&agr;1-Antichymotrypsin Polymorphism: A Risk Factor for Hemorrhagic Stroke in Normotensive Subjects

Background and Purpose— Although genetic factors may be important in the pathogenesis of ischemic stroke (IS), little is known on the potential role of genes in most cases of hemorrhagic stroke (HS). Preliminary data showed that the TT genotype of the &agr;1-antichymotrypsin (ACT) gene polymorphism was associated with HS, although it remained unsettled whether prevalence of this polymorphism might differ between hypertensive and normotensive HS. Methods— Ninety-nine patients with HS, 182 patients with IS (symptomatic control subjects), and 80 asymptomatic control subjects were genotyped for the ACT polymorphism using polymerase chain reaction amplification. Chronic hypertension was recorded in 66 patients with HS. Results— The ACT-TT genotype was more prevalent in patients than in asymptomatic or symptomatic control subjects: 26%, 15%, and 16%, respectively. The ACT-TT genotype was obtained in 33% of HS who lacked arterial hypertension (P <0.05). After adjustment for age, gender, and vascular risk factors, the ACT-TT genotype remained independently associated with HS (OR 2.80, 95% CI 1.19 to 6.58, compared with asymptomatic control subjects; OR 1.79, 95% CI 0.95 to 3.40, compared with symptomatic control subjects). In analyses restricted to HS in normotensive patients, the ORs were 3.10 (95% CI 1.10 to 8.68) and 2.53 (95% CI 1.04 to 6.18), respectively. Conclusions— These findings confirm in a larger series of patients the association between the ACT-TT genotype and HS. This polymorphism is more prevalent in normotensive bleedings. Pathological studies will be required to establish whether the ACT-TT genotype facilitates proteolytic rupture of vessels that harbor amyloidotic changes or another form of nonhypertensive cerebral angiopathy.

[1]  S. Greenberg,et al.  Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria , 2003, Current atherosclerosis reports.

[2]  P. Lapchak,et al.  Metalloproteinase Inhibition Reduces Thrombolytic (Tissue Plasminogen Activator)–Induced Hemorrhage After Thromboembolic Stroke , 2000, Stroke.

[3]  NicolásVila,et al.  α1-Antichymotrypsin Gene Polymorphism in Patients With Stroke , 2000 .

[4]  P. Riederer,et al.  Increased frequency of the α‐1‐antichymotrypsin T allele in cerebral amyloid angiopathy , 2000, Neuropathology (Kyoto. 1993).

[5]  K. Furie,et al.  Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. , 2000, The New England journal of medicine.

[6]  H Yonas,et al.  Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. , 1999, Stroke.

[7]  M. Ezquerra,et al.  α1-Antichymotrypsin gene polymorphism and susceptibility to Parkinson’s disease , 1999, Neurology.

[8]  E. Otomo,et al.  Association of α1‐antichymotrypsin polymorphism with cerebral amyloid angiopathy , 1998 .

[9]  A. Carter,et al.  Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage. , 1998, Stroke.

[10]  C. Graffagnino,et al.  Endoglin gene polymorphism as a risk factor for sporadic intracerebral hemorrhage , 1997, Annals of neurology.

[11]  Á. Chamorro,et al.  Contribution of arterial blood pressure to the clinical expression of lacunar infarction. , 1996, Stroke.

[12]  M. Ilyas Kamboh,et al.  A4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphism , 1995, Nature Genetics.

[13]  H. Brewer,et al.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments , 1994, Nature.

[14]  T Brott,et al.  Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. , 1993, Journal of neurosurgery.

[15]  J. Broderick,et al.  Lobar Hemorrhage in the Elderly: The Undiminishing Importance of Hypertension , 1993, Stroke.

[16]  Thomas Wisniewski,et al.  Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid , 1992, Neuroscience Letters.

[17]  Daniel B Hier,et al.  Clinical discriminators of lobar and deep hemorrhages , 1991, Neurology.

[18]  P. Krack,et al.  Age-related spontaneous intracerebral hematoma in a German community. , 1990, Stroke.

[19]  D. Abrahamson,et al.  Degradation of basement membrane laminin by human neutrophil elastase and cathepsin G. , 1990, The American journal of pathology.

[20]  H. Vinters.  Cerebral amyloid angiopathy. A critical review. , 1987, Stroke.

[21]  T. Brott,et al.  Hypertension as a risk factor for spontaneous intracerebral hemorrhage. , 1986, Stroke.

[22]  H. Vinters,et al.  Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. , 1983, Stroke.

[23]  P. Fraser,et al.  Alpha 1-antichymotrypsin binding to Alzheimer A beta peptides is sequence specific and induces fibril disaggregation in vitro. , 1993, Journal of neurochemistry.

[24]  R. Campbell,et al.  Clinicopathologic studies of primary cerebral amyloid angiopathy. , 1979, Mayo Clinic proceedings.