Fibrinogen Gene Promoter ⴚ455 A Allele as a Risk Factor
for Lacunar Stroke
M. Martiskainen, MD; T. Pohjasvaara, MD, PhD; J. Mikkelsson, MD, PhD; R. Mäntylä, MD;
T. Kunnas, MSc; P. Laippala, PhD; E. Ilveskoski, MD, PhD; M. Kaste, MD, PhD;
P. J. Karhunen, MD, PhD; T. Erkinjuntti, MD, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Elevated fibrinogen levels are suggested to increase the risk of myocardial infarction and
stroke. Carriers of the A allele of the fibrinogen ⫺455G/A polymorphism have increased plasma fibrinogen levels. We
studied the association of this polymorphism with stroke subtype in the Stroke Aging Memory (SAM) cohort.
Methods—The SAM cohort comprises 486 consecutive patients 55 to 85 years of age who, 3 months after ischemic stroke,
completed a detailed stroke assessment. Stroke subtypes were examined with MRI. ⫺455G/A genotype was determined
by polymerase chain reaction. MRI and genotype data were available for the 299 patients who constitute the present
study population.
Results—Genotype distributions were 64.9% (GG), 31.8% (GA), and 3.3% (AA). In a logistic regression model with age,
sex, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, myocardial infarction, arrhythmia, atrial
fibrillation, peripheral arterial disease, and smoking as possible confounders, there was a significant association between
A⫹ genotype and ⱖ3 lacunar infarcts (odds ratio [OR], 2.57; 95% CI, 1.23 to 5.36; P⫽0.01). Hypertensive patients
carrying the A allele had increased risk (OR, 4.24; 95% CI, 1.29 to 13.99; P⫽0.02) for ⱖ3 lacunar infarcts. A similar
increase in risk was observed among smokers with the A⫹ genotype (OR, 2.67; 95% CI, 0.92 to 7.77; P⫽0.07).
Conclusions—Stroke patients carrying the A allele of the B␤-fibrinogen ⫺455G/A polymorphism frequently presented
with multiple lacunar infarcts. This association was stronger among hypertensives and smokers. These associations
suggest that the A allele may predispose to atherothrombotic events in cerebrovascular circulation. (Stroke. 2003;34:
886-891.)
Key Words: fibrinogen 䡲 genetics 䡲 infarcts 䡲 lacunar infarction 䡲 stroke
S
the vessel wall/subendothelial collagen.16 –19 Fibrinogen levels
rise transiently as a result of inflammation, smoking, and
cold.20 –24 Age, sex, and genetic and hormonal factors also
contribute to fibrinogen levels.21–23,25
G/A variability in the ⫺455 locus of the B␤-fibrinogen
promoter region, especially the carrier status of the A allele,
has previously been shown to be associated with elevated
fibrinogen levels and to increase the risk of cardiovascular
diseases and ischemic stroke.15,26 –33 In this study, we evaluated the association of the B␤-fibrinogen ⫺455G/A promoter
polymorphism with the type and number of strokes in a
population of 299 stroke patients.
troke is a leading cause of death in Western societies,
resulting in disability and socioeconomic burden. There
are several known risk factors for stroke and cerebral arteriosclerosis, including dyslipidemia, hypertension, diabetes,
smoking, heart failure, atrial fibrillation (AF), and increasing
age.1,2 Little is known about inherited factors that could
predispose or modify the type and consequences of stroke.
Some studies have reported that family history of stroke is an
independent risk factor for all stroke types, whereas others
have failed to find such an association.3,4
Several studies indicate the role of fibrinogen as a risk factor
for ischemic heart disease, myocardial infarction (MI), stroke,
venous thrombosis, and peripheral arterial disease (PAD).5–14
Blood viscosity and fibrin formation are affected by circulating
fibrinogen concentration.15 Immobilized fibrinogen on endothelial cells acts as a substrate for platelet aggregation by binding to
␣IIb/␤3 integrins on the adjacent platelet surfaces and adhering to
Subjects and Methods
Patients
Procedures of the Helsinki Stroke Aging Memory (SAM) stroke
cohort were detailed in a report on methods and baseline findings.34
Received September 24, 2002; accepted October 11, 2002.
From the School of Medicine (M.M., J.M., T.K., E.I., P.J.K.) and School of Public Health (P.L.), University of Tampere, Tampere, Finland; Centre
of Laboratory (M.M., J.M., T.K., E.I., P.J.K.) and Research Unit (P.L.), Tampere University Hospital, Tampere, Finland; Memory Research and Stroke
Units, Department of Clinical Neurosciences (T.P., M.K., T.E.), and Department of Radiology (R.M., P.L.), Helsinki University Central Hospital,
Helsinki, Finland; and Lohja District Hospital (T.P.), Lohja, Finland.
Correspondence to Pekka J Karhunen, MD, Department of Forensic Medicine, Medical School, University of Tampere, 33014 Tampere, Finland.
E-mail [email protected]
© 2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000060029.23872.55
886
Martiskainen et al
Fibrinogen Gene ⴚ455 A Allele and Lacunar Infarcts
887
Briefly, 486 consecutive patients 55 to 85 years of age were
evaluated 3 months after ischemic stroke (the index stroke). Subjects
underwent a structured medical and neurological history based on
review of all available hospital charts, interview of the subject and a
knowledgeable informant, and a structured clinical and neurological
examination performed by a board-certified neurologist (T.P.). In
addition, all cases were reviewed by a senior neurologist (T.E.).
History of hypertension was defined as blood pressure ⱖ160/
95 mm Hg. The neurological examination focused on factors and
features related to dementia and stroke similar to the method of the
Memory Research Unit, Department of Neurology, University of
Helsinki, and the National Stroke Data Bank.35,36 Laboratory evaluations included total and high-density lipoprotein cholesterol,
triglycerides, and fasting blood glucose. Total cholesterol was
considered high at ⬎6.5 mmol/L. History of main vascular risk
factors was obtained as described earlier.34,37
The study was approved by the ethics committee of the Department of Clinical Neurosciences, Helsinki University Central Hospital (Helsinki, Finland). The study design was fully explained, and
written information was offered to the patients; if they agreed to
participate, they signed a written consent form.
TABLE 1. Main Characteristics of Patients in the SAM Cohort
With MRI and Genotype Data According to ⴚ455G/A Genotypes
Genotype
Characteristic
G/G (n⫽119)
G/A⫹A/A (n⫽66)
P*
Mean age (SD), y
70.8 (7.45)
71.8 (7.17)
0.37†
Male sex, %
50.4
45.5
0.52
Hypertension, %
52.9
53.0
0.99
Diabetes, %
20.2
22.7
0.68
Hyperchol, %
16.0
13.6
0.67
Mean fs-Chol (SD)
6.1 (5.2)
6.1 (5.3)
0.68†
Mean fs-Chol-HDL
(SD)
1.2 (0.6)
1.2 (0.7)
0.93†
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1.7
1.5
0.93
Smoking, %
51.3
60.6
0.22
MI, %
15.1
18.2
0.59
Arrhythmia, %
20.2
19.7
0.94
General Clinical Assessment
AF, %
13.6
15.2
0.77
A total of 396 patients (81.5%) in the SAM cohort underwent MRI.
From the MRI data, stroke subtypes were then examined. Inclusion
and exclusion criteria are detailed elsewhere.38 – 40 Fibrinogen
⫺455G/A genotype was successfully determined for 371 subjects
(76.3%). Information on both genotype and MRI was available on
299 subjects (61.5%), who formed the final study population. The
study population did not differ from the remaining 187 patients
(⫺455G/A genotype or MRI data were not available) in terms of
demographic and clinical characteristics (age, sex, history of hypertonia, MI, angina pectoris, AF, smoking, diabetes, hypercholesterolemia, hypertriglyceridemia, or history of previous cerebrovascular
disease). The 96 patients for whom MRI was but ⫺455G/A genotype
was not performed did not differ in radiological (MRI) features,
including mean Fazekas WM score, percentage of moderate or
severe degree of medial temporal lobe atrophy, presence of any
central or cortical atrophy, or number of lacunar infarcts.38 The
analyzed and excluded patients did not differ in either vascular risk
factors or stroke type.
PAD, %
15.1
9.1
0.24
Infarct Subtypes
Different infarct subtypes were determined by MRI findings. Infarction was defined as lacunar if it was situated in deep white or gray
matter and its diameter was 3 to 9 mm. By definition, a large-vessel
infarct was located in the corticosubcortical layers of cerebral
hemispheres in the territories of superficial branches of anterior,
middle, or posterior cerebral artery, and its diameter was
ⱖ10 mm.39,40
DNA Procedures
DNA was separated from frozen blood samples through standard
procedures. Polymerase chain reaction (PCR) for DNA amplification
was carried out as previously described.41 PCR reactions were
performed with a PTC 100 (Perkin-Elmer) in a 50-␮L reaction with
50 ng of genomic DNA, 200 ng of each appropriate primer
(5⬘-CTCCTCATTGTCGTTGACACCTTGGGAC-3⬘ and 5⬘GAATTTGGGAATGCAATCTCT GCTACCT-3⬘), 200 ␮mol/L of
each deoxynucleotide triphosphate, and 1 U of Dynazyme II DNA
polymerase in 1⫻ reaction buffer (Finnzymes OY). Samples were
incubated for 5 minutes at 95°C, followed by 34 cycles of 1 minute
at 95°C, 1 minute at 55°C, and 1 minute at 72°C. PCR products (20
␮L) were digested with 10 U of the HaeIII restriction enzyme
(Promega Corp) and resolved in 2% agarose gel for determination of
⫺455G/A genotype.
Statistical Analysis
SPSS/WIN (version 10.0, SPSS Inc) software was used to carry out
statistical analyses. The association of age with the lacunar and
Hypertriglycerides, %
*Pearson’s ␹2.
†t test.
large-vessel infarcts was calculated by Student’s t test. The associations of sex, hypertension, hypercholesterolemia, hypertriglyceridemia, smoking, and diabetes with lacunar and large-vessel infarcts
were examined by Pearson’s ␹2 test. Logistic regression analysis
(enter and forward stepwise models) with age, sex, hypertension,
diabetes, hypercholesterolemia, hypertriglyceridemia, MI, arrhythmia, AF, PAD, and smoking as confounders was used to further
study the association of ⫺455G/A genotype with lacunar and
large-vessel infarcts, as well as the dependence between genotype
and conventional risk factors.
Results
Fibrinogen ⴚ455G/A Polymorphism and Lacunar
Infarcts in Stroke Patients
The allele distribution was in Hardy-Weinberg equilibrium.
Genotype distributions of the ⫺455G/A locus were 64.9% for
GG, 31.8% for G/A, and 3.3% for A/A. The frequency of the
A allele was 19.2%. These frequencies closely correspond to
the population frequencies among whites; in the Etude
Cas-Temoins sur l’Infarctus du Myocarde (ECTIM) study,
the allele frequencies were 65.9%, 29.1%, and 4.9%, respectively.26 No relation between known stroke risk factors and
⫺455G/A genotypes was observed (Table 1). Of the 299
patients, 61.9% (n⫽185) had lacunar and 58.2% (n⫽174) had
large-vessel infarcts. Thus, 20.1% of the patients (n⫽60) had
both types of stroke.
Patients with the A⫹ genotype were overrepresented
(P⫽0.01) among individuals with ⱖ3 lacunar infarcts (49.1%
versus 27.3%), whereas patients who had 1 lacunar infarct
were more often G/G homozygotes. In a forced logistic
regression analysis, there was an association between the A⫹
genotype (odds ratio [OR], 2.72; 95% CI, 1.18 to 6.27;
P⫽0.02) and ⱖ3 lacunar infarcts (Table 2). Age was significantly associated with 2 (OR, 1.06; 95% CI, 1.00 to 1.13;
P⫽0.04) and ⱖ3 (OR, 1.06; 95% CI, 1.00 to 1.13; P⫽0.04)
lacunar infarcts. The association between A⫹ genotype and
ⱖ3 lacunar infarcts persisted in a forward stepwise logistic
888
Stroke
TABLE 2.
April 2003
Comparisons of Characteristics Between 1 and 2 Lacunar Infarcts and Between 1 and Multiple (>3) Lacunar Infarcts
Lacunar Infarcts
Significance
Significance
OR (95% CI)*
P*
ⱖ3 Lacunar Infarcts
(n⫽53)
72.3 (6.55)
1.06 (1.00–1.13)
0.04
72.1 (7.29)
1.06 (1.00–1.13)
0.04
45.5
1.67 (0.73–3.86)
0.23
58.5
2.07 (0.88–4.88)
0.10
51.9
54.5
1.34 (0.61–2.93)
0.47
52.8
1.31 (0.59–2.91)
0.51
Diabetes, %
19.5
16.4
0.77 (0.28–2.08)
0.60
28.3
1.75 (0.67–4.56)
0.25
Hypercholesterolemia, %
15.6
16.4
2.47 (0.75–8.10)
0.14
13.2
1.31 (0.39–4.38)
0.66
Hypertriglyceridemia, %
3.9
0
NA†
0.71
0
NA†
0.82
MI, %
13.0
20.0
1.28 (0.44–3.72)
0.66
17.0
0.91 (0.29–2.81)
0.86
Arrhythmia, %
22.1
27.3
0.70 (0.17–2.88)
0.62
9.4
NA†
0.74
AF, %
14.3
18.5
1.76 (0.33–9.50)
0.51
9.4
NA†
0.75
PAD, %
10.4
18.2
2.32 (0.75–7.18)
0.14
11.3
1.01 (0.28–3.70)
0.99
Smoking, %
53.2
47.3
0.57 (0.24–1.35)
0.20
64.2
0.98 (0.39–249)
0.97
⫺455G/A A⫹, %
27.3
34.5
1.51 (0.68–3.35)
0.31
49.1
2.72 (1.18–6.27)
0.02
Variable
1 (n⫽77)
2 (n⫽55)
Mean age (SD), y
69.6 (7.76)
Male sex, %
44.2
Hypertension, %
OR (95% CI)*
P*
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*Forced logistic regression model.
†Not available because of 0 frequencies.
regression model (OR, 2.57; 95% CI, 1.23 to 5.36; P⫽0.01).
Multiple lacunar infarcts showed no association with other
known risk factors.
Dependence Between ⴚ455G/A Genotype and Risk
Factors for Lacunar Infarcts
In a logistic regression model, the ⫺455G/A genotype
showed a significant interaction with hypertension (P⫽0.004)
and smoking (P⫽0.03) on the occurrence of multiple lacunar
infarcts, whereas there was no significant dependence between genotype and other stroke risk factors. The significant
interactions between genotype and hypertension or smoking
were further studied by forming a new variable with different
risk factor combinations. In these variables, categories were
generated in ascending order of possible risk for stroke: (1)
GG homozygotes without risk factor, (2) GG homozygotes
with risk factor, (3) carriers of the A allele (GA⫹AA) without
other risk factor, and (4) individuals with both risk factors (A
allele and other). When studying the dependence between age
and genotype, we used mean age (71.1 years) as a cutoff point
to form a categorical variable, which was then combined with
genotype.
Forced logistic regression analysis of the genotypehypertension variable, including sex, age, diabetes, hypertriglyceridemia, hypercholesterolemia, MI, arrhythmia,
AF, PAD, and smoking as confounders, revealed an
association in which individuals with both risk factors
(genotype and hypertension) had a significantly higher risk
(OR, 4.24; 95% CI, 1.29 to 13.99; P⫽0.02) for ⱖ3
(multiple) lacunar infarcts compared with individuals who
were GG homozygotes without hypertension (Table 3). In
addition, smokers carrying the A allele had increased risk
(OR, 2.67; 95% CI, 0.92 to 7.77; P⫽0.07) for developing
multiple lacunar infarcts, although the association was
marginal. Similar results were observed in forward stepwise logistic regression analysis.
Large-Vessel Infarcts and the ⴚ455G/A
Polymorphism
In a forced logistic regression model, male sex (P⫽0.03) was
associated with 2 large-vessel infarcts compared with 1
large-vessel infarct (Table 4). In addition, age (P⫽0.01) was
associated with ⱖ3 large-vessel infarcts (Table 4). In a
TABLE 3. Dependence Between ⴚ455G/A Genotypes and Risk Factors (Hypertension and Smoking) and Their Associations With
Number of Lacunar Infarcts
Lacunar Infarcts
Interaction Variables
1 (n⫽77)
2 (n⫽55)
Significance
OR (95% CI)*
P*
ⱖ3 Lacunar Infarcts
(n⫽53)
Significance
OR (95% CI)*
P*
Hypertension⫺ and GG-genotype, %
32.5
29.1
Reference
28.3
Reference
Hypertension⫹ and GG-genotype, %
40.3
36.4
1.16 (0.45–2.97)
0.75
22.6
0.86 (0.32–2.35)
0.77
Hypertension⫺ and A⫹ genotype, %
15.6
16.4
1.21 (0.39–3.80)
0.74
18.9
1.60 (0.52–4.94)
0.41
0.19
30.2
4.24 (1.29–13.99)
0.02
22.6
Reference
Hypertension⫹ and A⫹ genotype, %
11.7
18.2
2.18 (0.67–7.05)
Smoking⫺ and GG-genotype, %
37.7
30.9
Reference
Smoking⫹ and GG-genotype, %
35.1
34.5
0.92 (0.34–2.51)
0.88
28.3
1.07 (0.35–3.29)
0.91
Smoking⫺ and A⫹ genotype, %
9.1
21.8
3.42 (1.03–11.34)
0.05
13.2
3.16 (0.76–13.03)
0.11
Smoking⫹ and A⫹ genotype, %
18.2
12.7
0.65 (0.19–2.17)
0.48
35.8
2.67 (0.92–7.77)
0.07
*Forced logistic regression model.
Martiskainen et al
TABLE 4.
Fibrinogen Gene ⴚ455 A Allele and Lacunar Infarcts
889
Comparisons of Characteristics Between 1 and 2 Large-Vessel Infarcts and Between 1 and >3 Large-Vessel Infarcts
Large-Vessel Infarcts
Significance
OR (95% CI)*
P*
Significance
ⱖ3 Large-Vessel
Infarcts (n⫽25)
OR (95% CI)*
P*
Characteristic
1 (n⫽113)
2 (n⫽36)
Age mean (SD)
70.7 (7.75)
71.4 (7.94)
1.03 (0.97–1.10)
0.28
74.2 (6.20)
1.10 (1.02–1.19)
0.01
Male sex, %
45.1
66.7
2.82 (1.08–7.35)
0.03
52.0
1.79 (0.61–5.28)
0.29
Hypertension, %
48.7
44.4
1.13 (0.47–2.70)
0.78
52.0
1.60 (0.59–4.36)
0.36
Diabetes, %
26.5
11.1
0.30 (0.09–1.05)
0.06
28.0
1.15 (0.38–3.45)
0.81
Hypercholesterolemia, %
15.9
5.6
0.78 (0.14–4.41)
0.78
8.0
1.12 (0.20–6.46)
0.90
Hypertriglyceridemia, %
5.3
0
NA†
0.79
0
NA†
0.77
MI, %
16.8
27.8
2.10 (0.76–5.78)
0.15
24.0
1.48 (0.45–4.87)
0.52
Arrhythmia, %
31.0
27.8
0.71 (0.12–4.39)
0.71
32.0
0.49 (0.07–3.66)
0.49
AF, %
24.1
22.2
1.11 (0.16–7.58)
0.92
24.0
1.68 (0.20–14.38)
0.64
PAD, %
9.7
19.4
2.90 (0.86–9.86)
0.09
32.0
5.44 (1.55–19.12)
0.008
Smoking, %
49.6
55.6
0.96 (0.37–2.45)
0.92
56.0
1.05 (0.34–3.20)
0.94
⫺455G/A A⫹, %
27.3
34.5
1.08 (0.45–2.58)
0.86
36.0
1.16 (0.42–3.19)
0.78
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*Forced logistic regression model.
†Not available because of 0 frequencies.
forward stepwise logistic regression model, male sex (OR,
2.57; 95% CI, 1.15 to 5.72; P⫽0.02) and diabetes (OR, 0.31;
95% CI, 0.10 to 0.97; P⫽0.04) were significantly associated
with 2 large-vessel infarcts, whereas age (OR, 1.08; 95% CI,
1.01 to 1.15; P⫽0.03) and PAD (OR, 5.04; 95% CI, 1.68 to
15.10; P⫽0.004) were significantly associated with ⱖ3
large-vessel infarcts. There were no significant dependencies
between the variables studied and genotype as risk factors for
large-vessel infarcts.
Discussion
In previous studies, fibrinogen has emerged as a risk factor
for stroke, ischemic heart disease, MI, venous thrombosis,
and PAD.9 –13 In this study, we report that the A allele of the
functional fibrinogen promoter ⫺455G/A polymorphism was
associated with lacunar infarcts, thus predicting the type of
stroke. Age also contributed to lacunar infarcts. There was a
significant dependence between hypertension and the A
allele, contributing to multiple lacunar stroke phenotypes. In
addition, smoking increased the risk of A⫹ genotype for
multiple lacunar stroke phenotypes. However, hypercholesterolemia and hypertriglyceridemia did not show an association with A⫹ genotype on the risk for multiple lacunar
infarcts. These findings imply that the ⫺455G/A fibrinogen
polymorphism may aid in the development and progression
of cerebral arteriosclerosis.
The fibrinogen ⫺455G/A polymorphism has been associated with stroke in 3 previous studies.29,32,33 Kessler et al32
found an association between the AA genotype and largevessel infarcts (P⫽0.045), and Liu et al33 associated the A⫹
genotype with ischemic stroke (P⬍0.02). The significant
association (OR, 2.05; P⫽0.05) between fibrinogen genotype
and ischemic stroke has been reported among hypertensive
patients by Nishiuma et al.29 They also found that the A⫹
genotype was more common in the atherothrombotic
(P⫽0.009) and lacunar (P⫽0.063) stroke groups than in
controls.29
The limitations of our study include the fact that plasma
fibrinogen measurements were not available. However, several studies have shown that the A allele of the ⫺455G/A
polymorphism is associated with elevated plasma fibrinogen
concentration and that A instead of G in the ⫺455 position
produces a 1.2- to 1.5-fold increase in fibrinogen B␤ chain
transcription.41– 46 The B␤ chain transcription is a ratelimiting step in the synthesis of the total functional fibrinogen
molecule. Fibrinogen is synthesized in hepatocytes, and
cytokines and growth factors participate in the process.46
Increased viscosity and higher available substrate quantity
resulting from elevated plasma fibrinogen concentration may
promote coagulation and act as a risk for small-vessel
thrombotic occlusion, thus affecting the phenotype of the
cerebral infarction.
Smoking is a risk factor for atherosclerosis, and it increases
fibrinogen levels by increasing B␤-chain transcription similar
to an ongoing low-grade acute-phase reaction.21,47 Along that
line, we found an association between the A⫹ genotype and
smoking on the occurrence of multiple lacunar infarcts,
although the statistical significancy was marginal (P⫽0.07).
We believe that the A⫹ genotype and smoking, both of which
increase fibrinogen levels, act synergistically to increase the
risk of stroke and that hypertension participates in the
atherosclerotic process by injuring vascular endothelial cells.
In our study, hypertension showed a significant association
with the A⫹ genotype as a predisposing factor for multiple
lacunar infarcts. It has been shown that in hypertensive
patients higher fibrinogen levels are associated with targetorgan damage.48
Our results may be explained by assuming that the A⫹
genotype and resulting increased fibrinogen concentration in
circulation may contribute to the progression of arteriosclerosis primarily in smaller cerebral arteries with slower blood
flow rather than in large vessel.5,10 –14 In this way, it may
predispose to the development of occlusions in small cerebral
arteries and finally to multiple lacunar infarcts. The present
results also suggest that along with known risk factors,
890
Stroke
April 2003
genetic variation in fibrinogen synthesis seems to play a
strong role both as a risk factor and as a modifying factor
affecting stroke phenotype.
It is also known that cardiovascular disease phenotypes are
complex and polygenic in nature and that disease phenotype
is under the negative or positive influence of geneenvironment interactions. Our study thus suggests that combining genetics with the traditional risk factors may increase
diagnostic accuracy and provide possibilities for more targeted preventive interventions, progression indicators, and
possibly effective treatments. These findings also suggest that
high-risk groups could be screened for a prothrombotic
variant associated with multiple lacunar infarcts. More research is needed to reveal the complex picture of geneenvironment interactions.
Acknowledgments
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
This study was supported in part by grants from the Medical Council
of the Academy of Finland (Helsinki); Clinical Research Institute,
Helsinki University Central Hospital; Finnish Alzheimer Foundation
for Research; Yrjö Jahnsson Foundation (Helsinki); Elli and Elvi
Oksanen Fund of the Pirkanmaa Fund under the auspices of the
Finnish Cultural Foundation (Tampere); Medical Research Fund of
Tampere University Hospital; Finnish Medical Foundation; Aarne
Koskelo Foundation; and Finnish Foundation for Cardiovascular
Research (Helsinki).
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Stroke. 2003;34:886-891; originally published online March 13, 2003;
doi: 10.1161/01.STR.0000060029.23872.55
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