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

Sandro Marini; Katherine Crawford; Andrea Morotti; Myung J. Lee; Alessandro Pezzini; Charles J. Moomaw; Matthew L. Flaherty; Joan Montaner; Jaume Roquer; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano-Tarraga; Agnieszka Slowik; Jeremiasz M. Jagiella; Joanna Pera; Andrzej Urbanik; Alexander Pichler; Bjorn M. Hansen; Jacob L. McCauley; David L. Tirschwell; Magdy Selim; Devin L. Brown; Scott L. Silliman; Bradford B. Worrall; James F. Meschia; Chelsea S. Kidwell; Fernando D. Testai; Steven J. Kittner; Helena Schmidt; Christian Enzinger; Lan J. Deary; Kristiina Rannikmae; Neshika Samarasekera; Rustam Al-Shahi Salman; Catherine L. Sudlow; Catharina J. M. Klijn; Koen M. van Nieuwenhuizen; Israel Fernandez-Cadenas; Pilar Delgado; Bo Nonving; Ame Lindgren; Joshua N. Goldstein; Anand Viswanathan; Steven M. Greenberg; Guido J. Falcone; Alessandro Biffi; Carl D. Langefeld; Julie Staals; International Stroke Genetics Consortium; Christopher D. Anderson

doi:10.1001/jamaneurol.2018.4519

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

Sandro Marini, Katherine Crawford, Andrea Morotti, Myung J. Lee, Alessandro Pezzini, Charles J. Moomaw, Matthew L. Flaherty, Joan Montaner, Jaume Roquer, Jordi Jimenez-Conde, Eva Giralt-Steinhauer, Roberto Elosua, Elisa Cuadrado-Godia, Carolina Soriano-Tarraga, Agnieszka Slowik, Jeremiasz M. Jagiella, Joanna Pera, Andrzej Urbanik, Alexander Pichler, Bjorn M. HansenJacob L. McCauley, David L. Tirschwell, Magdy Selim, Devin L. Brown, Scott L. Silliman, Bradford B. Worrall, James F. Meschia, Chelsea S. Kidwell, Fernando D. Testai, Steven J. Kittner, Helena Schmidt, Christian Enzinger, Lan J. Deary, Kristiina Rannikmae, Neshika Samarasekera, Rustam Al-Shahi Salman, Catherine L. Sudlow, Catharina J. M. Klijn, Koen M. van Nieuwenhuizen, Israel Fernandez-Cadenas, Pilar Delgado, Bo Nonving, Ame Lindgren, Joshua N. Goldstein, Anand Viswanathan, Steven M. Greenberg, Guido J. Falcone, Alessandro Biffi, Carl D. Langefeld, Julie Staals, International Stroke Genetics Consortium, Christopher D. Anderson^*

^*Corresponding author for this work

Carim - Cerebral small vessel disease

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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) epsilon 4 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 epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P <.001) and APOE epsilon 4 (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 epsilon 4 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 epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity.

CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 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.

Original language	English
Pages (from-to)	480-491
Number of pages	12
Journal	JAMA Neurology
Volume	76
Issue number	4
DOIs	https://doi.org/10.1001/jamaneurol.2018.4519
Publication status	Published - Apr 2019

Keywords

ALLELE
ALZHEIMER-DISEASE
APOE EPSILON-4
BLACKS
COA REDUCTASE INHIBITORS
E GENOTYPE
ETHNICITY
GENETIC-VARIATION
LOBAR
WHITES

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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., ... Anderson, C. D. (2019). Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis. JAMA Neurology, 76(4), 480-491. https://doi.org/10.1001/jamaneurol.2018.4519

@article{97f1b9d006c7400382749176a882a4b4,

title = "Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis",

abstract = "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) epsilon 4 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 epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P <.001) and APOE epsilon 4 (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 epsilon 4 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 epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity.CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 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.",

keywords = "ALLELE, ALZHEIMER-DISEASE, APOE EPSILON-4, BLACKS, COA REDUCTASE INHIBITORS, E GENOTYPE, ETHNICITY, GENETIC-VARIATION, LOBAR, WHITES",

author = "Sandro Marini and Katherine Crawford and Andrea Morotti and Lee, {Myung J.} and Alessandro Pezzini and Moomaw, {Charles J.} and Flaherty, {Matthew L.} and Joan Montaner and Jaume Roquer and Jordi Jimenez-Conde and Eva Giralt-Steinhauer and Roberto Elosua and Elisa Cuadrado-Godia and Carolina Soriano-Tarraga and Agnieszka Slowik and Jagiella, {Jeremiasz M.} and Joanna Pera and Andrzej Urbanik and Alexander Pichler and Hansen, {Bjorn M.} and McCauley, {Jacob L.} and Tirschwell, {David L.} and Magdy Selim and Brown, {Devin L.} and Silliman, {Scott L.} and Worrall, {Bradford B.} and Meschia, {James F.} and Kidwell, {Chelsea S.} and Testai, {Fernando D.} and Kittner, {Steven J.} and Helena Schmidt and Christian Enzinger and Deary, {Lan J.} and Kristiina Rannikmae and Neshika Samarasekera and Salman, {Rustam Al-Shahi} and Sudlow, {Catherine L.} and Klijn, {Catharina J. M.} and {van Nieuwenhuizen}, {Koen M.} and Israel Fernandez-Cadenas and Pilar Delgado and Bo Nonving and Ame Lindgren and Goldstein, {Joshua N.} and Anand Viswanathan and Greenberg, {Steven M.} and Falcone, {Guido J.} and Alessandro Biffi and Langefeld, {Carl D.} and Julie Staals and {International Stroke Genetics Consortium} and Anderson, {Christopher D.}",

year = "2019",

month = apr,

doi = "10.1001/jamaneurol.2018.4519",

language = "English",

volume = "76",

pages = "480--491",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "4",

}

Marini, S, Crawford, K, Morotti, A, Lee, MJ, Pezzini, A, Moomaw, CJ, Flaherty, ML, Montaner, J, Roquer, J, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano-Tarraga, C, Slowik, A, Jagiella, JM, Pera, J, Urbanik, A, Pichler, A, Hansen, BM, McCauley, JL, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Testai, FD, Kittner, SJ, Schmidt, H, Enzinger, C, Deary, LJ, Rannikmae, K, Samarasekera, N, Salman, RA-S, Sudlow, CL, Klijn, CJM, van Nieuwenhuizen, KM, Fernandez-Cadenas, I, Delgado, P, Nonving, B, Lindgren, A, Goldstein, JN, Viswanathan, A, Greenberg, SM, Falcone, GJ, Biffi, A, Langefeld, CD, Staals, J, International Stroke Genetics Consortium & Anderson, CD 2019, 'Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis', JAMA Neurology, vol. 76, no. 4, pp. 480-491. https://doi.org/10.1001/jamaneurol.2018.4519

TY - JOUR

T1 - Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis

AU - Marini, Sandro

AU - Crawford, Katherine

AU - Morotti, Andrea

AU - Lee, Myung J.

AU - Pezzini, Alessandro

AU - Moomaw, Charles J.

AU - Flaherty, Matthew L.

AU - Montaner, Joan

AU - Roquer, Jaume

AU - Jimenez-Conde, Jordi

AU - Giralt-Steinhauer, Eva

AU - Elosua, Roberto

AU - Cuadrado-Godia, Elisa

AU - Soriano-Tarraga, Carolina

AU - Slowik, Agnieszka

AU - Jagiella, Jeremiasz M.

AU - Pera, Joanna

AU - Urbanik, Andrzej

AU - Pichler, Alexander

AU - Hansen, Bjorn M.

AU - McCauley, Jacob L.

AU - Tirschwell, David L.

AU - Selim, Magdy

AU - Brown, Devin L.

AU - Silliman, Scott L.

AU - Worrall, Bradford B.

AU - Meschia, James F.

AU - Kidwell, Chelsea S.

AU - Testai, Fernando D.

AU - Kittner, Steven J.

AU - Schmidt, Helena

AU - Enzinger, Christian

AU - Deary, Lan J.

AU - Rannikmae, Kristiina

AU - Samarasekera, Neshika

AU - Salman, Rustam Al-Shahi

AU - Sudlow, Catherine L.

AU - Klijn, Catharina J. M.

AU - van Nieuwenhuizen, Koen M.

AU - Fernandez-Cadenas, Israel

AU - Delgado, Pilar

AU - Nonving, Bo

AU - Lindgren, Ame

AU - Goldstein, Joshua N.

AU - Viswanathan, Anand

AU - Greenberg, Steven M.

AU - Falcone, Guido J.

AU - Biffi, Alessandro

AU - Langefeld, Carl D.

AU - Staals, Julie

AU - International Stroke Genetics Consortium

AU - Anderson, Christopher D.

PY - 2019/4

Y1 - 2019/4

N2 - 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) epsilon 4 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 epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P <.001) and APOE epsilon 4 (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 epsilon 4 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 epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity.CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 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.

AB - 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) epsilon 4 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 epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P <.001) and APOE epsilon 4 (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 epsilon 4 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 epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity.CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 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.

KW - ALLELE

KW - ALZHEIMER-DISEASE

KW - APOE EPSILON-4

KW - BLACKS

KW - COA REDUCTASE INHIBITORS

KW - E GENOTYPE

KW - ETHNICITY

KW - GENETIC-VARIATION

KW - LOBAR

KW - WHITES

U2 - 10.1001/jamaneurol.2018.4519

DO - 10.1001/jamaneurol.2018.4519

M3 - Article

C2 - 30726504

SN - 2168-6149

VL - 76

SP - 480

EP - 491

JO - JAMA Neurology

JF - JAMA Neurology

IS - 4

ER -

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

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