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1. PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

Author

Mola-Caminal, Marina, Carrera, Caty, Soriano-Tárraga, Carolina, Giralt-Steinhauer, Eva, Díaz-Navarro, Rosa M., Tur, Sílvia, Jiménez, Carmen, Medina-Dols, Aina, Cullell, Natàlia, Torres-Aguila, Nuria P., Muiño, Elena, Rodríguez-Campello, Ana, Ois, Angel, Cuadrado-Godia, Elisa, Vivanco-Hidalgo, Rosa M., Hernandez-Guillamon, Mar, Solé, Montse, Delgado, Pilar, Bustamante, Alejandro, García-Berrocoso, Teresa, Mendióroz, Maite, Castellanos, Mar, Serena, Joaquín, Martí-Fàbregas, Joan, Segura, Tomás, Serrano-Heras, Gemma, Obach, Victor, Ribó, Marc, Molina, Carlos A., Alvarez-Sabín, José, Palomeras, Ernest, Freijo, Mar, Font, Maria A., Rosand, Jonathan, Rost, Natalia S., Gallego-Fabrega, Cristina, Lee, Jin-Moo, Heitsch, Laura, Ibanez, Laura, Cruchaga, Carlos, Phuah, Chia-Ling, Lemmens, Robin, Thijs, Vincent, Lindgren, Arne, Maguire, Jane, Rannikmae, Kristiina, Sudlow, Catherine L., Jern, Christina, Stanne, Tara M., Lorentzen, Erik, Muñoz-Narbona, Lucía, Dávalos, Antonio, López-Cancio, Elena, Worrall, Bradford B., Woo, Daniel, Kittner, Steven J., Mitchell, Braxton D., Montaner, Joan, Roquer, Jaume, Krupinski, Jurek, Estivill, Xavier, Rabionet, Raquel, Vives-Bauzá, Cristòfol, Fernández-Cadenas, Israel, and Jiménez-Conde, Jordi

Published
2019
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2. Association of Apolipoprotein e with Intracerebral Hemorrhage Risk by Race/Ethnicity : A Meta-analysis

Author

Marini, Sandro, Crawford, Katherine, Morotti, Andrea, Lee, Myung J, Pezzini, Alessandro, Moomaw, Charles J, Flaherty, Matthew L, Montaner, Joan, Roquer, Jaume, Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano-Tarraga, Carolina, Slowik, Agnieszka, Jagiella, Jeremiasz M, Pera, Joanna, Urbanik, Andrzej, Pichler, Alexander, Hansen, Bjorn M, McCauley, Jacob L, Tirschwell, David L, Selim, Magdy, Brown, Devin L, Silliman, Scott L, Worrall, Bradford B, Meschia, James F, Kidwell, Chelsea S, Testai, Fernando D, Kittner, Steven J, Schmidt, Helena, Enzinger, Christian, Deary, Lan J, Rannikmae, Kristiina, Samarasekera, Neshika, Salman, Rustam Al-Shahi, Sudlow, Catherine L, Klijn, Catharina JM, van Nieuwenhuizen, Koen M, Fernandez-Cadenas, Israel, Delgado, Pilar, Nonving, Bo, Lindgren, Ame, Goldstein, Joshua N, Viswanathan, Anand, Greenberg, Steven M, Falcone, Guido J, Biffi, Alessandro, Langefeld, Carl D, Woo, Daniel, Rosand, Jonathan, Anderson, Christopher D, Smoller, Sylvia, Sorkin, John, Wang, Xingwu, Pikula, Aleksandra, Wolf, Philip, Debette, Stephanie, Seshadri, Sudha, de Bakker, Paul, Chasman, Daniel, Rexrode, Kathryn, Chen, Ida, Rotter, Jerome, Luke, May, Sale, Michelle, Lee, Tsong-Hai, Chang, Ku-Chou, Elkind, Mitchell, Goldstein, Larry, James, Michael Luke, Breteler, Monique, O'Donnell, Chris, Leys, Didier, Carty, Cara, Kidwell, Chelsea, Olesen, Jes, Sharma, Pankaj, Rich, Stephen, Tatlisumak, Turgot, Happola, Olli, Bijlenga, Philippe, Soriano, Carolina, Giralt, Eva, Cotlarcius, Loana, Hardy, John, Korostynski, Michal, Boncoraglio, Giorgio, Ballabio, Elena, Parati, Eugenio, Mateusz, Adamski, Dziedzic, Tomasz, Jagiella, Jeremiasz, Gasowski, Jerzy, Wnuk, Marcin, Olszanecki, Rafaf, Juchniewicz, Karol Jozef, Levi, Christopher, Nyquist, Paul, Cendes, Iscia, Cabral, Norberto, Franca, Paulo, Goncalves, Anderson, Keller, Lina, Crisby, Milita, Kostulas, Konstantinos, Lennnnens, Robin, Ahmadi, Kourosh, Opherk, Christian, Duering, Marco, Dichgans, Martin, Malik, Rainer, Gonik, Mariya, Staals, Julie, Melander, Olle, Burri, Philippe, Sadr-Nabavi, Ariane, Romero, Javier, Anderson, Chris, Falcone, Guido, Brouwers, Bart, Rost, Natalia, Du, Rose, Kourkoulis, Christina, Battey, Thomas, Lubitz, Steven, Mueller-Myhsok, Bertram, Meschia, James, Brott, Thomas, Pare, Guillaume, Schmidt, Reinhold, Seiler, Stephan, Blanton, Susan, Yamada, Yoshiji, Bersano, Anna, Rundek, Tatiana, Sacco, Ralph, Chan, Yu-Feng Yvonne, Gschwendtner, Andreas, Deng, Zhen, Barr, Taura, Gwinn, Katrina, Corriveau, Roderick, Singleton, Andrew, Waddy, Salina, Launer, Lenore, Chen, Christopher, Le, Kim En, Lee, Wei Ling, Tan, Eng King, Olugbodi, Akintomi, Rothwell, Peter, Schilling, Sabrina, Mok, Vincent, Lebedeva, Elena, Jem, Christina, Jood, Katarina, Olsson, Sandra, Kim, Helen, Lee, Chaeyoung, Kilarski, Laura, Markus, Hugh, Peycke, Jennifer, Bevan, Steve, Sheu, Wayne, Chiou, Hung Yi, Chern, Joseph, Giraldo, Elias, Taqi, Muhammad, Jain, Vivek, Lam, Olivia, Howard, George, Kittner, Steven, Mitchell, Braxton, Cole, John, O'Connell, Jeff, Milewicz, Dianna, Illoh, Kachikwu, Worrall, Bradford, Stine, Colin, Karaszewski, Bartosz, Werring, David, Sofat, Reecha, Smalley, June, Lindgren, Arne, Hansen, Bjorn, Norrving, Bo, Smith, Gustav, Martin, Juan Jose, Thijs, Vincent, Klijn, Karin, van't Hof, Femke, Algra, Ale, Macleod, Mary, Perry, Rodney, Arnett, Donna, Padovani, Alessandro, Cramer, Steve, Fisher, Marl, Saleheen, Danish, Broderick, Joseph, Kissela, Brett, Doney, Alex, Sudlow, Cathie, Silliman, Scott, McDonough, Caitrin, Walters, Matthew, Pedersen, Annie, Nakagawa, Kazuma, Chang, Christy, Dobbins, Mark, McArdle, Patrick, Chang, Yu-Ching, Brown, Robert, Brown, Devin, Holliday, Elizabeth, Kalaria, Raj, Maguire, Jane, Hunter, John, Attia, John, Farrall, Martin, Giese, Anne-Katrin, Fomage, Myriam, Majersik, Jennifer, Cushman, Maly, Keene, Keith, Bennett, Siiri, Tirschwell, David, Psaty, Bruce, Reiner, Alex, Longstreth, Will, Spence, David, Langefeld, Carl, Bushnell, Cheryl, Heitsch, Laura, Lee, Jin-Moo, Sheth, Kevin, Consortium, Int Genetics, Neurologian yksikkö, Department of Neurosciences, Clinicum, Doctoral Programme in Clinical Research, HUS Neurocenter, RS: Carim - B05 Cerebral small vessel disease, RS: CARIM - R3.03 - Cerebral small vessel disease, and Epidemiology

Subjects
Male, Race ethnicity, Hemorràgia cerebral, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, WHITES, BLACKS, 030212 general & internal medicine, Biological sciences, Original Investigation, ALZHEIMER-DISEASE, African Americans, Aged, 80 and over, GENETIC-VARIATION, Hispanic or Latino, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Medical research, University hospital, 3. Good health, ETHNICITY, ALLELE, Research centre, Hypertension, lipids (amino acids, peptides, and proteins), Female, Apolipoprotein E, Core laboratory, Hispanic Americans, medicine.medical_specialty, COA REDUCTASE INHIBITORS, European Continental Ancestry Group, Clinical Neurology, Raça, APOE EPSILON-4, White People, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Apolipoproteins E, Political science, medicine, Journal Article, Online First, Humans, Genetic Predisposition to Disease, cardiovascular diseases, General hospital, Aged, Cerebral Hemorrhage, Research, LOBAR, 3112 Neurosciences, E GENOTYPE, United States, nervous system diseases, Black or African American, Cognitive epidemiology, Family medicine, Case-Control Studies, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Key Points Question Is history of hypertension and apolipoprotein E (APOE) associated with intracerebral hemorrhage risk in participants stratified by self-reported race/ethnicity? Findings In this case-control study of 13 124 adults, having a copy of APOE ε4 alleles increased the risk for lobar intracerebral hemorrhage only in white individuals, but after propensity score matching for hypertension burden, Hispanic individuals showed the same risk of APOE ε4. Meaning APOE ε4 appears to be confirmed as a risk factor for lobar intracerebral hemorrhage in nonwhite populations but is masked by differential hypertension burden in Hispanic individuals; further studies are needed to explore the interactions between APOE alleles and environmental exposures., Importance Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. Objective To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH. Design, Setting, and Participants This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Main Outcomes and Measures Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. Results In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P, This case-control study examines whether the risk for intracerebral hemorrhage presented by apolipoprotein E ε4 and ε2 alleles varies by race/ethnicity.

Published
2019

3. A Genome-Wide Meta-Analysis

Author

Mola-Caminal, Marina, Carrera, Caty, Soriano-Tárraga, Carolina, Giralt-Steinhauer, Eva, Díaz-Navarro, Rosa M., Tur, Sílvia, Jiménez, Carmen, Medina-Dols, Aina, Cullell, Nàtalia, Torres-Águila, Nuria P., Muiño, Elena, Rodríguez-Campello, Ana, Ois, Ángel, Cuadrado-Godia, Elisa, Vivanco-Hidalgo, Rosa M., Hernández-Guillamón, Mar, Solé, Montse, Delgado, Pilar, Bustamante, Alejandro, García-Berrocoso, Teresa, Mendióroz, Maite, Castellanos, Mar, Serena, Joaquín, Marti-Fabregas, Joan, Segura, Tomás, Serrano-Heras, Gemma, Obach, Víctor, Ribó, Marc, Molina, Carlos A., Álvarez-Sabín, José, Palomeras, Ernest, Freijo, Mar, Font, Maria A., Rosand, Jonathan, Rost, Natalia S., Gallego-Fabrega, Cristina, Lee, Jin-Moo, Heitsch, Laura, Ibáñez, Laura, Cruchaga, Carlos, Phuah, Chia-Ling, Lemmens, Robin, Thijs, Vincent, Lindgren, Arne, Maguire, Jane, Rannikmae, Kistiina, Sudlow, Catherine L., Jern, Christina, Stanne, Tara M., Lorentzen, Erik, Muñoz-Narbona, Lucía, Dávalos, Antonio, López-Cancio, Elena, Worrall, Bradford B., Woo, Daniel, Kittner, Steven J., Mitchell, Braxton D., Montaner, Joan, Roquer, Jaume, Krupinski, Jurek, Estivill, Xavier, Rabionet, Raquel, Vives-Bauzá, Cristòfol, Fernández-Cadenas, Israel, Jiménez-Conde, Jordi, Fundació La Marató de TV3, Instituto de Salud Carlos III, National Institutes of Health (US), and National Institute of Neurological Disorders and Stroke (US)

Subjects
Allele, Genome-wide association study, Ischemic stroke, Genetic loci, cardiovascular diseases, Genetic variant
Abstract

[Rationale] Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome., [Objective] Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date., [Methods and Results] A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10−9)., [Conclusions] Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci., Genetic contribution to functional outcome and disability after stroke (GODS) project, Fundació Marató-TV3 Grant 2011 (76/C/2011), Recercaixa’13; Generación Project, Instituto de Salud Carlos III; GENISIS (Genetics of Early Neurological InStability After Ischemic Stroke) project, National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke Stroke Genetics Network (SiGN) Project, NIH.

Published
2019

4. A Genome-Wide Meta-Analysis

Author

Mola-Caminal, Marina, Carrera, Caty, Soriano-Tárraga, Carolina, Giralt-Steinhauer, Eva, Díaz-Navarro, Rosa M., Tur, Sílvia, Jiménez, Carmen, Medina-Dols, Aina, Cullell, Nàtalia, Torres-Águila, Nuria P., Muiño, Elena, Rodríguez-Campello, Ana, Ois, Ángel, Cuadrado-Godia, Elisa, Vivanco-Hidalgo, Rosa M., Hernández-Guillamón, Mar, Solé, Montse, Delgado, Pilar, Bustamante, Alejandro, García-Berrocoso, Teresa, Mendióroz, Maite, Castellanos, Mar, Serena, Joaquín, Marti-Fabregas, Joan, Segura, Tomás, Serrano-Heras, Gemma, Obach, Víctor, Ribó, Marc, Molina, Carlos A., Álvarez-Sabín, José, Palomeras, Ernest, Freijo, Mar, Font, Maria A., Rosand, Jonathan, Rost, Natalia S., Gallego-Fabrega, Cristina, Lee, Jin-Moo, Heitsch, Laura, Ibáñez, Laura, Cruchaga, Carlos, Phuah, Chia-Ling, Lemmens, Robin, Thijs, Vincent, Lindgren, Arne, Maguire, Jane, Rannikmae, Kistiina, Sudlow, Catherine L., Jern, Christina, Stanne, Tara M., Lorentzen, Erik, Muñoz-Narbona, Lucía, Dávalos, Antonio, López-Cancio, Elena, Worrall, Bradford B., Woo, Daniel, Kittner, Steven J., Mitchell, Braxton D., Montaner, Joan, Roquer, Jaume, Krupinski, Jurek, Estivill, Xavier, Rabionet, Raquel, Vives-Bauzá, Cristòfol, Fernández-Cadenas, Israel, Jiménez-Conde, Jordi, Fundació La Marató de TV3, Instituto de Salud Carlos III, National Institutes of Health (US), and National Institute of Neurological Disorders and Stroke (US)

Subjects
genetic variant, genome-wide association study, Tight Junction Proteins, allele, Stroke Rehabilitation, genetic loci, Recovery of Function, Polymorphism, Single Nucleotide, Brain Ischemia, Stroke, Disability Evaluation, Phenotype, Treatment Outcome, Gene Frequency, Risk Factors, ischemic stroke, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

[Rationale] Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. [Objective] Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. [Methods and Results] A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10−9). [Conclusions] Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci. Genetic contribution to functional outcome and disability after stroke (GODS) project, Fundació Marató-TV3 Grant 2011 (76/C/2011), Recercaixa’13; Generación Project, Instituto de Salud Carlos III; GENISIS (Genetics of Early Neurological InStability After Ischemic Stroke) project, National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke Stroke Genetics Network (SiGN) Project, NIH.

Published
2018

5. Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

Author

Anderson, Christopher D., Falcone, Guido J., Phuah, Chia-Ling, Radmanesh, Farid, Bart Brouwers, H., Battey, Thomas W. K., Biffi, Alessandro, Peloso, Gina M., Liu, Dajiang J., Ayres, Alison M., Goldstein, Joshua N., Viswanathan, Anand, Greenberg, Steven M., Selim, Magdy, Meschia, James F., Brown, Devin L., Worrall, Bradford B., Silliman, Scott L., Tirschwell, David L., Flaherty, Matthew L., Kraft, Peter, Jagiella, Jeremiasz M., Schmidt, Helena, Hansen, Björn M., Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano, Carolina, Van Nieuwenhuizen, Koen M., Klijn, Catharina J.M., Rannikmae, Kristiina, Samarasekera, Neshika, Al-Shahi Salman, Rustam, Sudlow, Catherine L., Deary, Ian J., Morotti, Andrea, Pezzini, Alessandro, Pera, Joanna, Urbanik, Andrzej, Pichler, Alexander, Enzinger, Christian, Norrving, Bo, Montaner, Joan, Fernandez-Cadenas, Israel, Delgado, Pilar, Roquer, Jaume, Lindgren, Arne, Slowik, Agnieszka, and Schmidt, Reinhold

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Objective: In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH.Methods: We performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk.Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6).Interpretation: Genetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted.

Published
2016

6. Mendelian Randomization Study of Obesity and Cerebrovascular Disease.

Author

Marini, Sandro, Merino, Jordi, Montgomery, Bailey E., Malik, Rainer, Sudlow, Catherine L., Dichgans, Martin, Florez, Jose C., Rosand, Jonathan, Gill, Dipender, Anderson, Christopher D., and International Stroke Genetics Consortium

Subjects
CEREBROVASCULAR disease, SYSTOLIC blood pressure, WAIST-hip ratio, CEREBRAL hemorrhage, BLOOD sugar, BODY mass index, OBESITY, BRAIN, CEREBRAL small vessel diseases, BLOOD pressure, RESEARCH, STROKE, RESEARCH methodology, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, RESEARCH funding
Abstract

Objective: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.Methods: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.Results: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose.Interpretation: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524. [ABSTRACT FROM AUTHOR]

Published
2020
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7. Abstract 154: Genetic Variants in CETP That Increase HDL Levels also Increase Risk of Intracerebral Hemorrhage.

Author

Falcone, Guido J, Phuah, Chia-Ling, Radmanesh, Farid, Peloso, Gina M, Meschia, James F, Selim, Magdy, Brown, Devin L, Worrall, Bradford B, Silliman, Scott L, Tirschwell, David L, Jimenez-Conde, Jordi, Klijn, Catharina J, Sudlow, Catherine L, Rannikmae, Kristiina, Pezzini, Alessandro, Norrving, Bo, Montaner, Joan, Lindgren, Arne, Slowik, Agnieszka, and Kidwell, Chelsea S

Published
2017
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8. Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.

Author

Chung J, Hamilton G, Kim M, Marini S, Montgomery B, Henry J, Cho AE, Brown DL, Worrall BB, Meschia JF, Silliman SL, Selim M, Tirschwell DL, Kidwell CS, Kissela B, Greenberg SM, Viswanathan A, Goldstein JN, Langefeld CD, Rannikmae K, Sudlow CLM, Samarasekera N, Rodrigues M, Al-Shahi Salman R, Prendergast JGD, Harris SE, Deary I, Woo D, Rosand J, Van Agtmael T, and Anderson CD

Abstract

Objective: To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH., Methods: We performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States-based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling., Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1 I110T ) and rs201716258 (COL4A2 H203L ), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States-based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk ( p = 0.05), but not with lobar ICH ( p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant ( p > 0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen)., Conclusions: We identified rare missense variants in COL4A1 / A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2021
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9. Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.

Author

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 IJ, Rannikmae K, Samarasekera N, Al-Shahi Salman R, Sudlow CL, Klijn CJM, van Nieuwenhuizen KM, Fernandez-Cadenas I, Delgado P, Norrving B, Lindgren A, Goldstein JN, Viswanathan A, Greenberg SM, Falcone GJ, Biffi A, Langefeld CD, Woo D, Rosand J, and Anderson CD

Subjects
Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Male, Middle Aged, Risk Factors, United States ethnology, Black or African American ethnology, Black or African American genetics, Apolipoproteins E genetics, Cerebral Hemorrhage ethnology, Cerebral Hemorrhage genetics, Genetic Predisposition to Disease ethnology, Genetic Predisposition to Disease genetics, Hispanic or Latino genetics, Hispanic or Latino statistics & numerical data, Hypertension ethnology, Hypertension genetics, White People ethnology, White People genetics
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) ε4 alleles, the most potent genetic risk factor for ICH., Design, Setting, and Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study., Main Outcomes and Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies., Results: In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity., Conclusions and Relevance: APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.

Published
2019
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10. Genetic variants in CETP increase risk of intracerebral hemorrhage.

Author

Anderson CD, Falcone GJ, Phuah CL, Radmanesh F, Brouwers HB, Battey TW, Biffi A, Peloso GM, Liu DJ, Ayres AM, Goldstein JN, Viswanathan A, Greenberg SM, Selim M, Meschia JF, Brown DL, Worrall BB, Silliman SL, Tirschwell DL, Flaherty ML, Kraft P, Jagiella JM, Schmidt H, Hansen BM, Jimenez-Conde J, Giralt-Steinhauer E, Elosua R, Cuadrado-Godia E, Soriano C, van Nieuwenhuizen KM, Klijn CJ, Rannikmae K, Samarasekera N, Al-Shahi Salman R, Sudlow CL, Deary IJ, Morotti A, Pezzini A, Pera J, Urbanik A, Pichler A, Enzinger C, Norrving B, Montaner J, Fernandez-Cadenas I, Delgado P, Roquer J, Lindgren A, Slowik A, Schmidt R, Kidwell CS, Kittner SJ, Waddy SP, Langefeld CD, Abecasis G, Willer CJ, Kathiresan S, Woo D, and Rosand J

Subjects
Adult, Aged, Cholesterol, HDL blood, Cholesterol, HDL genetics, Female, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Cerebral Hemorrhage genetics, Cholesterol Ester Transfer Proteins genetics, Genetic Predisposition to Disease genetics
Abstract

Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH., Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk., Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10 -4 ) with no heterogeneity across studies (I 2  = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10 -6 )., Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740., (© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Published
2016
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