Genetics
CETP variants that raise HDL cholesterol also increase risk of intracerebral haemorrhage (Ann Neurol 2016)
Original title: Genetic variants in CETP increase risk of intracerebral hemorrhage
Since higher plasma HDL cholesterol has been observationally linked to increased intracerebral haemorrhage (ICH) risk, and CETP variants that raise HDL-C are being pursued therapeutically, researchers tested whether CETP gene variants associated with higher HDL-C also raise ICH risk. In a discovery cohort of 1149 ICH cases and 1238 controls, replicated in 1625 cases and 1845 controls, the strongest single-variant association was at rs173539 (odds ratio 1.25, P = 6.010-4, no heterogeneity across studies), replicated in patients of European ancestry (P = 0.03). A genetic risk score of seven CETP variants known to raise HDL-C by about 2.85 mg per dL was strongly associated with ICH risk (odds ratio 1.86, P = 1.3910-6). The authors call for further exploration of adverse cerebrovascular outcomes as CETP inhibitors and other HDL-raising therapies advance in development.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.