Genetic variants in CETP increase risk of intracerebral hemorrhage

on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)730-740
Number of pages11
JournalAnnals of Neurology
Volume80
Issue number5
DOIs
StatePublished - Nov 1 2016

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Cholesterol Ester Transfer Proteins
Cerebral Hemorrhage
HDL Cholesterol
Odds Ratio
Genetic Association Studies
Observational Studies
Epidemiologic Studies

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium (2016). Genetic variants in CETP increase risk of intracerebral hemorrhage. Annals of Neurology, 80(5), 730-740. https://doi.org/10.1002/ana.24780

Genetic variants in CETP increase risk of intracerebral hemorrhage. / on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium.

In: Annals of Neurology, Vol. 80, No. 5, 01.11.2016, p. 730-740.

Research output: Contribution to journalArticle

on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium 2016, 'Genetic variants in CETP increase risk of intracerebral hemorrhage', Annals of Neurology, vol. 80, no. 5, pp. 730-740. https://doi.org/10.1002/ana.24780
on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium. Genetic variants in CETP increase risk of intracerebral hemorrhage. Annals of Neurology. 2016 Nov 1;80(5):730-740. https://doi.org/10.1002/ana.24780
on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium. / Genetic variants in CETP increase risk of intracerebral hemorrhage. In: Annals of Neurology. 2016 ; Vol. 80, No. 5. pp. 730-740.
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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.",
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TY - JOUR

T1 - Genetic variants in CETP increase risk of intracerebral hemorrhage

AU - on behalf of the Global Lipids Genetics Consortium and International Stroke Genetics Consortium

AU - Anderson, Christopher D.

AU - Falcone, Guido J.

AU - Phuah, Chia Ling

AU - Radmanesh, Farid

AU - Brouwers, H. Bart

AU - Battey, Thomas W.K.

AU - Biffi, Alessandro

AU - Peloso, Gina M.

AU - Liu, Dajiang J.

AU - Ayres, Alison M.

AU - Goldstein, Joshua N.

AU - Viswanathan, Anand

AU - Greenberg, Steven M.

AU - Selim, Magdy

AU - Meschia, James F.

AU - Brown, Devin L.

AU - Worrall, Bradford B.

AU - Silliman, Scott L.

AU - Tirschwell, David L.

AU - Flaherty, Matthew L.

AU - Kraft, Peter

AU - Jagiella, Jeremiasz M.

AU - Schmidt, Helena

AU - Hansen, Björn M.

AU - Jimenez-Conde, Jordi

AU - Giralt-Steinhauer, Eva

AU - Elosua, Roberto

AU - Cuadrado-Godia, Elisa

AU - Soriano, Carolina

AU - van Nieuwenhuizen, Koen M.

AU - Klijn, Catharina J.M.

AU - Rannikmae, Kristiina

AU - Samarasekera, Neshika

AU - Salman, Rustam Al Shahi

AU - Sudlow, Catherine L.

AU - Deary, Ian J.

AU - Morotti, Andrea

AU - Pezzini, Alessandro

AU - Pera, Joanna

AU - Urbanik, Andrzej

AU - Pichler, Alexander

AU - Enzinger, Christian

AU - Norrving, Bo

AU - Montaner, Joan

AU - Fernandez-Cadenas, Israel

AU - Delgado, Pilar

AU - Roquer, Jaume

AU - Lindgren, Arne

AU - Slowik, Agnieszka

AU - Kidwell, Stella

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

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