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Genetic variants in CETP increase risk of intracerebral hemorrhage.


ABSTRACT: 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 (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 ).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.

SUBMITTER: Anderson CD 

PROVIDER: S-EPMC5115931 | BioStudies | 2016-01-01

REPOSITORIES: biostudies

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