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Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

Research output: Contribution to journalArticle

  • 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. Flaherty
  • Peter 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
  • 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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Original languageEnglish
Pages (from-to)730–740
JournalAnnals of Neurology
Volume80
Issue number5
Early online date22 Sep 2016
DOIs
Publication statusE-pub ahead of print - 22 Sep 2016

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. Ann Neurol 2016;80:730–740

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