Schlaganfall im Kindesalter:Zusammenhang zwischen prothrombotischen Risikofaktoren in Bezug auf Ersterkrankung und Rezidiv

Zur Untersuchung der Relevanz prothrombotischer Faktoren auf das Auftreten eines Schlaganfallrezidivs im Kindesalter wurden in der vorliegenden Multicenter-Studie 301 Kinder im Alter von 6 Monaten bis 18 Jahren untersucht, von denen 20 (6,6%) ein Rezidiv erlitten. Das relative Risiko (RR) war signifikant erhöht bei Kindern mit Protein C-Mangel (RR 3,5/ 95%iges Konfidenzintervall 1,1-10,9) und erhöhten Lipoprotein (a)-Werten (RR 4,4/ 95%iges Konfidenzintervall 1,9-10,5). Auch eine vaskuläre Genese des ersten Ereignisses zeigte einen signifikanten Einfluss auf das Auftreten eines Rezidivs (Odds Ratio 3,9/ 95%iges Konfidenzintervall 1,4-10,6). Die Wahl einer antithrombotischen Therapie zeigte keinen signifikanten Einfluss auf die Rezidivrate. Eine Moratalität von 15% in der Rezidivgruppe verdeutlicht die Notwendigkeit, geeignete Präventivmaßnahmen zu untersuchen

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

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Abstract: Objectives: To investigate the relationship between an insertion/deletion (4G/5G) polymorphism of the plasminogen activator inhibitor (PAI)-1 gene and childhood patients with a past history of ischemic stroke. Methods: The PAI-1 4G/4G genotype and the coinheritance with lipoprotein (Lp) (a) levels, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, and the methylenetetrahydrofolate reductase (MTHFR) T677T genotype were studied in 198 Caucasian children with stroke and 951 controls (same age, sex and ethnical distribution). In a randomly selected subgroup of patients/ controls (n=60) PAI-1 activities have been investigated. Results: The distribution of the 4G/5G genotypes was no different in childhood stroke patients and controls, with a 4G allele frequency of 55.8% in patients compared with 53.8% in control subjects (P=0.49). The 4G/4G genotype compared with the remaining genotypes was present in 43 cases and 167 (17.6% vs. 21.7%; OR/CI: 1.30/0.89±1.98; P=0.3). PAI-1 activity was signi®cantly elevated (P<0.001) in the patient group. Conclusions: Data presented here suggest that the 4G/4G genotype is not a major risk factor in the aetiology of childhood ischemic stroke