Rationale: Ischemic stroke (IS) is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest genome-wide association study (GWAS) in IS recovery to date. Methods and Results: A 12-cohort, two-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent IS cases. Functional outcome was recorded using 3-month modified Rankin Scale (mRS). Analyses were adjusted for confounders such as discharge NIHSS. A gene-based burden test was performed. The discovery phase (n=1,225) was followed by open (n=2,482) and stringent joint-analyses (n=1,791). Those cohorts with mRS recorded at timepoints other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in Pals1-Associated Tight Junction (PATJ) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, beta=0•40, p=1•70×10 −9). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population.

Background and Purpose-There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration. Methods-A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity. Results-After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in IL1B Key Words: genetics Ⅲ pharmacogenetics Ⅲ recanalization Ⅲ stroke Ⅲ tPA I ntravenous tissue-type plasminogen activator (tPA) is the only drug currently approved for acute stroke treatment. The clinical response to intravenous tPA may be poor, because of a lack of efficacy in terms of early recanalization of the occluded vessel in 48% to 65% of patients 1 or because of safety concerns such as symptomatic hemorrhagic transformation occurring in 1.7% to 6.4% of cases and leading to death in 6.5% to 12.7% of cases. 2 A longer time to recanalization highly correlates with a larger infarcted area and worse neurological outcome, overall leading to poor clinical recovery from stroke. 3 The identification of factors predicting tPA efficacy could be useful to improve the management of patients with stroke, especially those not responding well to tPA treatment, because in these patients, the intra-arterial administration of tPA with or without coadjuvant drugs could be more effective than intravenous tPA treatment alone. In previous studies, we already identified some predictors of recanalization efficacy, namely thrombin-antithrombin complex levels and variants in the thrombin activable fibrinolysis inhibitor gene. 4,5 The aim of this study was to identify single nucleotide polymorphisms (SNPs) that could be used by physicians as new predictors of early recanalization to individualize and improve acute ischemic stroke treatment. Methods Study PopulationWhite patients with an acute ischemic stroke with a documented arterial occlusion by transcranial Doppler (TCD) and who received tPA in a standard dose of 0.9 mg/kg (10% bolus, 90% 1-hour continuous infusion) within the first 4.5 hours after onset of symptoms were consecutively recruited in the emergency department.The original The clinical data of both cohorts is available in online-only Data Supplement Table I. Clinical and TCD ProtocolOn admission to the emergency department, a detailed history of vascular risk factors and current medication was obtained from each patient. Stroke severity was assessed with the National In...

Background and Purpose Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack (TIA). Clinical scores do not predict the whole vascular recurrence risk, therefore we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. Methods We analyzed 256 polymorphisms from 115 candidate genes in three patient cohorts comprising 4,482 IS or TIA patients. The discovery cohort was prospectively recruited and included 1,494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2,988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score), and generated risk groups using a classification tree method. Results The analyses revealed that rs1800801 in the MGP gene (HR: 1.33, p= 9×10−03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305), however it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (p= 3.2×10−09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared to previous SPI-II score (p=0.03). Conclusions The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare disease that leads to migraine, mood disorders, recurrent lacunar strokes and early vascular dementia. This autosomal-dominant condition is caused by mutations in the NOTCH3 gene and is characterized by degeneration of vascular smooth muscle cells. At present, no evidence-based treatment for CADASIL is available and only relief of symptoms can be offered to patients. This review focuses on an update of CADASIL management, based on the recent clinical and basic evidence, and discusses possible new treatment targets for CADASIL.