Genetic variants in CETP increase risk of intracerebral hemorrhage
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Author
Falcone, Guido J.
Phuah, Chia‐Ling
Radmanesh, Farid
Brouwers, H. Bart
Battey, Thomas W. K.
Peloso, Gina M.
Liu, Dajiang J.
Ayres, Alison M.
Goldstein, Joshua N.
Viswanathan, Anand
Greenberg, Steven M.
Meschia, James F.
Brown, Devin L.
Worrall, Bradford B.
Silliman, Scott L.
Tirschwell, David L.
Flaherty, Matthew L.
Jagiella, Jeremiasz M.
Schmidt, Helena
Hansen, Björn M.
Jimenez‐Conde, Jordi
Giralt‐Steinhauer, Eva
Elosua, Roberto
Cuadrado‐Godia, Elisa
Soriano, Carolina
van Nieuwenhuizen, Koen M.
Klijn, Catharina J. M.
Rannikmae, Kristiina
Samarasekera, Neshika
Salman, Rustam Al‐Shahi
Sudlow, Catherine L.
Deary, Ian J.
Morotti, Andrea
Pezzini, Alessandro
Pera, Joanna
Urbanik, Andrzej
Pichler, Alexander
Enzinger, Christian
Norrving, Bo
Montaner, Joan
Fernandez‐Cadenas, Israel
Delgado, Pilar
Roquer, Jaume
Lindgren, Arne
Slowik, Agnieszka
Schmidt, Reinhold
Kidwell, Chelsea S.
Kittner, Steven J.
Waddy, Salina P.
Langefeld, Carl D.
Abecasis, Goncalo
Willer, Cristen J.
Kathiresan, Sekar
Woo, Daniel
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1002/ana.24780Metadata
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Anderson, C. D., G. J. Falcone, C. Phuah, F. Radmanesh, H. B. Brouwers, T. W. K. Battey, A. Biffi, et al. 2016. “Genetic variants in CETP increase risk of intracerebral hemorrhage.” Annals of Neurology 80 (5): 730-740. doi:10.1002/ana.24780. http://dx.doi.org/10.1002/ana.24780.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 (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;80:730–740Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115931/pdf/Terms of Use
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