Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

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 two candidate-gene analyses of CETP. First, we tested individual CETPvariants in a discovery cohort of 1149 ICH cases and 1238 controls from 3 studies, followed by replication in 1625 cases and 1845 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=6.0x10−4) 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=1.39x10−6).

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. 

Annals Of Neurology 2016