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(Stroke. 2004;35:1090.)
© 2004 American Heart Association, Inc.

Original Contributions

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 Simon A. Koblar, PhD

From Departments of Medicine (J.J., S.K.), Neurology (M.H.-B.), and Respiratory Medicine (B.J.S.), University of Adelaide, The Queen Elizabeth Hospital, Woodville South, South Australia; Department of General Practice (L.P.), Flinders Medical Centre, Bedford Park, 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.

Correspondence to Dr Simon Koblar, Department of Medicine, University of Adelaide, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, South Adelaide, South Australia 5011. E-mail simon.koblar{at}adelaide.edu.au

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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

	Introduction

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Occlusive thrombosis is an important component of small- and large-vessel ischemic stroke. It is usually caused by focal disruption of an atheromatous plaque, exposing subendothelial tissues that trigger a local hemostatic response. Thrombosis may also occur under conditions of high shear stress, such as those induced by atherosclerotic stenosis.¹ Irrespective of the cause, the endogenous fibrinolytic defense system plays an important role in counteracting thrombus formation, with the degree of thrombosis governed by the balance of prothrombotic and antithrombotic forces.²

Endothelium-derived tissue plasminogen activator is the primary mediator of local intravascular fibrinolysis. Knockout mice deficient for tissue plasminogen activator (TPA) have markedly slower rates of reperfusion after thrombotic occlusion of a carotid artery when compared with their wild-type counterparts.³ In humans, plasma TPA levels are regulated by 2 mechanisms: (1) an acute release of local TPA that is precipitated by vascular injury and (2) a long-term change in the rate of synthesis of TPA that reflects the chronic activation of the fibrinolytic system.⁴ The latter is a marker of atherosclerotic burden, with a high plasma TPA level being an independent predictor of ischemic stroke in cross-sectional^5–11 and prospective cohort studies.^12,13 The rapid release of local TPA by the endothelium is considered to be the most important mechanism mediating the dissolution of arterial thrombus.⁴ Hence, a low capacity for rapid TPA release is likely to predispose to ischemic stroke. Furthermore, because small vessels predominantly express TPA within the brain,^14,15 factors that influence its release may have particular relevance to lacunar stroke.

In humans, genetic factors play an important role in the variance of endothelial TPA release.¹⁶ Recently, a single nucleotide polymorphism located at position –7351 within the enhancer region of the TPA gene was identified and shown to be strongly correlated with endothelial TPA release rates.¹⁷ The polymorphism was also found to have functional importance as it occurred within an Sp1 binding site, a factor promoting DNA transcription. Possession of a thymidine (T) allele was shown to inhibit Sp1 binding and was associated with less than half the TPA release observed in those homozygous for the cytosine (C) allele.¹⁷ The TPA –7351C/T polymorphism has subsequently been shown to be clinically relevant, having a strong association with first myocardial infarction.¹⁸

The risk of ischemic stroke associated with the TPA –7351C/T polymorphism has not been reported. We therefore performed a case-control study to determine the risk of ischemic stroke in relation to either lacunar or nonlacunar events associated with this genetic determinant of intravascular fibrinolysis, with adjustment for known risk factors.

	Subjects and Methods

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Patients admitted with acute ischemic stroke to 1 of 5 major hospitals within metropolitan Adelaide, South Australia were invited to participate in the study. The diagnosis of ischemic stroke was made by a neurologist (J.J.) in accordance with the World Health Organization definition.¹⁹ All patients underwent brain computerized tomography or MRI, allowing exclusion of intracerebral and subarachnoid hemorrhage. Ischemic stroke was subtyped into 4 categories using the Oxfordshire Community Stroke Project (OCSP) classification system:²⁰ (1) total anterior circulation syndrome; (2) partial anterior circulation syndrome; (3) posterior circulation syndrome; and (4) lacunar syndrome. The control group consisted of nonhospitalized subjects who resided predominantly in metropolitan Adelaide and did not have a personal history of cerebrovascular disease. Controls were selected by means of random sampling of the South Australian electronic telephone directory and group-matched with batches of patients for age (within 5-year strata) and gender.

After informed written consent, patients and controls were interviewed and demographic information was recorded. If the patient was unable to communicate verbally, then information was recorded from the next of kin. Cerebrovascular risk factors including hypertension, hypercholesterolemia, and diabetes were recorded if there was a self-reported history or if the individual was receiving medical treatment for the condition or conditions at the time of investigation. An ECG was performed at the time of the interview to determine the presence of atrial fibrillation. Patients were coded with artrial fibrillation (AF) if there was objective evidence on ECG or if there was a reported history of paroxysmal AF. Subjects were classified as smokers if they smoked cigarettes or tobacco on a regular basis at the time of the interview or within the past 5 years. A history of stroke in a first-degree relative was also recorded. A venous blood sample was taken from all participants for genetic analysis. The study was approved by the clinical research ethics committees of participating hospitals.

Genotype Determination
Genomic DNA was isolated from 6 mL of whole blood by a standard method.²¹ A 405-bp DNA fragment involving the –7351C/T polymorphism of the TPA gene was amplified using the sequence-specific primer polymerase chain reaction (PCR) method.²² The sequence of the 2 reverse allele-specific primers was 5'-ATGGCTGTGTCTGGGGCG-3', 5'-ATGGCTGTGTCTGG-GGCA-3', and that of the forward consensus primer was 5'-ATTGGCGCAAACTCCTCA-3' (Genbank Accession Number: Z48484). The PCR products were separated on a 2% agarose gel and the allelic frequency was determined. DNA was de-identified and analyzed in coded form, blinding laboratory staff and data abstractors to case/control status. Genotyping was also performed by 2 independent investigators. They were in full agreement.

Statistical Analysis
Statistical analysis was performed using STATA statistical software (Version 7.0; College Station, Tex). Based on a population TPA –7351 TT genotype frequency of 10%,¹⁸ we estimated that a sample size of 150 patients and 150 controls would be sufficient to determine a minimum odds ratio (OR) of 2.5 (80% power, 95% confidence interval [CI]). The strength of association between TPA –7351C/T genotype and ischemic stroke was estimated by calculating the OR and 95% CI. ORs were also calculated to determine the relative strength of association of known risk factors. Unconditional logistic regression analysis was used to examine the modifying effect of known risk factors (age, gender, ethnicity, family history of stroke, hypertension, diabetes, smoking, hypercholesterolemia, and atrial fibrillation) on the risk of stroke associated with the TPA –7351C/T genotype. Although cases and controls were matched for age and gender, the matching was not on an individual basis and these variables were included as potential confounders. Variables that altered the univariate odds ratio by 10% were then incorporated into an unconditional logistic regression model to determine of the risk of ischemic stroke associated with the TPA –7351C/T polymorphism. This model also examined for the effect of interaction between the TPA –7351C/T genotype and each of the known risk factors. A univariate analysis stratified for ischemic stroke subtype was performed. A two-tailed P<0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study, 201 consecutive patients with acute ischemic stroke were invited to participate. Of these, 182 (90.5%) agreed to participate, and 137 patients (75%) presented with first ischemic stroke. The demographic characteristics and prevalence of cerebrovascular risk factors for cases and 301 controls are shown in Table 1. No significant differences were observed between the 2 groups in terms of demographic variables. Of the known risk factors examined, atrial fibrillation was associated with the highest risk of ischemic stroke, with 23% of cases versus 3% of controls affected (OR: 8.5; 95% CI: 4.1 to 17.4). A history of smoking within the past 5 years (OR: 3.1; 95% CI: 1.9 to 5.2) and diabetes (OR: 2.7; 95% CI; 1.6 to 4.4) were also found to be associated significantly with ischemic stroke. No association was observed between ischemic stroke and a history of stroke in a first-degree relative, hypertension, hypercholesterolemia (Table 1), or for the use of antihypertensive, antiplatelet, and lipid-lowering medication (results not shown).

View this table: [in this window] [in a new window]   TABLE 1. Demographic Characteristics and Prevalence of Risk Factors for Patients With Ischemic Stroke and Controls

Two patients died after enrollment in the study and before venous blood sampling, thus genetic analysis could not be performed in these cases. Table 2 shows the prevalence of the TPA –7351C/T polymorphism in the remaining 180 ischemic stroke cases and 301 controls. The allelic frequencies were in Hardy-Weinberg equilibrium. Among the control group, 46% were homozygous for the TPA –7351 C allele (CC), and 45% were heterozygous (CT) and 9% were homozygous for the T allele (TT). The genotype distribution in the ischemic stroke cohort was 41% (CC), 46% (CT), and 13% (TT), respectively. In a univariate analysis, the risk of ischemic stroke was not significantly associated with the TT genotype (OR: 1.5; 95% CI: 0.8 to 2.8). Atrial fibrillation was the only variable that significantly altered the univariate risk of ischemic stroke associated with the TT genotype, and after adjustment for this, a significant association between this genotype and ischemic stroke was observed. The distribution of the TPA –7351C/T genotype among patients stratified for stroke subtype and controls is shown in Table 3. Forty-four ischemic stroke patients (24.5%) were classified as having lacunar stroke. In this subgroup, the TPA –7351 TT genotype was significantly associated with lacunar stroke (OR: 2.6; 95% CI: 1.1 to 6.4; P=0.039). The corresponding attributable risk associated with the TPA –7351 TT genotype was 13% (2% to 17%). Removal of the nonwhite participants from the analysis did not alter the significance of this finding. In contrast, the TPA –7351C/T polymorphism was not associated with an increased risk of nonlacunar stroke. No interaction between the TPA TT genotype and smoking, hypertension, hypercholesterolemia, diabetes, family history for stroke, atrial fibrillation, or a combination of these was found (results not shown).

View this table: [in this window] [in a new window]   TABLE 2. Prevalence, OR, 95% CI, and P Values for the TPA –7351 C/T Polymorphism Among Patients With Ischemic Stroke and Controls

View this table: [in this window] [in a new window]   TABLE 3. Prevalence, OR, 95% CI, and P Values for the TPA –7351 C/T Polymorphism Among Patients With Ischemic Stroke Stratified for Stroke Subtype and Controls

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This is the first study to our knowledge to identify an association between the TPA –7351C/T polymorphism and ischemic stroke after adjustment for most known cerebrovascular risk factors. In a subgroup analysis, the TPA –7351TT genotype was significantly associated with lacunar, but not nonlacunar stroke. The prevalence of the TPA –7351TT genotype among cases was low; consequently, the risk of lacunar stroke attributable to the TPA –7351TT genotype was 13%. This implicates other factors in the pathogenesis of lacunar stroke and is in keeping with the polygenic model of ischemic stroke, in which the predisposition arises after the accumulation and interaction of multiple genetic loci, each of which possess a weak phenotypic effect.²³

Two distinct small-vessel pathologies underlie most lacunar stroke: lipohyalinosis and microatheroma.²⁴ Both lead to slow luminal narrowing causing hemodynamic compromise that may initially present with the capsular warning syndrome.²⁵ Subsequent lacunar infarction occurs after nonthrombotic obliteration of diseased small vessels or from occlusive thrombus.²⁴ The finding of a nearly 3-fold increase in risk of lacunar stroke associated with homozygosity for the T allele of the TPA –7351C/T polymorphism suggests that fibrinolytic factors may play an important role in the preservation of small vessel patency. This is supported by studies of normal primate and rat brains, which show that TPA expression is restricted to the endothelial cells of precapillary arterioles and postcapillary venules, with no expression by the endothelium of large arteries.^14,15 This differential expression of TPA suggests that under normal circumstances, vascular patency of small vessels relies on an intact fibrinolytic system and that these vessels may be vulnerable to thrombotic occlusion by factors that impair fibrinolytic potential. Functional studies have also shown that impaired fibrinolytic activity may be particularly important in the pathogenesis of lacunar stroke. Fibrinolytic activity, as measured by plasma fibrinogen degradation products, varies considerably between lacunar, cardioembolic, and atherothrombotic ischemic stroke, with the lowest levels being observed in lacunar stroke.²⁶ In another study, impairment of fibrinolytic potential, as determined by the euglobulin lysis time, was observed more often in patients with lacunar stroke than in those with cortical infarction caused by large-vessel occlusion.²⁷

Our findings are consistent with those of a recent study showing an increased risk of ischemic stroke associated with the D allele of the TPA Alu-repeat insertion/deletion polymorphism.²⁸ This polymorphism is in tight linkage disequilibrium with the TPA –7351C/T polymorphism with a linkage disequilibrium coefficient of 0.71.¹⁷ Functional significance, however, is greatest for the TPA –7351C/T polymorphism, which accounts for 18% of the phenotypic variance in TPA release rates, a finding nearly double that associated with the TPA Alu-repeat insertion/deletion polymorphism (10%).²⁹ It is thus plausible that the positive association between the TPA Alu-repeat insertion/deletion polymorphism and ischemic stroke occurs through linkage disequilibrium with the functional TPA –7351C/T polymorphism.

The potential limitations of our study warrant consideration. The sample size was small, resulting in wide confidence intervals that approached unity. Therefore, the possibility of a type 1 error cannot be excluded and a study of greater power is required to confirm the strength of association. Various sources of bias may have also arisen. Bias caused by incomplete ascertainment of cases may have occurred because the study sample consisted entirely of hospitalized stroke survivors who were able to give informed consent and did not include patients with severe stroke or those who did not present to hospital. Although this study controlled for many of the known cerebrovascular risk factors, other potential risk factors such as alcohol intake and markers of inflammation were not recorded and remain a potential source of confounding bias. Furthermore, misclassification of diabetes, hypertension, and hypercholesterolemia may have occurred because diagnosis was based on self-reported history alone. The risk factor profile (excluding hypertension) for stroke patients was, however, consistent with that previously reported.³⁰ The limitations associated with the OCSP classification system could have also led to misclassification of stroke subtype. For example, the OCSP cannot differentiate between lacunar infarction (small-vessel disease) and striatocapsular infarction without cortical signs (large-vessel disease). However, the OCSP classification system has been validated, with concordance between clinical subtype and brain neuroimaging reported in 75% of cases.³¹ In the present study, clinical subtype was made in conjunction with neuroimaging, thus further limiting this error. This study did not measure for the effects of population stratification, which may have led to a spurious association. The distribution of the TPA –7351C/T genotype among controls, however, was similar to that reported in another white population from Sweden (CC: 50.8%; CT: 39.2%; TT: 10.0%).¹⁸

In conclusion, the results of this study suggest that impaired fibrinolysis plays a role in pathogenesis of lacunar stroke and supports the hypothesis that the TPA –7351C/T polymorphism represents an inherited risk factor in a white population. Confirmation by a larger study is required, which may then provide a better means to predict the risk of lacunar stroke.

	Acknowledgments

 
This study was funded by the Sylvia and Charles Viertel Foundation, The Queen Elizabeth Hospital (Department of Neurology), and Adelaide University. We thank the members of the Adelaide Stroke Genomics Collaboration (Dr M. Robinson, The Queen Elizabeth Hospital; Dr D.Thyagarajan, Flinders Medical Centre; Dr W. Jeffries, Lyell McEwin Health Service; and Dr R. Casse, Memorial Hospital). We are also grateful for the voluntary efforts of Sr J. Bradford and Sr F. Buchan, and Dr C. Rowe for his encouragement. The authors acknowledge the excellent technical assistance of A. Condina and S. Davis (molecular neurogenetics), B. Kenny (South Australian Department of Human Services, control recruitment), R. Attewell (Covance Pty Ltd, biostatistics), The Australian Red Cross (South Australia) tissue-typing laboratory (DNA preparation), and we thank Professor Geoffrey Donnan for reviewing the manuscript.

Received July 11, 2003; revision received January 9, 2004; accepted January 12, 2004.

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