Genetic variants in CETP increase risk of intracerebral hemorrhage

被引：32

作者：

Anderson, Christopher D. ^{[1
,2
,3
,4
]}

Falcone, Guido J. ^{[1
,2
,3
,4
,5
,6
]}

Phuah, Chia-Ling ^{[1
,2
,3
,4
]}

Radmanesh, Farid ^{[1
,2
,3
,4
]}

Brouwers, H. Bart ^{[1
,2
,3
,4
]}

Battey, Thomas W. K. ^{[1
,2
,3
,4
]}

Biffi, Alessandro ^{[1
,2
,4
,7
,8
]}

Peloso, Gina M. ^{[1
,4
]}

Liu, Dajiang J. ^{[9
]}

Ayres, Alison M. ^{[1
,2
]}

Goldstein, Joshua N. ^{[10
]}

Viswanathan, Anand ^{[2
]}

Greenberg, Steven M. ^{[2
]}

Selim, Magdy ^{[11
]}

Meschia, James F. ^{[12
]}

Brown, Devin L. ^{[13
]}

Worrall, Bradford B. ^{[14
,15
]}

Silliman, Scott L. ^{[16
]}

Tirschwell, David L. ^{[17
]}

Flaherty, Matthew L. ^{[18
]}

Kraft, Peter ^{[5
,6
]}

Jagiella, Jeremiasz M. ^{[19
]}

Schmidt, Helena ^{[20
]}

Hansen, Bjorn M. ^{[21
,22
]}

Jimenez-Conde, Jordi ^{[23
,24
]}

Giralt-Steinhauer, Eva ^{[23
,24
]}

Elosua, Roberto ^{[23
,24
]}

Cuadrado-Godia, Elisa ^{[23
,24
]}

Soriano, Carolina ^{[23
,24
]}

van Nieuwenhuizen, Koen M. ^{[25
]}

Klijn, Catharina J. M. ^{[25
,26
]}

Rannikmae, Kristiina ^{[27
]}

Samarasekera, Neshika ^{[27
]}

Salman, Rustam Al-Shahi ^{[27
]}

Sudlow, Catherine L. ^{[27
,28
]}

Deary, Ian J. ^{[29
]}

Morotti, Andrea ^{[30
]}

Pezzini, Alessandro ^{[30
]}

Pera, Joanna ^{[19
]}

Urbanik, Andrzej ^{[19
]}

Pichler, Alexander ^{[31
]}

Enzinger, Christian ^{[31
,32
]}

Norrving, Bo ^{[21
,22
]}

Montaner, Joan ^{[33
,34
]}

Fernandez-Cadenas, Israel ^{[33
,34
,35
]}

Delgado, Pilar ^{[33
,34
]}

Roquer, Jaume ^{[23
,24
]}

Lindgren, Arne ^{[21
,22
]}

Slowik, Agnieszka ^{[19
,32
]}

Schmidt, Reinhold ^{[31
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St

[2] MGH, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA USA

[3] MGH, Div Neurocrit Care & Emergency Neurol, Dept Neurol, Boston, MA USA

[4] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[5] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[6] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[7] MGH, Div Behav Neurol, Dept Neurol, Boston, MA USA

[8] MGH, Dept Psychiat, Div Psychiat, Boston, MA USA

[9] Penn State Coll Med, Inst Personalized Med, Dept Publ Hlth Sci, Hershey, PA USA

[10] MGH, Dept Emergency Med, Boston, MA USA

[11] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA

[12] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[13] Univ Michigan Hlth Syst, Dept Neurol, Stroke Program, Ann Arbor, MI USA

[14] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA

[15] Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA

[16] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA

[17] Univ Washington, Harborview Med Ctr, Stroke Ctr, 325 9Th Ave, Seattle, WA 98104 USA

[18] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA

[19] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland

[20] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[21] Lund Univ, Div Neurol, Dept Clin Sci Lund, Lund, Sweden

[22] Skane Univ Hosp, Div Neurol, Dept Neurol & Rehabil Med, Lund, Sweden

[23] Autonomous Univ Barcelona, Municipal Inst Med Invest Hosp Sea, Dept Neurol, Neurovasc Res Unit, Barcelona, Spain

[24] Autonomous Univ Barcelona, Municipal Inst Med Invest Hosp Sea, Program Inflammat & Cardiovasc Disorders, Barcelona, Spain

[25] Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus, Utrecht, Netherlands

[26] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands

[27] Univ Edinburgh, Div Clin Brain Sci, Edinburgh, Midlothian, Scotland

[28] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[29] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[30] Univ Brescia, Dept Clin & Expt Sci, Neurol Clin, Brescia, Italy

[31] Med Univ Graz, Dept Neurol, Graz, Austria

[32] Med Univ Graz, Div Neuroradiol, Dept Radiol, Graz, Austria

[33] Autonomous Univ Barcelona, Res Inst, Vall dHebron Hosp, Neurovasc Res Lab, Barcelona, Spain

[34] Autonomous Univ Barcelona, Res Inst, Vall dHebron Hosp, Neurovasc Unit, Barcelona, Spain

[35] Terrassa Mutual Hosp, Stroke Pharmacogen & Genet Terrassa Mutual Teachi, Terrassa, Spain

[36] Univ Arizona, Dept Neurol, Tucson, AZ USA

[37] Baltimore Vet Adm Med Ctr, Dept Neurol, Baltimore, MD USA

[38] Univ Maryland, Sch Med, Baltimore, MD 21201 USA

[39] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA

[40] Wake Forest Univ, Ctr Publ Hlth Genom, Winston Salem, NC 27109 USA

[41] Wake Forest Univ, Dept Biostat Sci, Winston Salem, NC 27109 USA

[42] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[43] Univ Michigan, Dept Internal Med, Sch Med, Div Cardiol, Ann Arbor, MI 48109 USA

[44] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI USA

[45] MGH, Cardiovasc Dis Prevent Ctr, Boston, MA USA

来源：

ANNALS OF NEUROLOGY | 2016年 / 80卷 / 05期

关键词：

AGGRESSIVE REDUCTION; CHOLESTEROL LEVELS; STROKE PREVENTION; VASCULAR EVENTS; PLASMA-LIPIDS; METAANALYSIS; ASSOCIATION; HDL; ANACETRAPIB; LOCATION;

D O I：

10.1002/ana.24780

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveIn 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. MethodsWe 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. ResultsTwelve 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=6.0x10(-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 approximate to 2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR=1.86, SE=0.13, p=1.39x10(-6)). InterpretationGenetic 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

引用

页码：730 / 740

页数：11

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