Genetic variants in CETP increase risk of intracerebral hemorrhage.

Ann Neurol 2016 11 19;80(5):730-740. Epub 2016 Oct 19.

Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.

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 ) with no heterogeneity across studies (I  = 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 ).

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.

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.24780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115931PMC
November 2016
69 Reads

Publication Analysis

Top Keywords

variants cetp
16
cetp
11
cetp variants
8
intracerebral hemorrhage
8
associated increased
8
dna sequence
8
risk intracerebral
8
sequence variants
8
controls studies
8
genetic variants
8
increase risk
8
variants
7
hdl-c
7
ich
6
risk
6
ich riskresults
4
nominal association
4
cetp demonstrated
4
association ich
4
twelve variants
4

Similar Publications