Genetic variants in CETP increase risk of intracerebral hemorrhage

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

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18 Citations (Scopus)

Abstract

© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association 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. Ann Neurol 2016;80:730–740.
Original languageEnglish
Pages (from-to)730-740
JournalAnnals of Neurology
Volume80
Issue number5
DOIs
Publication statusPublished - 1 Nov 2016

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