Published Online
on March 18, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on July 11, 2003
Revised on January 9, 2004
Accepted on January 12, 2004

Tissue Plasminogen Activator -7351C/T Enhancer Polymorphism Is a Risk Factor for Lacunar Stroke

Jim Jannes BM, BS; Monica A. Hamilton-Bruce PhD; Louis Pilotto PhD; Brian J. Smith PhD; Charles G. Mullighan MD; Peter G. Bardy MBBS; and Simon A. Koblar PhD^*

From Department of Medicine (J.J., S.K.), University of Adelaide, The Queen Elizabeth Hospital Woodville South, South Australia; Department of Neurology (M.H.-B.), The Queen Elizabeth Hospital, Woodville South, South Australia; Department of General Practice (L.P.), Flinders Medical Centre, Bedford Park, South Australia; Department of Respiratory Medicine (B.J.S.), The Queen Elizabeth Hospital, Woodville South, South Australia; Department of Haematology (C.G.M.), The Royal Adelaide Hospital, Adelaide, South Australia; Research and Development/Transplant Services (P.G.B.), Australian Red Cross-South Australian Branch, Adelaide, South Australia.

^* To whom correspondence should be addressed. E-mail: simon.koblar{at}adelaide.edu.au.

Background and Purpose--Occlusive thrombosis is an important component of small- and large-vessel ischemic stroke. Endogenous tissue plasminogen activator (TPA) is the primary mediator of intravascular fibrinolysis and is predominantly expressed by the endothelium of small vessels. The acute release of TPA is influenced by the TPA -7351C/T polymorphism and therefore may play an important role in the pathogenesis of lacunar stroke. In this study, we investigated the risk of lacunar and nonlacunar ischemic stroke associated with the TPA -7351C/T polymorphism.

Methods--We conducted a case-control study of 182 cases of ischemic stroke and 301 community controls. Participants were evaluated for known cerebrovascular risk factors, and the TPA -7351C/T genotype was established by a polymerase chain reaction (PCR) method. Logistic regression was used to determine the risk of lacunar and nonlacunar ischemic stroke associated with the TPA -7351C/T polymorphism.

Results--The prevalence of the TPA -7351 CC, CT, and TT genotypes were 46%, 45%, and 9% for controls and 41%, 46%, and 13% for stroke patients, respectively. After adjustment for known cerebrovascular risk factors, the TT genotype was significantly associated with ischemic stroke (OR: 1.9; 95% CI: 1.01 to 3.6). Stratification for stroke subtype showed a significant association between the TT genotype and lacunar stroke but not nonlacunar stroke (OR: 2.7; 95% CI: 1.1 to 6.7).

Conclusions--The TPA -7351C/T polymorphism is an independent risk factor for lacunar stroke. The findings suggest that impaired fibrinolysis may play a role in the pathogenesis of lacunar stroke.

Key words: genetics • polymorphism • lacunar infarction • tissue plasminogen activator

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