Genetic factors for ischemic and hemorrhagic stroke in Japanese individuals.
OBJECTIVE
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(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.
Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurima-machiya, Tsu, Mie 514-8507, Japan. yamada@gene.mie-u.ac.jp
Yoshiji
Y
Yamada
Norifumi
N
Metoki
Hidemi
H
Yoshida
Kei
K
Satoh
Kimihiko
K
Kato
Takeshi
T
Hibino
Kiyoshi
K
Yokoi
Sachiro
S
Watanabe
Sahoko
S
Ichihara
Yukitoshi
Y
Aoyagi
Akitomo
A
Yasunaga
Hyuntae
H
Park
Masashi
M
Tanaka
Yoshinori
Y
Nozawa
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D002545:Brain Ischemia / Q000208:ethnology* / Q000235:genetics*; D002543:Cerebral Hemorrhage / Q000208:ethnology* / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D007564:Japan / Q000453:epidemiology; D054461:Lim Kinases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000208:ethnology* / Q000235:genetics*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D011518:Proto-Oncogene Proteins; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases