XVII. European Stroke Conference
Nice, France

Poster Session: Genetic disorders
 

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
The CCR5 chemokine receptor delta32 polymorphism in ischemic stroke.
N. Kostulas    I. Markaki    V. Kostulas     K. Kostulas                                            
 
Neuro-Angiological Research Center, Karolinska Institutet

SWEDEN

Background: The immune inflammatory response is involved in the development of the arteriosclerotic lesion. CCR5 is a chemokine receptor which plays a role in the pro-inflammatory response. A 32-bp deletion of the CCR5 gene (the CCR5 delta32 mutation) abolishes the receptor from the cell surface. The delta32 allele has been associated with genetic susceptibility to abdominal aortic aneurysm development and a higher risk of rupture. Carriers of the CCR5 delta32 allele have also been reported to be protected against early myocardial infarction and severe coronary artery disease. The purpose of this study was to examine the association between ischemic stroke (IS) and the CCR5 delta32 polymorphism. Methods: The CCR5 delta32 polymorphism was genotyped in 1111 individuals: 303 IS patients and 808 healthy controls. Genotyping was performed with TaqMan polymerase chain reaction. Alleles not carrying the mutation were coded as wild-type (wt). Genotype and allele frequencies of patients and controls were compared using the chi-squared test. Results: The study included 303 patients (mean age: 70+/-11 years old; females: 36%). A total of 203 patients (66%) were ≥ 65 years old (mean age: 76+/- 6) and 100 patients (34%) were younger than 65 years old (mean age: 57+/-7). The presence in the genotype of at least one delta32 allele in IS (wt/wt vs. wt/d32 + d32/d32 genotype) did not differ in frequency compared to controls (OR: 1.1; 95% CI, 0.8-1.5; P=0.5). The delta32 allele frequency was 12% in IS versus 13% in healthy controls (P=0.4). No significant differences were found in genotype and allele frequencies between age groups in IS and controls. Discussion: The delta32 polymorphism of the CCR5 chemokine receptor does not seem to influence the susceptibility of ischemic stroke. Further studies are warranted.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
The International Stroke Genetics Consortium: A Progress Report
L. Lynelle                                                                  
International Stroke Genetics Consortium
Center for Human Genetic Research

USA

Background: While accumulated evidence points to a substantial role for genetics in stroke susceptibility, traditional candidate gene studies have generally failed to yield replicated genetic associations for common forms of stroke. This failure is likely due to limitations resulting from small sample sizes (hence low power), lack of phenotypic uniformity across studies, inadequately conservative p value thresholds, and, limited assessment of the extent of human genetic variation. The revolutionary approach of genome-wide association has overcome these limitations, yielding dozens of novel confirmed genetic risk factors for common conditions such as myocardial infarction, diabetes, atrial fibrillation and many others. The International Stroke Genetics Consortium (ISGC) was formed in April 2007 in order to take advantage of this revolution in human genetics and discover the genes that cause stroke. Methods: Committed to the principles of pursuing the highest quality genetic investigations and awarding credit in a manner that fairly recognizes the contributions of all collaborators, the ISGC currently consists of 15 member institutions from Europe, North America, and Asia. There have been 4 international meetings in Europe and North America. Results: ISGC members have agreed to share their more than 15,000 cases and 15,000 controls for ISGC studies. Six joint projects have been initiated and more are planned. Interim analyses of ongoing projects, including whole genome association studies, will be presented. Discussion: ISGC offers an excellent opportunity to explore genetic causes of stroke. The ISGC is open to all investigators with the interest and resources to participate.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
Phosphodiesterase 4D (PDE4D) gene variants on chromosome 5q are associated with ischemic stroke recovery at 3 months
H. Manso    T. Krug    T. Magalhaes     B.V.Fonseca     J. Sobral    I. Albergaria     G. Gaspar     J.M.Ferro    S.A.Oliveira   A.M.Vicente
PORTuguese Stroke GENetics (PORTSGEN) Group
Instituto Nacional de Saude Dr. Ricardo Jorge

PORTUGAL

Background - In spite of evidence for a familial aggregation of stroke and poor functional outcome, few studies so far have analysed the role of genetic factors in stroke outcome and recovery. Genes implicated in neuroprotection and neuroinflammation are plausible candidates for a role in functional recovery after a stroke event. One such gene is PDE4D, previously reported to be associated with stroke risk, which regulates the degradation of cAMP and thus plays a role in many processes crucial for neuroinflammation and protection. Methods – Genetic markers in PDE4D were tested for association with recovery measures in 430 ischemic stroke patients. Stroke recovery was assessed 3 months after a first stroke episode, using the modified Rankin Scale (mRS). Patients were classified in two groups: good recovery (mRS≤1) or poor recovery (2≤mRS<6). 52 markers in the 5’ region of PDE4D, covering genetic variation in this gene region and including SNPs previously associated with stroke risk, were tested for association with mRS scores. Binary logistic regression analysis was carried out to adjust for clinical severity parameters and risk factors with a significant impact on stroke recovery. Results – History of hypertension, aphasia, paresis, consciousness disturbance and medical complications during hospitalization were significantly associated with stroke recovery, and therefore were incorporated in the test model as co-variates. Seven SNPs were associated with stroke outcome (0.00098<P<0.048), with specific variants influencing good or poor recovery. Haplotype analysis corroborated single marker results. Discussion - The results suggest a contribution of PDE4D gene variants to the process of neuronal recovery after ischemic stroke that is independent of stroke severity.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
PDE4D and ALOX5AP genes in ischemic stroke: Meta-analysis in Caucasian population and pilot study in a Spanish population.
S. Domingues-Montanari    I. Fernández-Cadenas    A. Del Rio     M. Mendioroz     L. Ortega    P. Delgado     C.A.Molina     A. Rosell    J. Álvarez-Sabín   J. Montaner
 
Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Vall d’Hebron Hospital, Barcelona

SPAIN

Background: The deCODE project found an association between the Phosphodiesterase 4D (PDE4D) and Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) genes with ischemic stroke. We aimed to analyze the role of these genes in published reports and to determine the frequency of target polymorphisms in a Spanish population. Methods: We performed a meta-analysis with 19 reports in Caucasians with ischemic stroke analyzing 5 haplotypes and 14 SNPs in a total of 6679 cases and 7029 controls. We studied 5 SNPs of the PDE4D gene and 1 SNP of ALOX5AP in 450 Spanish ischemic stroke patients involving the middle cerebral artery territory. Results: For PDE4D, the meta-analysis showed 2 SNPs presenting association with ischemic stroke, rs153031 (p=0.02 OR=1.19) and rs1396476 (p=0.02 OR=1.34). In the Spanish population, we found a tendency of the same SNP rs1396476, (p=0.056; OR=0.649) and an association of rs152312 (p=0.005 OR=2.673) with ischemic stroke, when comparing with the frequencies observed in the European population of the HapMap project. For ALOX5AP, we observed an association of HapA haplotype with ischemic stroke (p=0.012; OR=1.27), but no association was found for the SNPs studied individually. In the Spanish population, no association was found among the different SNPs with ischemic stroke. Discussion: It exists an association between PDE4D and ALOX5AP genes with ischemic stroke in Caucasian patients. In fact, among Spanish population, we observed an association of 2 SNPs of the PDE4D gene with ischemic stroke. In conclusion these findings suggest that SNPs of the PDE4D and ALOX5AP genes could be genetic risk factors for ischemic stroke , justifying the need to perform a large case-control study in Spanish population and other non-studied European populations.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
Characterization of Notch3 mutations in Spanish CADASIL patients: implications for diagnosis and comparison among European populations
A. del Río Espínola    M. Mendióroz    I. Rojas Marcos     I. Ampuero     E. Coto    M.A.Galindo     M. Seijoo     S. Domingues    I. Fernández Cadenas   J. Montaner
 
Neurovascular Research Laboratory (Vall d'Hebron Hospital)

SPAIN

Introduction: Although CADASIL is caused by mutations in the NOTCH3 gene, screening of mutations in NOTCH3 gene usually focus only in exons 3 and 4, that present in several series the major incidence of mutations (hot spot). Therefore, we aimed to compare the variation in NOTCH3 mutations among Spain and different European populations. Methods: In a multicentric study we reviewed all definitive CADASIL cases reported in Spain (n=130) comparing the data with other European series . The presence of mutations in exons 3 and 4 of NOTCH3 was carried out by direct sequencing in 75 patients form our center with clinical suspicion of CADASIL. We performed a meta-analysis of the mutational spectrum with all the series of European patients (400 families). Results: In Spain, the highest incidence of mutations appeared in exons 3 and 4 (20 and 64% of all mutations described) followed by exons 11, 8, 15 and 19. Comparing our results with other series, exons 3 and 4 presented also the highest incidence in France, United Kingdom and Germany, but in Netherlands, Italy and Portugal other exons were more important. The meta-analysis of all reported series revealed that sequencing 9 of the 33 exons of NOTCH3 gene might be enough to identify the pathogenic mutation in 95% of the patients. Screening of exons 3 and 4 in our hospital detected the pathogenic mutation in <10% of patients with clinical suspicion of CADASIL. Conclusion: There is a geographical variation in NOTCH3 mutations among the different European series. Meta-analysis revealed that partial sequencing of NOTCH3 gene might be a sensitive genetic test. However, the screening restricted only to exons 3 and 4 in clinical suspicion of CADASIL is not definitive to rule out the presence of the disease among those patients.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
GENETIC POLYMORPHISMS FOR THE STUDY OF MULTIFACTORIAL STROKE: A COMPREHENSIVE REVIEW
A. Bersano    E. Ballabio    S. Lanfranconi     P.L.Baron     N. Bresolin    L. Candelise                             
 
Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena

ITALY

Background/Objectives: Stroke is believed to be a complex multifactorial disease arising from a wide number of gene-gene and gene-environment interactions. A wide number of candidate genes has been investigated in stroke even ifonly few polymorphisms have been consistently associated with stroke, probably for methodological bias. The clinical utility and validity of these associations has still to be assessed. Our aim is to identify thought a literature review a panel of possible genes associated with ischemic stroke risk that could be useful either for planning future meta-analyses either for deciding new research strategies for stroke genetics. Methods: Electronic databases were searched up until May 2007 for case control studies, prospective cohort studies, reviews and meta-analyses in English-language on any candidate gene for ischemic stroke in humans. The published results of association and linkage studies (case control studies and meta-analysis) were reported as odds ratio (OR) and 95% confidence intervals (95% CI) as calculated by the authors. No further statistical or quality analysis was performed Results Data from 181 case-control studies and 30 meta-analyses were included. We found a total of 8 polymorphisms of 7 candidate genes (F5, F2, PAI-1, GPIBA, ACE, MTHFR, APOE) possibly associated with an increased risk of stroke and worthy of deeper evaluation in further studies. The association between the other 44 SNPs evaluated and stroke was considered ‘uncertain’ or ‘not demonstrated’. Conclusions Since advanced research approaches suggest the need of replication on independent cohorts to confirm associations between molecular variants and stroke, our analysis could represent a useful tool to address further molecular investigations towards the candidate-genes SNPs, which seem more likely related to stroke. New prospectives could derive from the ongoing development of high-throughput genomic technologies such as genome-wide assays (GWA), which allows to identify contemporarily multiple SNPs across genome acting together in the genesis of stroke.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
Sex differences in the heritability of ischaemic stroke according to aetiological subtype: a pooled analysis of individual patient data
J. Peycke    C. Jackson    J. Labreuche     E. Touze     P. Amarenco    C. Sudlow     H. Markus     P.M.Rothwell             
 
Clinical Neuroscience, St George's, University of London

UNITED KINGDOM

BACKGROUND: Recent work has shown that women with ischaemic stroke are more likely than men to have a maternal history of stroke and are more likely to have an affected female sibling than an affected male sibling. However, it is uncertain how this sex-specific pattern of heritability is related to aetiological subtype of stroke. METHODS: We pooled individual patient data from four large prospective studies of ischaemic strokes, subtyped according to the TOAST Classification, each of which had detailed data on family history of stroke and family history of myocardial infarction (Oxford Vascular Study, Edinburgh Stroke Study, St George's Stroke Register and GENIC Study). RESULTS: Family history and stroke subtype were available for 1332 women and 1550 men. Maternal history of stroke was more common than paternal history in female probands (pooled OR=1.7, 95%CI 1.4-2.1, psig<0.0001, phet=0.66), but not in male probands (1.0, 0.9-1.3, psig=0.65, phet=0.31). The excess maternal history in female probands was present for all stroke subtypes apart from large artery disease. Female probands were also more likely than males to have an affected sister (2.2, 1.5-3.1, psig<0.0001, phet=0.24), an excess which was present for all subtypes of stroke. There were no similar interactions between sex of proband and sex of affected relative for family history of myocardial infarction. CONCLUSION: These results confirm the sex-specific differences in the heritability of ischaemic stroke, which could be explained by genetic, epigenetic, or non-genetic mechanisms, and show that these differences are not consistently related to the aetiological subtype of stroke.

Session: Poster Session I
Date: Wednesday 14 May 2008  
Time: 12:30 - 14:00
Room: Agora 2

  
Apolipoprotein E genotype (APOE) and ischaemic stroke: evidence from a series of meta-analyses for a specific association with large artery ischaemic stroke
E. Ballabio    L. Paternoster    N. Martinez-Gonzalez     S. Lewis     C. Jackson    C. Sudlow                             
 
University of Edinburgh

ITALY

Introduction: Apolipoprotein E genotype (APOE) influences cholesterol levels and ischaemic heart disease (IHD). Previous systematic reviews by our group and others found no convincing overall association with ischaemic stroke, but there remains the possibility of a specific association with large artery ischaemic stroke (LAIS). We therefore systematically reviewed evidence for an association between APOE and: ischaemic stroke subtypes, including LAIS; carotid intima media thickness (CIMT – an intermediate phenotype for LAIS); and white matter hypertensities (WMH – an intermediate phenotype for small artery ischaemic stroke). Methods: We used a series of comprehensive search strategies to identify all relevant studies up to January 2007, methodologically assessed included studies, extracted genotype and phenotype data, and performed meta-analyses. Results: We found 34 studies (6000 cases, 31000 controls) of the association between APOE and ischaemic stroke, of which 9 (1300 cases, 2200 controls) had data on ischaemic stroke subtypes. There was no overall association between APOE and ischaemic stroke. However, there was a trend towards association of e4 allele containing (e4+) genotypes with LAIS but not other ischaemic stroke subtypes, and a just significant association of e4+ genotypes with LAIS versus other ischaemic subtypes (OR 1.4, 95% CI 1.0 to 1.9, p=0.04). Meta-analyses of 28 studies in 32000 subjects found a small but significant association of APOE e4 with CIMT. But among 22 studies in 7500 subjects there was no evidence of an overall association between APOE and WMH. Conclusion: We found some evidence that APOE may specifically influence LAIS. Our findings of a significant effect on CIMT and lack of effect on WMH provide evidence in support of this.