Genetic Factors for Ischemic and Hemorrhagic Stroke in Japanese Individuals
Background and Purpose— Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confe...
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| Published in | Stroke (1970) Vol. 39; no. 8; pp. 2211 - 2218 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hagerstown, MD
Lippincott Williams & Wilkins
01.08.2008
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0039-2499 1524-4628 1524-4628 |
| DOI | 10.1161/STROKEAHA.107.507459 |
Cover
| Abstract | Background and Purpose—
Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage.
Methods—
The study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology.
Results—
An initial χ
2
test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors (
P
<0.05) revealed that the −14C→T polymorphism (rs1800977) of
ABCA1
, the A→C (rs3027898) and C→T (Ser532Leu, rs1059703) polymorphisms of
IRAK1
, and the G→C (Cys2229Ser) polymorphism (rs619203) of
ROS1
were significantly associated with atherothrombotic cerebral infarction; that the −428G→A polymorphism (rs710968) of
LIMK1
was significantly associated with intracerebral hemorrhage; and that the 13989A→G (Ile118Val) polymorphism (NC_000007.12) of
CYP3A4
was significantly associated with subarachnoid hemorrhage.
Conclusions—
Genotypes for
ABCA1
,
IRAK1
, and
ROS1
may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for
LIMK1
and
CYP3A4
may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels. |
|---|---|
| AbstractList | BACKGROUND: and Purpose- Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. METHODS: The study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: An initial chi super(2) test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors (P<0.05) revealed that the -14C arrow right T polymorphism (rs1800977) of ABCA1, the A arrow right C (rs3027898) and C arrow right T (Ser532Leu, rs1059703) polymorphisms of IRAK1, and the G arrow right C (Cys2229Ser) polymorphism (rs619203) of ROS1 were significantly associated with atherothrombotic cerebral infarction; that the -428G arrow right A polymorphism (rs710968) of LIMK1 was significantly associated with intracerebral hemorrhage; and that the 13989A arrow right G (Ile118Val) polymorphism (NC_000007.12) of CYP3A4 was significantly associated with subarachnoid hemorrhage. CONCLUSIONS: Genotypes for ABCA1, IRAK1, and ROS1 may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for LIMK1 and CYP3A4 may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels. Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage.BACKGROUND AND PURPOSEAlthough genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage.The study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology.METHODSThe study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology.An initial chi(2) test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors (P<0.05) revealed that the -14C-->T polymorphism (rs1800977) of ABCA1, the A-->C (rs3027898) and C-->T (Ser532Leu, rs1059703) polymorphisms of IRAK1, and the G-->C (Cys2229Ser) polymorphism (rs619203) of ROS1 were significantly associated with atherothrombotic cerebral infarction; that the -428G-->A polymorphism (rs710968) of LIMK1 was significantly associated with intracerebral hemorrhage; and that the 13989A-->G (Ile118Val) polymorphism (NC_000007.12) of CYP3A4 was significantly associated with subarachnoid hemorrhage.RESULTSAn initial chi(2) test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors (P<0.05) revealed that the -14C-->T polymorphism (rs1800977) of ABCA1, the A-->C (rs3027898) and C-->T (Ser532Leu, rs1059703) polymorphisms of IRAK1, and the G-->C (Cys2229Ser) polymorphism (rs619203) of ROS1 were significantly associated with atherothrombotic cerebral infarction; that the -428G-->A polymorphism (rs710968) of LIMK1 was significantly associated with intracerebral hemorrhage; and that the 13989A-->G (Ile118Val) polymorphism (NC_000007.12) of CYP3A4 was significantly associated with subarachnoid hemorrhage.Genotypes for ABCA1, IRAK1, and ROS1 may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for LIMK1 and CYP3A4 may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels.CONCLUSIONSGenotypes for ABCA1, IRAK1, and ROS1 may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for LIMK1 and CYP3A4 may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels. Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. The study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. An initial chi(2) test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors (P<0.05) revealed that the -14C-->T polymorphism (rs1800977) of ABCA1, the A-->C (rs3027898) and C-->T (Ser532Leu, rs1059703) polymorphisms of IRAK1, and the G-->C (Cys2229Ser) polymorphism (rs619203) of ROS1 were significantly associated with atherothrombotic cerebral infarction; that the -428G-->A polymorphism (rs710968) of LIMK1 was significantly associated with intracerebral hemorrhage; and that the 13989A-->G (Ile118Val) polymorphism (NC_000007.12) of CYP3A4 was significantly associated with subarachnoid hemorrhage. Genotypes for ABCA1, IRAK1, and ROS1 may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for LIMK1 and CYP3A4 may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels. Background and Purpose— Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. Methods— The study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Results— An initial χ 2 test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors ( P <0.05) revealed that the −14C→T polymorphism (rs1800977) of ABCA1 , the A→C (rs3027898) and C→T (Ser532Leu, rs1059703) polymorphisms of IRAK1 , and the G→C (Cys2229Ser) polymorphism (rs619203) of ROS1 were significantly associated with atherothrombotic cerebral infarction; that the −428G→A polymorphism (rs710968) of LIMK1 was significantly associated with intracerebral hemorrhage; and that the 13989A→G (Ile118Val) polymorphism (NC_000007.12) of CYP3A4 was significantly associated with subarachnoid hemorrhage. Conclusions— Genotypes for ABCA1 , IRAK1 , and ROS1 may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for LIMK1 and CYP3A4 may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels. |
| Author | Metoki, Norifumi Park, Hyuntae Yamada, Yoshiji Yokoi, Kiyoshi Tanaka, Masashi Nozawa, Yoshinori Hibino, Takeshi Kato, Kimihiko Aoyagi, Yukitoshi Satoh, Kei Ichihara, Sahoko Yasunaga, Akitomo Watanabe, Sachiro Yoshida, Hidemi |
| Author_xml | – sequence: 1 givenname: Yoshiji surname: Yamada fullname: Yamada, Yoshiji organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 2 givenname: Norifumi surname: Metoki fullname: Metoki, Norifumi organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 3 givenname: Hidemi surname: Yoshida fullname: Yoshida, Hidemi organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 4 givenname: Kei surname: Satoh fullname: Satoh, Kei organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 5 givenname: Kimihiko surname: Kato fullname: Kato, Kimihiko organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 6 givenname: Takeshi surname: Hibino fullname: Hibino, Takeshi organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 7 givenname: Kiyoshi surname: Yokoi fullname: Yokoi, Kiyoshi organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 8 givenname: Sachiro surname: Watanabe fullname: Watanabe, Sachiro organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 9 givenname: Sahoko surname: Ichihara fullname: Ichihara, Sahoko organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 10 givenname: Yukitoshi surname: Aoyagi fullname: Aoyagi, Yukitoshi organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 11 givenname: Akitomo surname: Yasunaga fullname: Yasunaga, Akitomo organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 12 givenname: Hyuntae surname: Park fullname: Park, Hyuntae organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 13 givenname: Masashi surname: Tanaka fullname: Tanaka, Masashi organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural – sequence: 14 givenname: Yoshinori surname: Nozawa fullname: Nozawa, Yoshinori organization: From the Department of Human Functional Genomics (Y.Y., S.I.), Life Science Research Center, Mie University, Tsu, Japan; Department of Internal Medicine (N.M.), Hirosaki Stroke Center, Hirosaki, Japan; Department of Vascular Biology (H.Y., K.S.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Cardiovascular Medicine (K.K., T.H., K.Y.), Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology (S.W.), Gifu Prefectural |
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| Keywords | Cerebral infarction Stroke Nervous system diseases Subarachnoid hemorrhage Cardiovascular disease Japanese Cerebral disorder Vascular disease genetics Cerebral hemorrhage Central nervous system disease Brain ischemia genetic polymorphism Cerebrovascular disease Polymorphism |
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| References | e_1_3_2_27_2 e_1_3_2_28_2 e_1_3_2_29_2 (e_1_3_2_12_2) 1995; 57 e_1_3_2_41_2 e_1_3_2_40_2 e_1_3_2_20_2 e_1_3_2_21_2 e_1_3_2_22_2 e_1_3_2_23_2 e_1_3_2_24_2 e_1_3_2_25_2 (e_1_3_2_26_2) 1985; 53 (e_1_3_2_35_2) 1994; 270 e_1_3_2_9_2 e_1_3_2_15_2 e_1_3_2_38_2 e_1_3_2_8_2 e_1_3_2_16_2 e_1_3_2_37_2 e_1_3_2_7_2 e_1_3_2_17_2 e_1_3_2_6_2 e_1_3_2_18_2 e_1_3_2_39_2 e_1_3_2_19_2 e_1_3_2_1_2 e_1_3_2_30_2 e_1_3_2_32_2 e_1_3_2_10_2 e_1_3_2_31_2 e_1_3_2_5_2 e_1_3_2_11_2 e_1_3_2_34_2 e_1_3_2_4_2 e_1_3_2_33_2 e_1_3_2_3_2 e_1_3_2_13_2 e_1_3_2_36_2 e_1_3_2_2_2 e_1_3_2_14_2 |
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Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the... Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of... BACKGROUND: and Purpose- Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke,... |
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| SubjectTerms | Adult Aged Asian Continental Ancestry Group - genetics Asian Continental Ancestry Group - statistics & numerical data ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters - genetics Biological and medical sciences Brain Ischemia - ethnology Brain Ischemia - genetics Cerebral Hemorrhage - ethnology Cerebral Hemorrhage - genetics Cytochrome P-450 CYP3A - genetics Female Genetic Predisposition to Disease - ethnology Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Humans Interleukin-1 Receptor-Associated Kinases - genetics Japan - epidemiology Lim Kinases - genetics Male Medical sciences Middle Aged Multivariate Analysis Nervous system (semeiology, syndromes) Neurology Oligonucleotide Array Sequence Analysis Polymorphism, Genetic Protein-Tyrosine Kinases - genetics Proto-Oncogene Proteins - genetics Risk Factors Stroke - ethnology Stroke - genetics Vascular diseases and vascular malformations of the nervous system |
| Title | Genetic Factors for Ischemic and Hemorrhagic Stroke in Japanese Individuals |
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