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Genetic variants in CETP increase risk of intracerebral hemorrhage

Anderson, Christopher D.; Falcone, Guido J.; Phuah, Chia-Ling; Radmanesh, Farid; Brouwers, H Bart; Battey, Thomas W K; Biffi, Alessandro; Peloso, Gina M.; Liu, Dajiang J and Ayres, Alison M., et al. (2016) In Annals of Neurology 80(5). p.730-740
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... (More)

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 (I(2)  = 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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Adult, Aged, Cerebral Hemorrhage, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Journal Article, Research Support, N.I.H., Extramural
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Annals of Neurology
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80
issue
5
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11 pages
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John Wiley and Sons Inc.
external identifiers
  • scopus:84991736574
  • wos:000388570800010
ISSN
1531-8249
DOI
10.1002/ana.24780
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English
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yes
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143e4406-326c-4bd4-83e4-180d889d76e7
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2017-03-30 14:32:28
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2017-11-14 09:55:10
@article{143e4406-326c-4bd4-83e4-180d889d76e7,
  abstract     = {<p>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.</p><p>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.</p><p>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 (I(2)  = 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) ).</p><p>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.</p>},
  author       = {Anderson, Christopher D. and Falcone, Guido J. and Phuah, Chia-Ling and Radmanesh, Farid and Brouwers, H Bart and Battey, Thomas W K and Biffi, Alessandro and Peloso, Gina M. and Liu, Dajiang J and Ayres, Alison M. and Goldstein, Joshua N. and Viswanathan, Anand and Greenberg, Steven M. and Selim, Magdy and Meschia, James F. and Brown, Devin L. and Worrall, Bradford and Silliman, Scott L. and Tirschwell, David L. and Flaherty, Matthew L. and Kraft, Peter and Jagiella, Jeremiasz M. and Schmidt, Helena and Hansen, Björn M and Jimenez-Conde, Jordi and Giralt-Steinhauer, Eva and Elosua, Roberto and Cuadrado-Godia, Elisa and Soriano, Carolina and van Nieuwenhuizen, Koen M and Klijn, Catharina J. M. and Rannikmae, Kristiina and Samarasekera, Neshika and Al-Shahi Salman, Rustam and Sudlow, Catherine L and Deary, Ian J and Morotti, Andrea and Pezzini, Alessandro and Pera, Joanna and Urbanik, Andrzej and Pichler, Alexander and Enzinger, Christian and Norrving, Bo and Montaner, Joan and Fernandez-Cadenas, Israel and Delgado, Pilar and Roquer, Jaume and Lindgren, Arne and Slowik, Agnieszka and Schmidt, Reinhold and Kidwell, Chelsea S. and Kittner, Steven J. and Waddy, Salina P and Langefeld, Carl D. and Abecasis, Goncalo and Willer, Cristen J. and Kathiresan, Sekar and Woo, Daniel and Rosand, Jonathan and , },
  issn         = {1531-8249},
  keyword      = {Adult,Aged,Cerebral Hemorrhage,Cholesterol Ester Transfer Proteins,Cholesterol, HDL,Female,Genetic Predisposition to Disease,Genotype,Humans,Male,Middle Aged,Polymorphism, Single Nucleotide,Journal Article,Research Support, N.I.H., Extramural},
  language     = {eng},
  number       = {5},
  pages        = {730--740},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Genetic variants in CETP increase risk of intracerebral hemorrhage},
  url          = {http://dx.doi.org/10.1002/ana.24780},
  volume       = {80},
  year         = {2016},
}