Katarina Jood

Family History in Ischemic Stroke Before 70 Years of Age The Sahlgrenska Academy Study on Ischemic Stroke

Background and Purpose— Results from twin and family history studies of ischemic stroke suggest that future molecular genetic studies should focus on strictly defined stroke subtypes and younger cases. Accordingly, we investigated stroke subtypes, vascular risk factors, and family history in a large study of patients with ischemic stroke onset before age 70 years. Methods— Six hundred consecutive white participants with ischemic stroke (18 to 69 years) and 600 age- and sex-matched controls were examined for vascular risk factors and family history of stroke and myocardial infarction (MI). Stroke subtype was defined using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results— Family history of stroke was associated with overall ischemic stroke (multivariate odds ratio [OR], 1.75; 95% confidence interval [CI], 1.26 to 2.43), large-vessel disease (LVD) (OR, 1.88; 95% CI, 1.02 to 3.44), small-vessel disease (SVD, OR, 1.79; 95% CI, 1.13 to 2.84), and cryptogenic stroke (OR, 1.70; 95% CI, 1.13 to 2.56), but not with cardioembolic stroke. Family history of MI was strongly associated with LVD (OR, 3.25; 95% CI, 1.74 to 6.07), whereas no significant association were observed for other subtypes. We also found an independent association between family history of stroke and a favorable outcome after 3 months. Conclusion— Family history of stroke is an independent risk factor for ischemic stroke with onset before age 70 years. For the first time to our knowledge, we report this association not only for LVD and SVD but also for cryptogenic stroke, implying that future studies of the genetics of ischemic stroke should target these 3 subtypes.

Serum C-Reactive Protein Concentration and Genotype in Relation to Ischemic Stroke Subtype

Background and Purpose— C-reactive protein (CRP) has evolved as an inflammatory risk marker of cardiovascular disease. Several single-nucleotide polymorphisms at the CRP locus have been found to be associated with CRP levels. The aim of the present study was to investigate CRP levels and genetic variants in etiological subtypes of ischemic stroke. Methods— The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 consecutive ischemic stroke cases (18 to 69 years) and 600 matched controls from western Sweden. Stroke subtypes were defined by the TOAST classification. Serum CRP levels were determined by a high-sensitivity immunometric assay. Results— CRP levels were significantly higher for all ischemic stroke subtypes compared with controls, both in the acute phase and at the 3-month follow-up. After adjustment for traditional risk factors, CRP at follow-up was related to higher odds ratios (ORs) of overall ischemic stroke (OR, 1.25; 95% CI, 1.09 to 1.43) and large-vessel disease (OR, 1.48; 95% CI, 1.09 to 2.00). The CRP −286C>T>A, 1059G>C, and 1444C>T single-nucleotide polymorphisms showed significant associations with CRP levels. However, neither CRP genotypes nor haplotypes showed an association to overall ischemic stroke. Conclusions— This is the first large study on CRP in different TOAST subtypes in a young ischemic stroke population. CRP levels differed between etiological subtypes of ischemic stroke both in the acute phase and at the 3-month follow-up. CRP at follow-up was associated with overall ischemic stroke and the large-vessel disease subtype. Genetic variants at the CRP locus were associated with CRP levels, but no association was detected for overall ischemic stroke.

Fibrinolytic Gene Polymorphism and Ischemic Stroke

Background and Purpose— The tissue-type plasminogen activator (tPA) −7351C>T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G >5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke. Methods— In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria. Results— There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotype combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; P<0.05). Plasma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was highest among those with large-vessel disease and cardioembolic stroke. Conclusions— Neither the tPA −7351C>T nor the PAI-1 to 675 4G >5G polymorphism showed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G genotype combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compared with the heart.

Self-perceived psychological stress and ischemic stroke: a case-control study

BackgroundA growing body of evidence suggests that psychological stress contributes to coronary artery disease. However, associations between stress and stroke are less clear. In this study, we investigated the possible association between ischemic stroke and self-perceived psychological stress, as measured by a single-item questionnaire, previously reported to be associated with myocardial infarction.MethodsIn the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 consecutive patients with acute ischemic stroke (aged 18 to 69 years) and 600 age-matched and sex-matched population controls were recruited. Ischemic stroke subtype was determined according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Self-perceived psychological stress preceding stroke was assessed retrospectively using a single-item questionnaire.ResultsPermanent self-perceived psychological stress during the last year or longer was independently associated with overall ischemic stroke (multivariate adjusted odds ratio (OR) 3.49, 95% confidence interval (CI) 2.06 to 5.93). Analyses by stroke subtype showed that this association was present for large vessel disease (OR 3.91, 95% CI 1.58 to 9.67), small vessel disease (OR 3.20, 95% CI 1.64 to 6.24), and cryptogenic stroke (OR 4.03, 95% CI 2.34 to 6.95), but not for cardioembolic stroke (OR 1.48, 95% CI 0.64 to 3.39).ConclusionIn this case-control study, we found an independent association between self-perceived psychological stress and ischemic stroke. A novel finding was that this association differed by ischemic stroke subtype. Our results emphasize the need for further prospective studies addressing the potential role for psychological stress as a risk factor for ischemic stroke. In such studies ischemic stroke subtypes should be taken into consideration.

Thrombin Activatable Fibrinolysis Inhibitor Activation Peptide Shows Association With All Major Subtypes of Ischemic Stroke and With TAFI Gene Variation

Objective—Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis. The aim of the present study was to investigate the possible association between TAFI and overall ischemic stroke and ischemic stroke subtypes. Methods and Results—The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 cases (18 to 69 years) and 600 matched population controls. Stroke subtype was defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. TAFI was investigated at the protein level, by analyzing plasma levels of intact TAFI and released activation peptide [AP], and at the genetic level, by genotyping a selection of eleven single nucleotide polymorphisms. After adjustment for traditional risk factors, both TAFI measurements showed association with overall ischemic stroke (AP: odds ratio, 2.22; 95% confidence interval, 1.89 to 2.61; intact TAFI: odds ratio, 1.21; 95% confidence interval, 1.06 to 1.38; for 1-SD increase in AP and intact TAFI, respectively). AP showed associations with all 4 major subtypes of ischemic stroke and intact TAFI to large vessel disease and cryptogenic stroke. TAFI genotypes and haplotypes showed significant associations with both TAFI measurements. In contrast, no association was observed between genetic variants and overall ischemic stroke. Conclusion—TAFI levels show independent association with overall ischemic stroke. This association is stronger for released AP than for intact TAFI, and for released AP, it is present in all ischemic stroke subtypes.

The Association of the 4q25 Susceptibility Variant for Atrial Fibrillation With Stroke Is Limited to Stroke of Cardioembolic Etiology

Background and Purpose— Genome-wide association studies recently identified 2 variants on chromosome 4q25 as susceptibility factors for atrial fibrillation. Interestingly, these variants were subsequently also shown to be associated with stroke. However, it remains unclear whether 4q25 associates with all the stroke subtypes or with cardioembolic stroke in particular, which is often attributable to atrial fibrillation. Methods— We performed a large case-control association study in 4199 ischemic stroke patients, all subtyped according to Trial of Org 10172 in Acute Stroke Treatment criteria, and 3750 controls derived from 6 studies conducted in Australia, Austria, Belgium, Poland, Spain, and Sweden. Two variants on chromosome 4q25, rs1906591 and rs10033464, were genotyped. Results— Within cases, the A-allele of rs1906591 was associated with atrial fibrillation (odds ratio, 1.64 [95% CI, 1.43 to 1.90]; P=9.2 · 10−12), whereas rs10033464 was only marginally associated. There was an association between overall ischemic stroke and rs1906591 (odds ratio, 1.20 [95% CI, 1.09 to 1.32]; P=1.2 · 10−4). However, this was probably caused by the large effect of stroke of cardioembolic etiology because no relation was obtained in any other subgroup of stroke. The rs10033464 variant failed to show any relationship with ischemic stroke. Conclusions— We replicated the association of the rs1906591 variant on chromosome 4q25 with atrial fibrillation and ischemic stroke of cardioembolic etiology. The 4q25 locus failed to associate with noncardiac subtypes of ischemic stroke.

Serum IGF-I Levels Correlate to Improvement of Functional Outcome after Ischemic Stroke

CONTEXT AND OBJECTIVEnGH has positive cognitive effects when given to GH-IGF-I-deficient patients. GH and IGF-I exert both neuroprotective and regenerative effects on experimental stroke. We investigated whether the endogenous serum IGF-I (s-IGF-I) levels correlated with recovery of functional independence in patients who had suffered an ischemic stroke.nnnSUBJECTS AND METHODSnThe s-IGF-I levels were measured in 407 patients (260 males, 147 females) with mean age of 55 (range, 18-69) yr and 40 randomly selected matched controls who were previously included in the Sahlgrenska Academy Study on Ischemic Stroke. Serum samples were collected on two occasions: acutely at 1-10 d (median, 4 d) after stroke and 3 months after the stroke. Recovery after ischemic stroke was evaluated using the modified Rankin scale 3 and 24 months after the stroke, and the Scandinavian Stroke Scale was used for assessments during the acute stage and 3 months after the stroke.nnnRESULTSnThe s-IGF-I levels were higher in the acute stage than after 3 months and compared with the controls (P < 0.001 and P < 0.01, respectively), and the s-IGF-I levels were progressively lower in the elderly patients. The levels of s-IGF-I in the acute phase and after 3 months both positively correlated with improvement in the modified Rankin scale scores between 3 and 24 months (P = 0.001; r = 0.174, and P < 0.001; r = 0.24, respectively).nnnCONCLUSIONnA high s-IGF-I during the rehabilitation phase of stroke correlates to better recovery of long-term function.

Plasma Levels of von Willebrand Factor in the Etiologic Subtypes of Ischemic Stroke

Summary.u2002 Background:u2002Compared with coronary artery disease, there are few studies on von Willebrand factor (VWF) in ischemic stroke (IS). Moreover, there is little information on VWF in the etiologic subtypes of IS. Objectives: The aim of the present study was to investigate VWF in IS and in the etiologic subtypes of IS. Patients/methods: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) is a case–control study comprising 600 patients and 600 matched controls. Etiologic IS subtype was defined according to the TOAST criteria. Blood sampling was performed in the acute phase and after 3u2003months. Results: The levels of VWF were increased in overall IS, at both time‐points. The 3‐month VWF levels were increased in the subtypes of large‐vessel disease (LVD), cardioembolic (CE) stroke and cryptogenic stroke, but not in the subtype of small‐vessel disease (SVD), as compared with the controls. The acute phase VWF levels were significantly increased in all four subtypes. In the multivariate regression analysis, with vascular risk factors as covariates, the 3‐month VWF levels were associated with CE stroke and cryptogenic stroke, and the acute phase VWF levels with all subtypes. There were significant subtype‐specific differences in VWF, with the highest levels in LVD and CE stroke. Conclusions: The present results show that VWF levels are increased in patients with IS. Furthermore, the VWF levels differ between etiologic IS subtypes and thus, it is important to consider etiologic subtypes in future studies of VWF in patients with IS.

Fibrinogen gene variation and ischemic stroke

Summary.u2002 Background:u2002Plasma fibrinogen level and fibrin clot structure are heritable traits that may be of importance in the pathogenesis of ischemic stroke. Objectives:u2002To investigate associations between variation in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes, fibrinogen level, and ischemic stroke. Methods:u2002The Sahlgrenska Academy Study on Ischemic Stroke comprises 600 cases and 600 matched population controls. Stroke subtypes were defined according to TOAST criteria. Plasma fibrinogen level was measured by an automated clot‐rate assay. Eight tagging single nucleotide polymorphisms (SNPs) were selected to capture genetic variation in the FGA, FGG, and FGB genes. Results:u2002Plasma fibrinogen was independently associated with overall ischemic stroke and all subtypes, both in the acute stage (Pu2003<u20030.001) and at three‐month follow‐up (Pu2003<u20030.05). SNPs belonged to two haplotype blocks, one containing the FGB gene and the other the FGG and FGA genes. FGB haplotypes were associated with fibrinogen level (Pu2003<u20030.01), but not with ischemic stroke. In contrast, FGG/FGA haplotypes showed independent association to ischemic stroke but not to fibrinogen level. In an additive model with the most common FGG/FGA haplotype (A1) as reference, the adjusted odds ratios of ischemic stroke were 1.4 [95% confidence interval (95% CI) 1.1–1.8], Pu2003<u20030.01, 1.4 (95% CI 1.0–1.8), Pu2003<u20030.05, and 1.5 (95% CI 1.0–2.1), Pu2003<u20030.05 for the A2, A3, and A4 FGG/FGA haplotypes, respectively. Conclusion:u2002FGG/FGA haplotypes show association to ischemic stroke. This association is independent of fibrinogen level, thus suggesting that the association between ischemic stroke and variation at the FGG/FGA genes is mediated by qualitative rather than quantitative effects on fibrin(ogen).

Genetic Variation Within the Interleukin-1 Gene Cluster and Ischemic Stroke

Background and Purpose— Evidence is emerging that inflammation plays a key role in the pathophysiology of ischemic stroke (IS). The aim of this study was to investigate whether genetic variation in the interleukin-1&agr;, interleukin-1&bgr;, and interleukin-1 receptor antagonist genes (IL1A, IL1B, and IL1RN) is associated with IS and/or any etiologic subtype of IS. Methods— Twelve tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), which comprises 844 patients with IS and 668 control subjects. IS subtypes were defined according to the Trial of Org 10172 in Acute Stroke Treatment criteria in SAHLSIS. The Lund Stroke Register and the Malmö Diet and Cancer study were used as a replication sample for overall IS (in total 3145 patients and 1793 control subjects). Results— The single nucleotide polymorphism rs380092 in IL1RN showed an association with overall IS in SAHLSIS (OR, 1.21; 95% CI, 1.02–1.43; P=0.03), which was replicated in the Lund Stroke Register and the Malmö Diet and Cancer study sample. An association was also detected in all samples combined (OR, 1.12; 95% CI, 1.04–1.21; P=0.03). Three single nucleotide polymorphisms in IL1RN (including rs380092) were nominally associated with the subtype of cryptogenic stroke in SAHLSIS, but the statistical significance did not remain after correction for multiple testing. Furthermore, increased plasma levels of interleukin-1 receptor antagonist were observed in the subtype of cryptogenic stroke compared with controls. Conclusion— This comprehensive study, based on a tagSNP approach and replication, presents support for the role of IL1RN in overall IS.