weight, Ethnicity No. OR (95% CI) Risk Risk % and nonlobar ICH risk, also seen in nonlobar ICH recurrence,17,53 White 1567 1.12 (1.08-1.17) 35.42 were not replicated in this study. Potential explanations in- Hispanic 669 1.07 (1.00-1.15) 29.72 clude a higher rate of participants affected by hypertension Black 833 1.01 (0.97-1.06) 34.86 and an overall younger age of participants in this study. These Subtotal (I2 = 83.2%; P = .003) 1.07 (0.99-1.15) 100 factors may reflect the associations of environmental or Overall non-APOE genetic exposures in younger populations with non- (I2 = 83.2%; P = .003) 1.07 (0.99-1.15) 100 lobar ICH in particular. Demographic heterogeneity is also 0.8 1 2 higher in this study, and the reduced availability of covari- OR (95% CI) ates such as steady state lipid levels53 for risk modeling may have affected this finding. In addition, a previous meta- Weights are from random-effects analysis. analysis of APOE risks in ICH also did not show the associa- tion between APOE ε4 and nonlobar ICH in black individuals, toward the null; we expect that a more precise index of a finding supported by the present analyses.17 Future studies hypertension burden would have increased our ability to in larger data sets with well-phenotyped cases are needed to normalize this phenotype across race/ethnicity and to dem- further elucidate the potential role of APOE ε4 in nonlobar ICH. onstrate even more homogeneous APOE ε4 risks. Finally, genomewide genotypes for the ERICH study participants are Strengths and Limitations not currently available, preventing us from determining The targeted enrollment of Hispanic and black individuals whether additional genetic exposures modify the associa- through the ERICH study, lacking in previous reports,17,54 is tion of APOE with ICH risk across race/ethnicity. an important strength of the present study. The high number of nonwhite individuals enrolled permits well-powered analyses in these populations and promotes confidence that the lack of observed associations is not a false accep- Conclusions tance of the null hypothesis, as supported by our post hoc In this meta-analysis, APOE ε2 and ε4 alleles remain genetic power calculations. risk factors for lobar ICH, but these results are largely driven Some limitations of the study should be acknowledged. by the associations in white individuals. However, the Diagnoses of comorbidities were based on self-identified results support a biological risk of APOE ε4 alleles that attestation and therefore affected by patient or caregiver seems to transcend ancestral backgrounds, 55 albeit with awareness. This concern is present in both cases and con- varying effect because of the presence of racial/ethnic dis- trols, however, and internal consistency between diagnoses parities across associated risk factors. As availability of and prescribed medications helps to limit this potential genetic data on US minority populations continues to source of bias. Furthermore, the propensity score was increase, it is hoped that improved modeling of covarying based on variables that only partially captured the complex genetic and nongenetic exposures in these populations will phenotype represented by hypertension. However, this provide new insights into treatment and prevention strate- lack of information content is likely to bias our score results gies in ICH that maximize the potential advantages for all. ARTICLE INFORMATION Woo); Neurovascular Research Laboratory and Rehabilitation Medicine, Skåne University Hospital, Accepted for Publication: November 9, 2018. Neurovascular Unit, Institut de Recerca, Hospital Lund, Sweden (Hansen, Norrving, Lindgren); John Vall d’Hebron, Universitat Autonoma de Barcelona, P. Hussman Institute for Human Genomics, Published Online: February 6, 2019. Barcelona, Spain (Montaner, Fernandez-Cadenas, University of Miami, Miller School of Medicine, doi:10.1001/jamaneurol.2018.4519 Delgado); Institute de Biomedicine of Seville, Miami (McCauley); Stroke Center, Harborview Open Access: This is an open access article IBiS/Hospital Universitario Virgen del Rocío/CSIC/ Medical Center, University of Washington, Seattle distributed under the terms of the CC-BY License. University of Seville, Seville, Spain (Montaner); (Tirschwell); Department of Neurology, Stroke © 2019 Marini S et al. JAMA Neurology. Department of Neurology, Hospital Universitario Division, Beth Israel Deaconess Medical Center, Author Affiliations: Center for Genomic Medicine, Virgen Macarena, Seville, Spain (Montaner); Boston, Massachusetts (Selim); Cardiovascular Massachusetts General Hospital, Boston (Marini, Department of Neurology, Neurovascular Research Center, University of Michigan, Ann Arbor (Brown); Crawford, Rosand, Anderson); Stroke Unit, IRCCS Unit, Institut Hospital del Mar d’Investigacions Department of Neurology, University of Florida Mondino Foundation, Pavia, Italy (Morotti); Mèdiques, Universitat Autonoma de Barcelona, College of Medicine, Jacksonville (Silliman); Department of Neurology, Massachusetts General Barcelona, Spain (Roquer, Jimenez-Conde, Department of Neurology and Public Health Hospital, Boston (Lee, Goldstein, Viswanathan, Giralt-Steinhauer, Elosua, Cuadrado-Godia, Sciences, University of Virginia Health System, Greenberg, Rosand, Anderson); Department of Soriano-Tarraga); Department of Neurology, Charlottesville (Worrall); Department of Neurology, Clinical and Experimental Sciences, Neurology Jagiellonian University Medical College, Krakow, Mayo Clinic, Jacksonville, Florida (Meschia); Clinic, University of Brescia, Brescia, Italy (Pezzini); Poland (Slowik, Jagiella, Pera, Urbanik, Pichler); Department of Neurology, University of Arizona, Department of Neurology and Rehabilitation Department of Clinical Sciences Lund, Neurology, Tucson (Kidwell); Department of Neurology and Medicine, University of Cincinnati College of Lund University, Lund, Sweden (Hansen, Norrving, Rehabilitation, University of Illinois College of Medicine, Cincinnati, Ohio (Moomaw, Flaherty, Lindgren); Department of Neurology and Medicine, Chicago (Testai); Department of jamaneurology.com (Reprinted) JAMA Neurology April 2019 Volume 76, Number 4 487 Downloaded From: https://jamanetwork.com/ on 01/29/2021 Research Original Investigation Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Neurology, Baltimore Veterans Administration Other - management of phenotyping data: of Medicine, Site co-investigator); Sudha Seshadri, Medical Center and University of Maryland School Fernandez-Cadenas. MD (Boston University School of Medicine, Site of Medicine, Baltimore (Kittner); Department of Other - data management: Moomaw. co-investigator); Paul de Bakker, PhD (Brigham and Neurology, Medical University of Graz, Graz, Austria Conflict of Interest Disclosures: Dr Anderson Women's Hospital, Site co-investigator); Daniel (Schmidt, Enzinger); Centre for Cognitive Ageing reported receiving grants from the National Institutes Chasman, MD (Brigham and Women's Hospital, Site and Cognitive Epidemiology, University of of Health, the American Heart Association, and the co-investigator); Kathryn Rexrode, MD (Brigham Edinburgh, Edinburgh, United Kingdom (Deary); Massachusetts General Hospital Center for Genomic and Women's Hospital, Harvard Medical School, Centre for Clinical Brain Sciences, University of Medicine, and having consulted for ApoPharma Inc. Site co-investigator); Ida Chen, MD (Cedars Sinai Edinburgh, Edinburgh, United Kingdom Prof Klijn reported receiving a clinical established Medical Center, Site co-investigator); Jerome (Rannikmae, Samarasekera, Salman); Centre for investigator grant (2012T077) from the Dutch Heart Rotter, MD (Cedars Sinai Medical Center, Site Medical Informatics, Usher Institute of Population Foundation and an Aspasia grant (045008048) from co-investigator); May Luke, MD (Celera, Site Health Sciences and Informatics, University of ZonMw. No other disclosures were reported. co-investigator); Michelle Sale, MD (University of Edinburgh, Edinburgh, United Kingdom (Sudlow); Virginia, Site co-investigator); Tsong-Hai Lee, MD Department of Neurology, Radboud University Funding/Support: This study was funded by grants (Chang Gung Memorial Hospital, Linkou Medical Medical Centre, Donders Institute for Brain, K23NS086873, R01NS103924, U01NS069763, Center, Site co-investigator); Ku-Chou Chang, MD Cognition and Behaviour, Nijmegen, the R01NS093870, R01AG047975, R01AG026484, (Chang Gung Memorial Hospital; College of Netherlands (Klijn, van Nieuwenhuizen); P50AG005134, and K23AG02872605 from the NIH Medicine, Chang Gung University, Site Department of Neurology and Neurosurgery, Brain National Institute of Neurological Disorders and co-investigator); Mitchell Elkind, MD, MS (Columbia Center Rudolf Magnus, University Medical Center Stroke; a Yale Pepper Scholar Award University, Site co-investigator); Larry Goldstein, Utrecht, Utrecht, the Netherlands (Klijn, (P30AG021342) and the Neurocritical Care Society MD, PhD (Duke University, Site co-investigator); van Nieuwenhuizen); Stroke Pharmacogenomics Research Fellowship (Dr Falcone); an American Michael (Luke) James, MD (Duke University, Site and Genetics, Sant Pau Institute of Research, Heart Association fellowship (18POST34080063) co-investigator); Monique Breteler, MD (Erasmus Hospital de la Santa Creu i Sant Pau, Barcelona, (Dr Marini); and a United Kingdom Medical University, Site co-investigator); Chris O'Donnell, Spain (Fernandez-Cadenas); Division of Research Council/Stroke Association Clinical MD (Framingham Heart Study, Site co-investigator); Neurocritical Care and Emergency Neurology, Research Training Fellowship and a United Kingdom Didier Leys, MD (France, Site co-investigator); Cara Department of Neurology, Yale University School of Medical Research Council Senior Clinical Fellowship. Carty, MD (Fred Hutchinson Cancer Research Medicine, New Haven, Connecticut (Falcone); The Lothian Birth Cohort 1936 is supported by Age Center, Site co-investigator); Chelsea Kidwell, MD Center for Neuroepidemiology and Clinical UK (The Disconnected Mind project), the Medical (Georgetown University, Site co-investigator); Jes Neurological Research, Yale School of Medicine, Research Council (MR/M01311/1), and the Centre for Olesen, MD (Glostrup Hospital, Site Yale University, New Haven, Connecticut (Falcone); Cognitive Ageing and Cognitive Epidemiology co-investigator); Pankaj Sharma, MD, PhD Division of Behavioral Neurology, Massachusetts (which is funded by the Medical Research Council (Hammersmith Hospitals & Imperial College General Hospital, Boston (Biffi); Center for Public and the Biotechnology and Biological Sciences London, Site co-investigator); Stephen Rich, MD, Health Genomics and Department of Biostatistical Research Council [MR/K026992/1]). The Edinburgh PhD (University of Virginia Health System, Site Sciences, Wake Forest University, Winston-Salem, Stroke Study was supported by the Wellcome Trust co-investigator); Turgot Tatlisumak, MD (Helsinki North Carolina (Langefeld); Program in Medical and and the Binks Trust. Sample processing occurred in University Central Hospital, Site co-investigator); Population Genetics, Broad Institute, Cambridge, the Genetics Core Laboratory of the Wellcome Trust Olli Happola, MD (Helsinki University Central Massachusetts (Rosand, Anderson). Clinical Research Facility, Western General Hospital. Hospital, Site co-investigator); Philippe Bijlenga, Much of the neuroimaging occurred in the Scottish MD (Hôpitaux Universityersitaires de Genève, Site Author Contributions: Dr Marini had full access to Funding Council Brain Imaging Research Centre, all of the data in the study and takes responsibility co-investigator); Carolina Soriano, MD; University of Edinburgh, a core area of the (IMIM-Hospital del Mar, Site co-investigator); Eva for the integrity of the data and the accuracy of the Wellcome Trust Clinical Research Facility and part of data analysis. Giralt, MD (IMIM-Hospital del Mar, Site the Scottish Imaging Network–A Platform for co-investigator); Jaume Roquer, MD (IMIM-Hospital Concept and design: Marini, Meschia, Lindgren, Scientific Excellence collaboration (funded by the Langefeld, Woo, Rosand, Anderson. del Mar, Site co-investigator); Jordi Jimenez-Conde, Scottish Funding Council and the Chief Scientist MD (IMIM-Hospital del Mar, Site co-investigator); Acquisition, analysis, or interpretation of data: Office). Lund Stroke Register is supported by the All authors. Ioana Cotlarcius, MD (Imperial College London, Site Swedish Heart and Lung Foundation, Region Skåne, co-investigator); John Hardy, MD (Institute of Drafting of the manuscript: Marini, Crawford, Lee, Skåne University Hospital, the Freemasons Lodge Meschia, Anderson. Neurology, UCL, Site co-investigator); Michal of Instruction EOS in Lund, King Gustaf V and Korostynski, MD (Institute of Pharmacology, Critical revision of the manuscript for important Queen Victoria’s Foundation, Lund University, the intellectual content: Marini, Crawford, Morotti, Krakow, Poland, Site co-investigator); Giorgio Foundation of Färs & Frosta (one of Sparbanken Boncoraglio, MD (IRCCS Istituto neurologico Carlo Pezzini, Moomaw, Flaherty, Montaner, Roquer, Skåne’s ownership Foundations), and the Swedish Jiménez-Conde, Giralt Steinhauer, Elosua, Besta, Site co-investigator); Elena Ballabio, MD Stroke Association. ICH case and control (IRCCS Istituto neurologico Carlo Besta, Site Cuadrado-Godia, Soriano-Tárraga, Slowik, recruitment from Spain has been supported by the Jagiella, Pera, Urbanik, Pichler, Hansen, co-investigator); Eugenio Parati, MD (IRCCS Istituto Spain Ministry of Health Instituto de Salud Carlos III neurologico Carlo Besta, Site co-investigator); McCauley, Tirschwell, Selim, Brown, Silliman, FEDER RD16/0019/0002.INVICTUS-PLUS. Worrall, Meschia, Kidwell, Testai, Kittner, Schmidt, Adamski Mateusz, MD (Jagiellonian University, Site Enzinger, Deary, Rannikmae, Samarasekera, Role of the Funder/Sponsor: The funding sources co-investigator); Andrzej Urbanik, MD (Jagiellonian Al-Shahi Salman, Sudlow, Klijn, had no role in the design and conduct of the study; University, Site co-investigator); Tomasz Dziedzic, van Nieuwenhuizen, Fernandez-Cadenas, collection, management, analysis, and MD (Jagiellonian University, Site co-investigator); Delgado, Norrving, Lindgren, Goldstein, interpretation of the data; preparation, review, or Jeremiasz Jagiella, MD (Jagiellonian University, Site Viswanathan, Greenberg, Falcone, Biffi, approval of the manuscript; and decision to submit co-investigator); Jerzy Gasowski, MD (Jagiellonian Langefeld, Woo, Rosand, Anderson. the manuscript for publication. University, Site co-investigator); Marcin Wnuk, MD Statistical analysis: Marini, Langefeld. The International Stroke Genetics Consortium: (Jagiellonian University, Site co-investigator); Rafał Obtained funding: Elosua, Schmidt, Deary, Sylvia Smoller, PhD (Albert Einstein College of Olszanecki, MD (Jagiellonian University, Site Al-Shahi Salman, Sudlow, Fernandez-Cadenas, Medicine, Site co-investigator); John Sorkin, MD co-investigator); Joanna Pera, MD (Jagiellonian Lindgren, Viswanathan, Woo, Rosand, Anderson. (Baltimore VA Medical Center, Site co-investigator); University, Site co-investigator); Agnieszka Slowik, Administrative, technical, or material support: Xingwu Wang, MD (Beijing Hypertension League MD (Jagiellonian University, Site co-investigator); Crawford, Morotti, Lee, Pezzini, Roquer, Institute, Site co-investigator); Magdy Selim, MD, Karol Józef Juchniewicz, MD (Jagiellonian Giralt Steinhauer, Elosua, Soriano-Tárraga, Slowik, PhD (Beth Israel Deaconess Medical Center, Site University, Site co-investigator); Christopher Levi, Jagiella, McCauley, Meschia, Testai, Enzinger, co-investigator); Aleksandra Pikula, MD, PhD MD (John Hunter Hospital, University of Newcastle, Deary, Al-Shahi Salman, Klijn, Lindgren, (Boston University Medical Center, Site Site co-investigator); Paul Nyquist, MD, PhD (Johns Goldstein, Biffi, Rosand. co-investigator); Philip Wolf, MD, PhD (Boston Hopkins School of Medicine, Scientific committee); Supervision: Marini, Montaner, Soriano-Tárraga, University School of Medicine, Site co-investigator); Iscia Cendes, MD (Joinville Biobank, Site Urbanik, Deary, Viswanathan, Rosand, Anderson. Stephanie Debette, MD (Boston University School co-investigator); Norberto Cabral, MD (Joinville 488 JAMA Neurology April 2019 Volume 76, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 01/29/2021 Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Original Investigation Research Biobank, Site co-investigator); Paulo Franca, MD (Ludwig-Maximilians-Univeritat Munchen, Site David Werring, MD (University College London, Site (Joinville Biobank, Site co-investigator); Anderson co-investigator); Zhen Deng, MD (Nanfang co-investigator); Reecha Sofat, MD (University Goncalves, MD (Joinville Biobank, Site Hospital, Southern Medical University, Site College London, Site co-investigator); June Smalley, co-investigator); Lina Keller, MD (Karolinska co-investigator); Taura Barr, MD (National Institutes MD (University College London, Site Institutet, Site co-investigator); Milita Crisby, MD of Health, Site co-investigator); Katrina Gwinn, MD co-investigator); Arne Lindgren, MD (University (Karolinska Institutet, Sweden, Site (National Institutes of Health, Site co-investigator); Hospital Lund, Steering committee, Scientific co-investigator); Konstantinos Kostulas, MD Roderick Corriveau, MD (National Institutes of committee); Bjorn Hansen, BA (University Hospital (Karolinska Institutet; Karolinska University Health, Site co-investigator); Andrew Singleton, Lund, Site co-investigator); Bo Norrving, MD Hospital, Huddinge unit, Site co-investigator); MD, PhD (National Institutes of Health, Site (University Hospital Lund, Site co-investigator); Robin Lemmens, MD (KULeuven, Site co-investigator); Salina Waddy, MD (National Gustav Smith, MD (University Hospital Lund, Site co-investigator); Kourosh Ahmadi, MD (London, Institutes of Health, Site co-investigator); Lenore co-investigator); Juan José Martín, MD (University Site co-investigator); Christian Opherk, MD Launer, MD (National Institutes of Health, Site Hospital Sanatorio Allende; Córdoba, Argentine, (Ludwig-Maximilians-Univeritat Munchen, Site co-investigator); Christopher Chen, MD (National Site co-investigator); Vincent Thijs, MD (University co-investigator); Marco Duering, MD Neuroscience Institute, Singapore General Hospital, Hospitals Leuven, Site co-investigator); Karin Klijn, (Ludwig-Maximilians-Univeritat Munchen, Site co-investigator); Kim En Le, MD (National MD (University Medical Center Utrecht, Site Site co-investigator); Martin Dichgans, MD Neuroscience Institute, Singapore General Hospital, co-investigator); Femke van't Hof, MD, PhD (Ludwig-Maximilians-Univeritat Munchen, Site Site co-investigator); Wei Ling Lee, MD (National (University Medical Center Utrecht, Site co-investigator); Rainer Malik, PhD Neuroscience Institute, Singapore General Hospital, co-investigator); Ale Algra, MD (University Medical (Ludwig-Maximilians-Univeritat Munchen, Site co-investigator); Eng King Tan, MD (National Center Utrecht, Site co-investigator); Mary Site co-investigator); Mariya Gonik, MD Neuroscience Institute, Singapore General Hospital, Macleod, MD (University of Aberdeen, Site (Ludwig-Maximilians-Univeritat Munchen, Site Site co-investigator); Akintomi Olugbodi, MD co-investigator); Rodney Perry, MD (University of co-investigator); Julie Staals, MD (Maastricht (Obafemi Awolowo University, Site co-investigator); Alabama at Birmingham School of Public Health, University Medical Centre, Maastricht, the Peter Rothwell, MD, PhD (Oxford; Radcliffe Site co-investigator); Donna Arnett, MD (University Netherlands, Site co-investigator); Olle Melander, Infirmary, Site co-investigator); Sabrina Schilling, of Alabama at Birmingham School of Public Health, MD, PhD (Malmo University Hospital, Site MD (Paris, France, Site co-investigator); Vincent Site co-investigator); Alessandro Pezzini, MD co-investigator); Philippe Burri, MD (Malmo Mok, MD (Prince of Wales Hospital, The Chinese (University of Brescia, Site co-investigator); University Hospital, Site co-investigator); Ariane University of Hong Kong, Site co-investigator); Alessandro Padovani, MD (University of Brescia, Sadr-Nabavi, MD (Mashhad University of Medical Elena Lebedeva, MD (Russia, Site co-investigator); Site co-investigator); Steve Cramer, MD, PhD Sciences, Site co-investigator); Javier Romero, MD, Christina Jern, MD (Sahlgrenska University (University of California Irvine, Site co-investigator); PhD (Massachusetts General Hospital, Site Hospital, Scientific committee); Katarina Jood, MD Mark Fisher, MD (University of California Irvine, Site co-investigator); Alessandro Biffi, MD (Sahlgrenska University Hospital, Site co-investigator); Danish Saleheen, MD (University (Massachusetts General Hospital, Site co-investigator); Sandra Olsson, MD (Sahlgrenska of Pennsylvania, Site co-investigator); Joseph co-investigator); Chris Anderson, MD University Hospital, Site co-investigator); Helen Broderick, MD (University of Cincinnati, Site (Massachusetts General Hospital, Site Kim, MD (San Francisco General Hospital; Center for co-investigator); Brett Kissela, MD (University of co-investigator); Guido Falcone, MD Cerebrovascular Research, Site co-investigator); Cincinnati, Site co-investigator); Alex Doney, MD (Massachusetts General Hospital, Site Chaeyoung Lee, MD (Soongsil University, Site (University of Dundee, Site co-investigator); Cathie co-investigator); Bart Brouwers, MD co-investigator); Laura Kilarski, MD (St. George's Sudlow, MD (University of Edinburgh; Western (Massachusetts General Hospital, Site University of London, Site co-investigator); Hugh General Hospital, Steering committee); Kristiina co-investigator); Jonathan Rosand, MD, MSc Markus, MD (St. George's, University of London, Rannikmae, MD (University of Edinburgh; Western (Massachusetts General Hospital, Site Site co-investigator); Jennifer Peycke, MD (St. General Hospital, Site co-investigator); Scott co-investigator); Natalia Rost, MD, MSc George's, University of London, Site Silliman, MD (University of Florida, Site (Massachusetts General Hospital, Site co-investigator); Steve Bevan, PhD (St. George's, co-investigator); Caitrin McDonough, MD co-investigator); Rose Du, MD (Massachusetts University of London, Site co-investigator); Wayne (University of Florida, Site co-investigator); General Hospital, Site co-investigator); Christina Sheu, MD (Taichung Veterans General Hospital, Site Matthew Walters, MD (University of Glasgow, Site Kourkoulis, BA (Massachusetts General Hospital, co-investigator); Hung Yi Chiou, MD (Taipei Medical co-investigator); Annie Pedersen, MD (University of Site co-investigator); Thomas Battey, BA University, Site co-investigator); Joseph Chern, MD Gothenburg, Site co-investigator); Kazuma (Massachusetts General Hospital, Site (Taipei Medical University, Site co-investigator); Nakagawa, MD(University of Hawaii, Site co-investigator); Steven Lubitz, MD, PhD Elias Giraldo, MD (The University of Tennessee co-investigator); Christy Chang, MD (University of (Massachusetts General Hospital, Site Health Science Center at Memphis, Site Maryland, Site co-investigator); Mark Dobbins, MD co-investigator); Bertram Mueller-Myhsok, MD co-investigator); Muhammad Taqi, MD (The (University of Maryland,, Site co-investigator); (Max Planck Institute of Psychiatry, Munich, Site University of Tennessee Health Science Center at Patrick McArdle, PhD (University of Maryland, Site co-investigator); James Meschia, MD (Mayo Clinic, Memphis, Site co-investigator); Vivek Jain, MD (UC co-investigator); Yu-Ching Chang, MD (University of Steering committee); Thomas Brott, MD, PhD Irvine Medical Center, Site co-investigator); Olivia Maryland, Site co-investigator); Robert Brown, MD (Mayo Clinic, Site co-investigator); Guillaume Pare, Lam, MD (University of California San Francisco, (University of Michigan, Site co-investigator); Devin MD (McMaster University, Steering committee, Site co-investigator); George Howard, MD Brown, MD (University of Michigan, Site Scientific committee); Alexander Pichler, MD (University of Alabama School of Public Health, Site co-investigator); Elizabeth Holliday, MD (University (Medical University Graz, Site co-investigator); co-investigator); Daniel Woo, MD (University of of Newcastle, Site co-investigator); Raj Kalaria, MD Christian Enzinger, MD (Medical University Graz, Cincinnati, Steering committee); Steven Kittner, MD (University of Newcastle, Site co-investigator); Jane Site co-investigator); Helena Schmidt, MD (Medical (University of Maryland Hospital, Site Maguire, MD (University of Newcastle; John Hunter University Graz, Site co-investigator); Reinhold co-investigator); Braxton Mitchell, PhD, MPH Hospital, Steering committee); John Attia, MD Schmidt, MD (Medical University Graz, Site (University of Maryland School of Medicine, Site (University of Newcastle; John Hunter Hospital, co-investigator); Stephan Seiler, MD (Medical co-investigator); John Cole, MD (University of Site co-investigator); Martin Farrall, MD (University University Graz, Site co-investigator); Susan Maryland School of Medicine, Site co-investigator); of Oxford; Wellcome Trust Center for Human Blanton, MD (Miami Institute of Human Genomics; Jeff O'Connell, MD (University of Maryland School Genetics, Site co-investigator); Anne-Katrin Giese, University of Miami Miller School of Medicine, Site of Medicine, Site co-investigator); Dianna Milewicz, MD (University of Rostock, Germany, Site co-investigator); Yoshiji Yamada, MD (Mie MD (University of Texas Medical School at Houston, co-investigator); Myriam Fornage, MD (University University, Site co-investigator); Anna Bersano, MD Site co-investigator); Kachikwu Illoh, MD of Texas- Houston; Health Sciences Center, (Milan University, Site co-investigator); Tatjana (University of Texas-Houston, Site co-investigator); Scientific committee); Jennifer Majersik, MD Rundek, MD (University of Miami, Site Bradford Worrall, MD (University of Virginia Health (University of Utah, Scientific committee); Mary co-investigator); Ralph Sacco, MD (University of System, Site co-investigator); Colin Stine, MD Cushman, MD (University of Vermont and Fletcher Miami, Site co-investigator); Yu-Feng Yvonne Chan, (University. of MD School of Medicine, Site Allen Health Care, Site co-investigator); Keith MD (Mount Sinai Medical Center, Site co-investigator); Bartosz Karaszewski, MD Keene, MD (University of Virginia, USA, Site co-investigator); Andreas Gschwendtner, MD, PhD (University College London, Site co-investigator); co-investigator); Siiri Bennett, MD (University of jamaneurology.com (Reprinted) JAMA Neurology April 2019 Volume 76, Number 4 489 Downloaded From: https://jamanetwork.com/ on 01/29/2021 Research Original Investigation Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Washington, Site co-investigator); David Tirschwell, for intracerebral hemorrhage in a pooled 24. Deary IJ, Gow AJ, Pattie A, Starr JM. Cohort MD, MSc (University of Washington, Site prospective study. Stroke. 2007;38(10):2718-2725. profile: the lothian birth cohorts of 1921 and 1936. co-investigator); Bruce Psaty, MD (University of doi:10.1161/STROKEAHA.107.487090 Int J Epidemiol. 2012;41(6):1576-1584. doi:10.1093/ Washington, USA, Site co-investigator); Alex Reiner, 10. Carpenter AM, Singh IP, Gandhi CD, ije/dyr197 MD (University of Washington, USA, Site Prestigiacomo CJ. Genetic risk factors for 25. Pezzini A, Grassi M, Iacoviello L, et al; co-investigator); Will Longstreth, MD (University of spontaneous intracerebral haemorrhage. Nat Rev Multicenter Study on Cerebral Haemorrhage in Italy Washington; Harborview Medical Center, Site Neurol. 2016;12(1):40-49. doi:10.1038/ (MUCH-Italy) Investigators. Serum cholesterol co-investigator); David Spence, MD (University of nrneurol.2015.226 levels, HMG-CoA reductase inhibitors and the risk Western Ontario, Robarts Research Institute, Site of intracerebral haemorrhage. J Neurol Neurosurg co-investigator); Joan Montaner, MD (Vall d’Hebron 11. Reitz C, Mayeux R. Genetics of Alzheimer’s disease in Caribbean Hispanic and African American Psychiatry. 2016;87(9):924-929. doi:10.1136/ Hospital, Site co-investigator); Israel jnnp-2015-312736 Fernandez-Cadenas, MD (Vall d’Hebron Hospital, populations. Biol Psychiatry. 2014;75(7):534-541. Steering committee); Carl Langefeld, MD (Wake doi:10.1016/j.biopsych.2013.06.003 26. Woo D, Falcone GJ, Devan WJ, et al; Forest University, Site co-investigator); Cheryl 12. Murrell JR, Price B, Lane KA, et al. Association International Stroke Genetics Consortium. Bushnell, MD (Wake Forest University Health of apolipoprotein E genotype and Alzheimer Meta-analysis of genome-wide association studies Sciences, Site co-investigator); Laura Heitsch, MD disease in African Americans. Arch Neurol. 2006;63 identifies 1q22 as a susceptibility locus for (Washington University of St. Louis, Site (3):431-434. doi:10.1001/archneur.63.3.431 intracerebral hemorrhage. Am J Hum Genet. 2014; co-investigator); Jin-Moo Lee, MD, PhD 94(4):511-521. doi:10.1016/j.ajhg.2014.02.012 13. Michaelson DM. APOE ε4: the most prevalent (Washington University of St. Louis, Site yet understudied risk factor for Alzheimer’s disease. 27. Anderson CD, Falcone GJ, Phuah CL, et al; co-investigator); Kevin Sheth, MD (Yale New Haven Alzheimers Dement. 2014;10(6):861-868. doi:10. Global Lipids Genetics Consortium and Hospital, Yale School of Medicine, Site 1016/j.jalz.2014.06.015 International Stroke Genetics Consortium. Genetic co-investigator). variants in CETP increase risk of intracerebral 14. Taylor MR, Sun AY, Davis G, Fiuzat M, Liggett hemorrhage. Ann Neurol. 2016;80(5):730-740. doi: Meeting Presentation: The results of this study SB, Bristow MR. Race, common genetic variation, were presented at the American Heart Association 10.1002/ana.24780 and therapeutic response disparities in heart 2019 International Stroke Conference; February 6, failure. JACC Heart Fail. 2014;2(6):561-572. doi:10. 28. Marini S, Morotti A, Ayres AM, et al. Sex 2019; Honolulu, Hawaii. 1016/j.jchf.2014.06.010 differences in intracerebral hemorrhage expansion and mortality. J Neurol Sci. 2017;379:112-116. doi:10. REFERENCES 15. Popejoy AB, Fullerton SM. Genomics is failing 1016/j.jns.2017.05.057 on diversity. Nature. 2016;538(7624):161-164. doi: 1. An SJ, Kim TJ, Yoon B-W. Epidemiology, Risk 10.1038/538161a 29. Woo D, Kissela BM, Khoury JC, et al. Factors, and Clinical Features of Intracerebral Hypercholesterolemia, HMG-CoA reductase Hemorrhage: An Update. J Stroke. 2017;19(1):3-10. 16. Anderson CD, Nalls MA, Biffi A, et al. The effect inhibitors, and risk of intracerebral hemorrhage: doi:10.5853/jos.2016.00864 of survival bias on case-control genetic association a case-control study. Stroke. 2004;35(6):1360-1364. studies of highly lethal diseases. Circ Cardiovasc doi:10.1161/01.STR.0000127786.16612.A4 2. Krishnamurthi RV, Moran AE, Forouzanfar MH, Genet. 2011;4(2):188-196. doi:10.1161/CIRCGENETICS. et al; Global Burden of Diseases, Injuries, and Risk 110.957928 30. Koch W, Ehrenhaft A, Griesser K, et al. TaqMan Factors 2010 Study Stroke Expert Group. The global systems for genotyping of disease-related burden of hemorrhagic stroke: a summary of 17. Biffi A, Sonni A, Anderson CD, et al; polymorphisms present in the gene encoding findings from the GBD 2010 study. Glob Heart. International Stroke Genetics Consortium. Variants apolipoprotein E. Clin Chem Lab Med. 2002;40(11): 2014;9(1):101-106. doi:10.1016/j.gheart.2014.01.003 at APOE influence risk of deep and lobar 1123-1131. doi:10.1515/cclm.2002.197 intracerebral hemorrhage. Ann Neurol. 2010;68(6): 3. Qureshi AI, Giles WH, Croft JB. Racial differences 934-943. doi:10.1002/ana.22134 31. Anderson CA, Pettersson FH, Clarke GM, in the incidence of intracerebral hemorrhage: Cardon LR, Morris AP, Zondervan KT. Data quality effects of blood pressure and education. Neurology. 18. Woo D, Sauerbeck LR, Kissela BM, et al. Genetic control in genetic case-control association studies. 1999;52(8):1617-1621. doi:10.1212/WNL.52.8.1617 and environmental risk factors for intracerebral Nat Protoc. 2010;5(9):1564-1573. doi:10.1038/ hemorrhage: preliminary results of a nprot.2010.116 4. Broderick JP, Brott T, Tomsick T, Huster G, Miller population-based study. Stroke. 2002;33(5):1190- R. The risk of subarachnoid and intracerebral 1195. doi:10.1161/01.STR.0000014774.88027.22 32. Purcell S, Neale B, Todd-Brown K, et al. PLINK: hemorrhages in blacks as compared with whites. a tool set for whole-genome association and N Engl J Med. 1992;326(11):733-736. doi:10.1056/ 19. Woo D, Rosand J, Kidwell C, et al. The population-based linkage analyses. Am J Hum Genet. NEJM199203123261103 ethnic/racial variations of intracerebral hemorrhage 2007;81(3):559-575. doi:10.1086/519795 (ERICH) study protocol. Stroke. 2013;44(10):e120- 5. Labovitz DL, Halim A, Boden-Albala B, Hauser e125. doi:10.1161/STROKEAHA.113.002332 33. Biffi A, Anderson CD, Desikan RS, et al; WA, Sacco RL. The incidence of deep and lobar Alzheimer’s Disease Neuroimaging Initiative intracerebral hemorrhage in whites, blacks, and 20. Gomis M, Ois A, Rodríguez-Campello A, et al. (ADNI). Genetic variation and neuroimaging Hispanics. Neurology. 2005;65(4):518-522. doi:10. Outcome of intracerebral haemorrhage patients measures in Alzheimer disease. Arch Neurol. 2010; 1212/01.wnl.0000172915.71933.00 pre-treated with statins. Eur J Neurol. 2010;17(3): 67(6):677-685. doi:10.1001/archneurol.2010.108 443-448. doi:10.1111/j.1468-1331.2009.02838.x 6. van Asch CJJ, Luitse MJA, Rinkel GJ, van der 34. Price AL, Patterson NJ, Plenge RM, Weinblatt Tweel I, Algra A, Klijn CJM. Incidence, case fatality, 21. Domingues-Montanari S, Hernandez-Guillamon ME, Shadick NA, Reich D. Principal components and functional outcome of intracerebral M, Fernandez-Cadenas I, et al; Stroke Project analysis corrects for stratification in genome-wide haemorrhage over time, according to age, sex, and Cerebrovascular Diseases Study Group, Spanish association studies. Nat Genet. 2006;38(8):904- ethnic origin: a systematic review and Society of Neurology. ACE variants and risk of 909. doi:10.1038/ng1847 meta-analysis. Lancet Neurol. 2010;9(2):167-176. intracerebral hemorrhage recurrence in amyloid angiopathy. Neurobiol Aging. 2011;32(3):551.e13- 35. Marini S, Lena UK, Crawford KM, et al. doi:10.1016/S1474-4422(09)70340-0 Comparison of Genetic and Self-Identified Ancestry 551.e22. doi:10.1016/j.neurobiolaging.2010.01.019 7. Giles T, Aranda JM Jr, Suh DC, et al. Ethnic/racial in Modeling Intracerebral Hemorrhage Risk. Front variations in blood pressure awareness, treatment, 22. Pera J, Slowik A, Dziedzic T, Pulyk R, Wloch D, Neurol. 2018;9:514. https://www.frontiersin.org/ and control. J Clin Hypertens (Greenwich). 2007;9 Szczudlik A. Glutathione peroxidase 1 C593T article/10.3389/fneur.2018.00514. doi:10.3389/fneur. (5):345-354. doi:10.1111/j.1524-6175.2007.06432.x polymorphism is associated with lobar intracerebral 2018.00514 hemorrhage. Cerebrovasc Dis. 2008;25(5):445-449. 8. Walsh KB, Woo D, Sekar P, et al. Untreated doi:10.1159/000126918 36. Devan WJ, Falcone GJ, Anderson CD, et al; Hypertension: A Powerful Risk Factor for Lobar and International Stroke Genetics Consortium. Nonlobar Intracerebral Hemorrhage in Whites, 23. Hallström B, Jönsson AC, Nerbrand C, Norrving Heritability estimates identify a substantial genetic Blacks, and Hispanics. Circulation. 2016;134(19): B, Lindgren A. Stroke incidence and survival in the contribution to risk and outcome of intracerebral 1444-1452. doi:10.1161/CIRCULATIONAHA.116.024073 beginning of the 21st century in southern Sweden: hemorrhage. Stroke. 2013;44(6):1578-1583. doi:10. comparisons with the late 20th century and 1161/STROKEAHA.111.000089 9. Sturgeon JD, Folsom AR, Longstreth WT Jr, projections into the future. Stroke. 2008;39(1): Shahar E, Rosamond WD, Cushman M. Risk factors 10-15. doi:10.1161/STROKEAHA.107.491779 490 JAMA Neurology April 2019 Volume 76, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 01/29/2021 Association of APOE With Intracerebral Hemorrhage Risk by Race/Ethnicity Original Investigation Research 37. Hong J, Lunetta KL, Cupples LA, Dupuis J, Liu 44. Farrer LA, Cupples LA, Haines JL, et al; APOE 50. Maestre G, Ottman R, Stern Y, et al. CT. Evaluation of a Two-Stage Approach in and Alzheimer Disease Meta Analysis Consortium. Apolipoprotein E and Alzheimer’s disease: ethnic Trans-Ethnic Meta-Analysis in Genome-Wide Effects of age, sex, and ethnicity on the association variation in genotypic risks. Ann Neurol. 1995;37(2): Association Studies. Genet Epidemiol. 2016;40(4): between apolipoprotein E genotype and Alzheimer 254-259. doi:10.1002/ana.410370217 284-292. doi:10.1002/gepi.21963 disease. A meta-analysis. JAMA. 1997;278(16):1349- 51. Charidimou A, Martinez-Ramirez S, Reijmer YD, 38. DerSimonian R, Laird N. Meta-analysis in 1356. doi:10.1001/jama.1997.03550160069041 et al. Total magnetic resonance imaging burden of clinical trials revisited. Contemp Clin Trials. 2015;45 45. Evans DA, Bennett DA, Wilson RS, et al. small vessel disease in cerebral amyloid angiopathy: (Pt A):139-145. doi:10.1016/j.cct.2015.09.002 Incidence of Alzheimer disease in a biracial urban an imaging-pathologic study of concept validation. 39. Austin PC. An introduction to propensity score community: relation to apolipoprotein E allele JAMA Neurol. 2016;73(8):994-1001. doi:10.1001/ methods for reducing the effects of confounding in status. Arch Neurol. 2003;60(2):185-189. doi:10. jamaneurol.2016.0832 observational studies. Multivariate Behav Res. 2011; 1001/archneur.60.2.185 52. Smith EE, Greenberg SM. Clinical diagnosis of 46(3):399-424. doi:10.1080/00273171.2011.568786 46. Graff-Radford NR, Green RC, Go RCP, et al. cerebral amyloid angiopathy: validation of the 40. Ho D, Imai K, King G, Stuart E. Matching as Association between apolipoprotein E genotype Boston criteria. Curr Atheroscler Rep. 2003;5(4): nonparametric preprocessing for reducing model and Alzheimer disease in African American subjects. 260-266. doi:10.1007/s11883-003-0048-4 dependence in parametric causal inference. Polit Anal. Arch Neurol. 2002;59(4):594-600. doi:10.1001/ 53. Raffeld MR, Biffi A, Battey TW, et al. APOE ε4 2007;15(3):199-236. archneur.59.4.594 and lipid levels affect risk of recurrent nonlobar 41. Evans DM, Purcell S. Power calculations in 47. Tzourio C, Arima H, Harrap S, et al. APOE intracerebral hemorrhage. Neurology. 2015;85(4): genetic studies. Cold Spring Harb Protoc. 2012;2012 genotype, ethnicity, and the risk of cerebral 349-356. doi:10.1212/WNL.0000000000001790 (6):664-674. doi:10.1101/pdb.top069559 hemorrhage. Neurology. 2008;70(16):1322-1328. 54. Woo D, Kaushal R, Chakraborty R, et al. doi:10.1212/01.wnl.0000308819.43401.87 Association of apolipoprotein E4 and haplotypes of 42. Tang MX, Stern Y, Marder K, et al. The APOE-epsilon4 allele and the risk of Alzheimer 48. Sawyer RP, Sekar P, Osborne J, et al. the apolipoprotein E gene with lobar intracerebral disease among African Americans, whites, and Racial/ethnic variation of APOE alleles for lobar hemorrhage. Stroke. 2005;36(9):1874-1879. doi:10. Hispanics. JAMA. 1998;279(10):751-755. doi:10. intracerebral hemorrhage. Neurology. 2018;91(5): 1161/01.STR.0000177891.15082.b9 1001/jama.279.10.751 e410-e420. doi:10.1212/WNL. 55. Tai LM, Thomas R, Marottoli FM, et al. The role 0000000000005908 of APOE in cerebrovascular dysfunction. Acta 43. O’Bryant SE, Johnson L, Reisch J, et al. Risk factors for mild cognitive impairment among 49. Lee JH, Cheng R, Vardarajan B, et al. Genetic Neuropathol. 2016;131(5):709-723. doi:10.1007/ Mexican Americans. Alzheimers Dement. 2013;9(6): modifiers of age at onset in carriers of the G206A s00401-016-1547-z 622-631.e1. doi:10.1016/j.jalz.2012.12.007 mutation in PSEN1 with familial Alzheimer disease among Caribbean hispanics. JAMA Neurol. 2015;72 (9):1043-1051. doi:10.1001/jamaneurol.2015.1424 jamaneurology.com (Reprinted) JAMA Neurology April 2019 Volume 76, Number 4 491 Downloaded From: https://jamanetwork.com/ on 01/29/2021