Dataset Information

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 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.

SUBMITTER: Anderson CD

PROVIDER: S-EPMC5115931 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Genetic variants in CETP increase risk of intracerebral hemorrhage.

Anderson Christopher D CD Falcone Guido J GJ Phuah Chia-Ling CL Radmanesh Farid F Brouwers H Bart HB Battey Thomas W K TW Biffi Alessandro A Peloso Gina M GM Liu Dajiang J DJ Ayres Alison M AM Goldstein Joshua N JN Viswanathan Anand A Greenberg Steven M SM Selim Magdy M Meschia James F JF Brown Devin L DL Worrall Bradford B BB Silliman Scott L SL Tirschwell David L DL Flaherty Matthew L ML Kraft Peter P Jagiella Jeremiasz M JM Schmidt Helena H Hansen Björn M BM Jimenez-Conde Jordi J Giralt-Steinhauer Eva E Elosua Roberto R Cuadrado-Godia Elisa E Soriano Carolina C van Nieuwenhuizen Koen M KM Klijn Catharina J M CJ Rannikmae Kristiina K Samarasekera Neshika N Al-Shahi Salman Rustam R Sudlow Catherine L CL Deary Ian J IJ Morotti Andrea A Pezzini Alessandro A Pera Joanna J Urbanik Andrzej A Pichler Alexander A Enzinger Christian C Norrving Bo B Montaner Joan J Fernandez-Cadenas Israel I Delgado Pilar P Roquer Jaume J Lindgren Arne A Slowik Agnieszka A Schmidt Reinhold R Kidwell Chelsea S CS Kittner Steven J SJ Waddy Salina P SP Langefeld Carl D CD Abecasis Goncalo G Willer Cristen J CJ Kathiresan Sekar S Woo Daniel D Rosand Jonathan J

Annals of neurology 20161019 5

<h4>Objective</h4>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 fo ...[more]

PMID: 27717122

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Project description:BackgroundIntracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores that quantify bleeding risk can guide decision-making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score into an existing risk factor-based CRS could improve risk stratification for anticoagulation-related ICH.MethodsWe constructed 153 genetic risk scores from genome-wide association data of 1545 ICH cases and 1481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with a combined clinical and genetic risk score incorporating an additional point for high genetic risk for ICH.ResultsAmong anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared with the lowest genetic risk score tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (hazard ratio, 2.08 [95% CI, 1.22-3.56]). Although the CRS predicted incident ICH with a hazard ratio of 1.24 per 1-point increase (95% CI [1.01-1.53]), adding a point for high genetic ICH risk led to a stronger association (hazard ratio of 1.33 per 1-point increase [95% CI, 1.11-1.59]) with improved risk stratification (C index 0.57 versus 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new clinical and genetic risk score showed 19% improvement in high-risk classification among individuals with ICH and a net reclassification improvement of 0.10.ConclusionsAmong anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision-making.

Dataset Information

Genetic variants in CETP increase risk of intracerebral hemorrhage.

Objective

Methods

Results

Interpretation

Publications

Genetic variants in CETP increase risk of intracerebral hemorrhage.

Similar Datasets

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