17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage
Por:
Marini, S, Devan, WJ, Radmanesh, F, Miyares, L, Poterba, T, Hansen, BM, Norrving, B, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano, C, Roquer, J, Kourkoulis, CE, Ayres, AM, Schwab, K, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Montaner, J, Fernandez-Cadenas, I, Delgado, P, Greenberg, SM, Lindgren, A, Matouk, C, Sheth, KN, Woo, D, Anderson, CD, Rosand, J, Falcone, GJ
Publicada:
1 jul 2018
Resumen:
Background and Purpose Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH.
Methods We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5x10(-8) were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively.
Results The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: , 1.84; SE, 0.32; P=4.4x10(-8)) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: , 0.95; SE, 0.17; P=4.3x10(-8)) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5x10(-9); heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045).
Conclusions We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.
Filiaciones:
Marini, S:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Devan, WJ:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Radmanesh, F:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Miyares, L:
Yale Univ, Sch Med, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Room 1004D,15 York St,Box 208018, New Haven, CT 06520 USA
Poterba, T:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Hansen, BM:
Skane Univ Hosp, Dept Neurol & Rehabil, Lund, Sweden
Lund Univ, Neurol, Dept Clin Sci Lund, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Norrving, B:
Skane Univ Hosp, Dept Neurol & Rehabil, Lund, Sweden
Lund Univ, Neurol, Dept Clin Sci Lund, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Jimenez-Conde, J:
Univ Autonoma Barcelona, Dept Neurol, Hosp Mar, Med Res Inst IMIM, Barcelona, Spain
Giralt-Steinhauer, E:
Univ Autonoma Barcelona, Dept Neurol, Hosp Mar, Med Res Inst IMIM, Barcelona, Spain
Elosua, R:
Univ Autonoma Barcelona, Dept Neurol, Hosp Mar, Med Res Inst IMIM, Barcelona, Spain
Cuadrado-Godia, E:
Univ Autonoma Barcelona, Dept Neurol, Hosp Mar, Med Res Inst IMIM, Barcelona, Spain
Soriano, C:
Univ Autonoma Barcelona, Dept Neurol, Hosp Mar, Med Res Inst IMIM, Barcelona, Spain
Roquer, J:
Univ Autonoma Barcelona, Dept Neurol, Hosp Mar, Med Res Inst IMIM, Barcelona, Spain
Kourkoulis, CE:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Ayres, AM:
Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA
Schwab, K:
Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA
Tirschwell, DL:
Univ Washington, Harborview Med Ctr, Stroke Ctr, 325 9th Ave, Seattle, WA 98104 USA
Selim, M:
Beth Israel Deaconess Med Ctr, Dept Neurol, Stroke Div, Boston, MA 02215 USA
Brown, DL:
Univ Michigan, Dept Neurol, Stroke Program, Ann Arbor, MI USA
Silliman, SL:
Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA
Worrall, BB:
Univ Virginia Hlth Syst, Dept Neurol & Publ Hlth Sci, Charlottesville, VA USA
Meschia, JF:
Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
Kidwell, CS:
Univ Arizona, Dept Neurol, Tucson, AZ USA
Montaner, J:
Univ Autonoma Barcelona, Neurovasc Res Lab, Inst Recerca, Hosp Vall dHebron, Barcelona, Spain
Univ Autonoma Barcelona, Neurovasc Unit, Inst Recerca, Hosp Vall dHebron, Barcelona, Spain
Fernandez-Cadenas, I:
Univ Autonoma Barcelona, Neurovasc Res Lab, Inst Recerca, Hosp Vall dHebron, Barcelona, Spain
Univ Autonoma Barcelona, Neurovasc Unit, Inst Recerca, Hosp Vall dHebron, Barcelona, Spain
Stroke Pharmacogen & Genet St Pau Inst Res, Barcelona, Spain
Delgado, P:
Univ Autonoma Barcelona, Neurovasc Res Lab, Inst Recerca, Hosp Vall dHebron, Barcelona, Spain
Univ Autonoma Barcelona, Neurovasc Unit, Inst Recerca, Hosp Vall dHebron, Barcelona, Spain
Greenberg, SM:
Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA
Lindgren, A:
Skane Univ Hosp, Dept Neurol & Rehabil, Lund, Sweden
Lund Univ, Neurol, Dept Clin Sci Lund, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Matouk, C:
Yale Univ, Sch Med, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Room 1004D,15 York St,Box 208018, New Haven, CT 06520 USA
Sheth, KN:
Yale Univ, Sch Med, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Room 1004D,15 York St,Box 208018, New Haven, CT 06520 USA
Woo, D:
Univ Cincinnati, Coll Med, Dept Neurol & Rehabil Med, Cincinnati, OH 45221 USA
Anderson, CD:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA
Broad Inst, Program Med & Populat Genet, Boston, MA USA
Rosand, J:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA
Broad Inst, Program Med & Populat Genet, Boston, MA USA
Falcone, GJ:
Yale Univ, Sch Med, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Room 1004D,15 York St,Box 208018, New Haven, CT 06520 USA
Bronze, Green Accepted
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