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Hospital de Órbigo, Spain

Debette S.,French Institute of Health and Medical Research | Debette S.,Institute Pasteur Of Lille | Debette S.,University of Lille Nord de France | Debette S.,Lille University Hospital Center | And 85 more authors.
Nature Genetics | Year: 2014

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1-3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10-10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10-3; combined P = 1.00 × 10-11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6-9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the. © 2014 Nature America, Inc. All rights reserved. Source


Gallego-Fabrega C.,Stroke Pharmacogenomics and Genetics | Gallego-Fabrega C.,University of Barcelona | Carrera C.,Autonomous University of Barcelona | Reny J.-L.,University of Geneva | And 16 more authors.
Stroke | Year: 2016

Background and Purpose - Despite great efforts by pharmacogenetic studies, the causes of aspirin failure to prevent the recurrence of ischemic events remain unclear. Our aim was to study whether epigenetics could be associated with the risk of vascular recurrence in aspirin-treated stroke patients. Methods - We performed an epigenetic joint analysis study in 327 patients treated with aspirin. In the discovery stage, we performed a nested case-control study in 38 matched ischemic stroke patients in whom 450 000 methylation sites were analyzed. Nineteen patients presented vascular recurrence after stroke, and 19 matched patients did not present vascular recurrence during the first year of follow-up. In a second stage, 289 new patients were analyzed by EpiTYPER. Results - The following 3 differentially methylated candidate CpG sites, were identified in the discovery stage and analyzed in the second stage: cg26039762 (P=9.69×10-06, RAF1), cg04985020 (P=3.47×10-03, PPM1A), and cg08419850 (P=3.47×10-03, KCNQ1). Joint analysis identified an epigenome-wide association for cg04985020 (PPM1A; P=1.78×10-07), with vascular recurrence in patients treated with aspirin. Conclusions - The pattern of differential methylation in PPM1A is associated with vascular recurrence in aspirin-treated stroke patients. © 2016 American Heart Association, Inc. Source


Muino E.,Stroke Pharmacogenomics and Genetics | Krupinski J.,Mutua de Terrassa Hospital | Carrera C.,Autonomous University of Barcelona | Gallego-Fabrega C.,Stroke Pharmacogenomics and Genetics | And 2 more authors.
Mediators of Inflammation | Year: 2015

Inflammation has been associated with atherothrombotic stroke and recently with cardioembolic stroke. Different genetic risk factors have been specifically associated with the subtypes of ischemic stroke (cardioembolic, atherothrombotic, and lacunar). However, there are no studies that have generated genetic risk scores for the different subtypes of ischemic stroke using polymorphisms associated with inflammation. Methods. We have analyzed 68 polymorphisms of 30 inflammatory mediator genes in 2,685 subjects: 1,987 stroke cases and 698 controls. We generated a genetic scoring system with the most significant polymorphisms weighted by the odds ratio of every polymorphism and taken into consideration the stroke subtype. Results. Three polymorphisms, rs1205 (CRP gene), rs1800779, and rs2257073 (NOS3 gene), were associated with cardioembolic stroke (p value <0.05). The score generated was only associated with the cardioembolic stroke subtype (p value: 0.001) and was replicated in an independent cohort (p value: 0.017). The subjects with the highest score presented a cardioembolic stroke in 92.2% of the cases (p value: 0.002). Conclusion. The genetics of inflammatory markers is more closely associated with cardioembolic strokes than with atherothrombotic or lacunar strokes. The genetic risk scoring system could be useful in the prediction and differentiation of ischemic stroke; however, it might be specific to particular ischemic stroke subtypes. © 2015 Elena Muiño et al. Source


Riera C.,Autonomous University of Barcelona | Lois S.,Autonomous University of Barcelona | Dominguez C.,Institute Of Recerca Hospital Vall Dhebron | Dominguez C.,Institute Salud Carlos III | And 9 more authors.
Proteins: Structure, Function and Bioinformatics | Year: 2015

Loss-of-function mutations of the enzyme alpha-galactosidase A (GLA) causes Fabry disease (FD), that is a rare and potentially fatal disease. Identification of these pathological mutations by sequencing is important because it allows an early treatment of the disease. However, before taking any treatment decision, if the mutation identified is unknown, we first need to establish if it is pathological or not. General bioinformatic tools (PolyPhen-2, SIFT, Condel, etc.) can be used for this purpose, but their performance is still limited. Here we present a new tool, specifically derived for the assessment of GLA mutations. We first compared mutations of this enzyme known to cause FD with neutral sequence variants, using several structure and sequence properties. Then, we used these properties to develop a family of prediction methods adapted to different quality requirements. Trained and tested on a set of known Fabry mutations, our methods have a performance (Matthews correlation: 0.56-0.72) comparable or better than that of the more complex method, Polyphen-2 (Matthews correlation: 0.61), and better than those of SIFT (Matthews correl.: 0.54) and Condel (Matthews correl.: 0.51). This result is validated in an independent set of 65 pathological mutations, for which our method displayed the best success rate (91.0%, 87.7%, and 73.8%, for our method, PolyPhen-2 and SIFT, respectively). These data confirmed that our specific approach can effectively contribute to the identification of pathological mutations in GLA, and therefore enhance the use of sequence information in the identification of undiagnosed Fabry patients. © 2014 Wiley Periodicals, Inc. Source

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