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Genetic variants in CETP increase risk of intracerebral hemorrhage
Author(s) -
Anderson Christopher D.,
Falcone Guido J.,
Phuah ChiaLing,
Radmanesh Farid,
Brouwers H. Bart,
Battey Thomas W. K.,
Biffi Alessandro,
Peloso Gina M.,
Liu Dajiang J.,
Ayres Alison M.,
Goldstein Joshua N.,
Viswanathan Anand,
Greenberg Steven M.,
Selim Magdy,
Meschia James F.,
Brown Devin L.,
Worrall Bradford B.,
Silliman Scott L.,
Tirschwell David L.,
Flaherty Matthew L.,
Kraft Peter,
Jagiella Jeremiasz M.,
Schmidt Helena,
Hansen Björn M.,
JimenezConde Jordi,
GiraltSteinhauer Eva,
Elosua Roberto,
CuadradoGodia Elisa,
Soriano Carolina,
Nieuwenhuizen Koen M.,
Klijn Catharina J. M.,
Rannikmae Kristiina,
Samarasekera Neshika,
Salman Rustam AlShahi,
Sudlow Catherine L.,
Deary Ian J.,
Morotti Andrea,
Pezzini Alessandro,
Pera Joanna,
Urbanik Andrzej,
Pichler Alexander,
Enzinger Christian,
Norrving Bo,
Montaner Joan,
FernandezCadenas 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,
Rosand Jonathan
Publication year - 2016
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24780
Subject(s) - cholesterylester transfer protein , medicine , odds ratio , intracerebral hemorrhage , locus (genetics) , genetic association , genetics , cholesterol , biology , endocrinology , bioinformatics , genotype , lipoprotein , gene , single nucleotide polymorphism , subarachnoid hemorrhage
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