Genetic variants in CETP increase risk of intracerebral hemorrhage
Anderson, Christopher D. (Broad Institute of MIT and Harvard)
Falcone, Guido J. (Departments of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health)
Phuah, Chia-Ling (Broad Institute of MIT and Harvard)
Radmanesh, Farid (Broad Institute of MIT and Harvard)
Brouwers, H. Bart (Broad Institute of MIT and Harvard)
Battey, Thomas W. K. (Broad Institute of MIT and Harvard)
Biffi, Alessandro (Division of Psychiatry, Department of Psychiatry, MGH)
Peloso, Gina M. (Broad Institute of MIT and Harvard)
Liu, Dajiang J. (Institute of Personalized Medicine, Penn State College of Medicine)
Ayres, Alison M. (J. Philip Kistler Stroke Research Center, Department of Neurology, MGH)
Goldstein, Joshua N. (Department of Emergency Medicine, MGH)
Viswanathan, Anand (J. Philip Kistler Stroke Research Center, Department of Neurology, MGH)
Greenberg, Steven M. (J. Philip Kistler Stroke Research Center, Department of Neurology, MGH)
Selim, Magdy (Beth Israel Deaconess Medical Center)
Meschia, James F. (Mayo Clinic (Jacksonville, Estats Units d'Amèrica))
Brown, Devin L. (University of Michigan Health System)
Worrall, Bradford B. (University of Virginia Health System)
Silliman, Scott L. (University of Florida College of Medicine)
Tirschwell, David L. (University of Washington)
Flaherty, Matthew L. (University of Cincinnati College of Medicine)
Kraft, Peter (Departments of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health)
Jagiella, Jeremiasz M. (Jagiellonian University Medical College)
Schmidt, Helena (Medical University Graz)
Hansen, Björn M. (Skåne University Hospital (Suècia))
Jimenez-Conde, Jordi (Institut Hospital del Mar d'Investigacions Mèdiques)
Giralt Steinhauer, Eva (Institut Hospital del Mar d'Investigacions Mèdiques)
Elosua, Roberto (Institut Hospital del Mar d'Investigacions Mèdiques)
Cuadrado-Godia, Elisa (Institut Hospital del Mar d'Investigacions Mèdiques)
Soriano Tàrraga, Carolina (Institut Hospital del Mar d'Investigacions Mèdiques)
van Nieuwenhuizen, Koen M. (University Medical Center Utrecht)
Klijn, Catharina J. M. (Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center)
Rannikmae, Kristiina (University of Edinburgh)
Samarasekera, Neshika (University of Edinburgh)
Salman, Rustam Al-Shahi (University of Edinburgh)
Sudlow, Catherine L. (University of Edinburgh)
Deary, Ian J. (University of Edinburgh)
Morotti, Andrea (Neurology Clinic, University of Brescia)
Pezzini, Alessandro (Neurology Clinic, University of Brescia)
Pera, Joanna (Jagiellonian University Medical College)
Urbanik, Andrzej (Jagiellonian University Medical College)
Pichler, Alexander (Medical University of Graz)
Enzinger, Christian (Medical University of Graz)
Norrving, Bo (Skåne University Hospital (Suècia))
Montaner, Joan (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernandez-Cadenas, Israel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Delgado Martínez, María Pilar (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Roquer González, Jaume (Institut Hospital del Mar d'Investigacions Mèdiques)
Lindgren, Arne (Skåne University Hospital (Suècia))
Slowik, Agnieszka (Jagiellonian University Medical College)
Schmidt, Reinhold (Medical University of Graz)
Kidwell, Chelsea S. (University of Arizona)
Kittner, Steven J. (Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine)
Waddy, Salina P. (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Langefeld, Carl D. (Wake Forest University)
Abecasis, Goncalo (University of Michigan School of Public Health)
Willer, Cristen J. (University of Michigan Medical School)
Kathiresan, Sekar (Cardiovascular Disease Prevention Center, MGH)
Woo, Daniel (University of Cincinnati College of Medicine)
Rosand, Jonathan (Broad Institute of MIT and Harvard)
Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya)

Data:	2016
Resum:	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. 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. 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). 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.
Nota:	Altres ajuts: MSC/RD12-0042-0020
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Annals of neurology, Vol. 80 (october 2016) , p. 730-740, ISSN 1531-8249

DOI: 10.1002/ana.24780
PMID: 27717122

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