Genetic variants in CETP increase risk of intracerebral hemorrhage

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


title = "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 (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.",
keywords = "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",
author = "Anderson, {Christopher D.} and Falcone, {Guido J.} and Chia-Ling Phuah and Farid Radmanesh and Brouwers, {H Bart} and Battey, {Thomas W K} and Alessandro Biffi and Peloso, {Gina M.} and Liu, {Dajiang J} and Ayres, {Alison M.} and Goldstein, {Joshua N.} and Anand Viswanathan and Greenberg, {Steven M.} and Magdy Selim and Meschia, {James F.} and Brown, {Devin L.} and Bradford Worrall and Silliman, {Scott L.} and Tirschwell, {David L.} and Flaherty, {Matthew L.} and Peter Kraft and Jagiella, {Jeremiasz M.} and Helena Schmidt and Hansen, {Bj{\"o}rn M} and Jordi Jimenez-Conde and Eva Giralt-Steinhauer and Roberto Elosua and Elisa Cuadrado-Godia and Carolina Soriano and {van Nieuwenhuizen}, {Koen M} and Klijn, {Catharina J. M.} and Kristiina Rannikmae and Neshika Samarasekera and {Al-Shahi Salman}, Rustam and Sudlow, {Catherine L} and Deary, {Ian J} and Andrea Morotti and Alessandro Pezzini and Joanna Pera and Andrzej Urbanik and Alexander Pichler and Christian Enzinger and Bo Norrving and Joan Montaner and Israel Fernandez-Cadenas and Pilar Delgado and Jaume Roquer and Arne Lindgren and Agnieszka Slowik and Reinhold Schmidt and {Global Lipids Genetics Consortium and International Stroke Genetics Consortium}",
note = "{\circledC} 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.",
year = "2016",
doi = "10.1002/ana.24780",
language = "English",
volume = "80",
pages = "730--740",
journal = "Annals of Neurology",
issn = "1531-8249",
publisher = "John Wiley and Sons Inc.",
number = "5",