Contribution of "Omic" studies to the understanding of CADASIL. A systematic review

Altres ajuts: Generación Project, Maestro Project, INVICTUS+ networkAltres ajuts: Fundació la Marató de TV (Epigenesis Project)CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets

Elements of gothic literature in the film Edward Scissorhands by Tim Burton

[ES] Eduardo Manostijeras (1990), del artista y cineasta Tim Burton, es una película sobre una creación inacabada, incomprendida y rechazada por la sociedad. Este artículo analiza dichos conceptos y cómo Burton, a través del código cinematográfico simbólico y la intertextualidad, reinterpreta diferentes rasgos clave y temas característicos del género gótico en su película más personal y aclamada por la crítica. Además, analizaremos las similitudes entre la novela Frankenstein (1818) de Mary Shelley, uno de los primeros y más excelentes ejemplos de la Literatura Gótica, y la película de Burton para mostrar cómo este combinó diferentes elementos propios de ese género para crear un cuento moderno y memorable dentro de la tradición cinematográfica.[EN] Edward Scissorhands (1990), by artist and film-maker Tim Burton, is a movie about an unfinished, misunderstood creation that is rejected by society. This paper analyzes such concepts as well as how Burton, through symbolic film code and intertextuality, reinterprets different key traits and signature topics of the gothic genre in his most personal and critically acclaimed film to date. Furthermore, this article will discuss the similarities between Mary Shelley’s Frankenstein (1818) —one of the first and most excellent examples of the Gothic literature— and Burton’s movie to show how he combined different elements that fit under such genre in order to create a modern, memorable tale in the cinematic tradition

RP11-362K2.2:RP11-767I20.1 genetic variation is associated with post-reperfusion therapy parenchymal hematoma. A GWAS meta-analysis

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09

Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants

Altres ajuts: This work was supported by Boeringher Ingelheim funding (SEDMAN Project).Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke. We conducted a literature search to review the current state of OAs pharmacogenomics, focusing on Genome Wide Association Studies (GWAs) in patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). VKAs: Warfarin, acenocoumarol, fluindione and phenprocoumon have long been used, but their interindividual variability and narrow therapeutic/safety ratio makes their dosage difficult. GWAs have been useful in finding genetic variants associated with VKAs response. The main genes involved in VKAs pharmacogenetics are: VKORC1, CYP2C19 and CYP4F2. Variants in these genes have been included in pharmacogenetic algorithms to predict the VKAs dose individually in each patient depending on their genotype and clinical variables. DOACs: Dabigatran, apixaban, rivaroxaban and edoxaban have been approved for patients with AF. They have stable pharmacokinetics and do not require routine blood checks, thus avoiding most of the drawbacks of VKAs. Except for a GWAs performed in patients treated with dabigatran, there is no Genome Wide pharmacogenomics data for DOACs. Pharmacogenomics could be useful to predict the better clinical response and avoid adverse events in patients treated with anticoagulants, identifying the most appropriate anticoagulant drug for each patient. Current pharmacogenomics data show that the polymorphisms affecting VKAs or DOACs are different, concluding that personalized medicine based on pharmacogenomics could be possible. However, more studies are required to implement personalized medicine in clinical practice with OA and based on pharmacogenetics of DOACs

Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes

COVID-19; Ischaemic stroke; Local genetic correlationCOVID-19; Ictus isquèmic; Correlació genètica localCOVID-19; Ictus isquémico; Correlación genética localWe aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10−2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = −0.04, p-value = 1.3 × 10−3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10−4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10−2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.This work was supported by the Spanish National Research Council (CSIC) via COVID-19 Funds (Ref.CSIC202020E086), the European Commission—NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform, the Instituto de Salud Carlos III through the iBioStroke project (AC19/00106 Eranet-Neuron, European research grants), the RICORS RD21/0006/0006, FEDER, NextGeneration EU, the PREVICTUS project (PMP21/00165), and the COPYCTUS project (PI21/01088). IIB SANT PAU is funded by the Catalan Government (CERCA Program/Generalitat de Catalunya). M.L. is funded by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud FI19/00309) from Instituto de Salud Carlos III (ISCIII). C.G.-F. is supported by a Sara Borrel contract (CD20/00043) from Instituto Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). The BelCovid cohort is funded by The Belgian National Funds for Scientific Research and Fondation Léon Fredericq

Sleep/wake cycle alterations as a cause of neurodegenerative diseases : A Mendelian randomization study

Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N = 17,996), AD (N = 21,235) and ALS (N = 40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p = 8.47×10 and 95%CI:-7.28 to -4.44, p = 5.87×10, respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p = 0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p = 0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS

RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis

Transformació hemorràgica; Hematoma parenquimàtic; Variants d'un sol nucleòtidTransformación hemorrágica; Hematoma parenquimatoso; Variantes de un solo nucleótidoHemorrhagic transformation; Parenchymal hematoma; Single nucleotide variantsStroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 × 10−8) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 × 10−8) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer’s disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-β, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.This work was supported by grants from the Instituto de Salud Carlos III (PI 11/0176), Generación Project, Maestro Project (PI18/01338), INVICTUS+ network, Epigenesis Project (Marató de TV3), FEDER funds. E. Muiño is supported by a Río Hortega Contract (CM18/00198) from the Instituto de Salud Carlos III. J. Cárcel-Márquez is supported by an AGAUR Contract (agència de gestió d’ajuts universitaris i de recerca; FI_DGR 2020, grant number 2020FI_B1 00157) co-financed with Fons Social Europeu (FSE). C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). M. Lledós is supported by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud) from the Instituto de Salud Carlos III. I (FI19/00309). Fernández-Cadenas (CP12/03298), Tomás Sobrino (CPII17/00027), and Francisco Campos (CPII19/00020) are supported by a research contract from Miguel Servet Program from the Instituto de Salud Carlos III

A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype

Multi-trait analysis; Polygenic risk score; StrokeAnálisis de múltiples rasgos; Puntuación de riesgo poligénico; IctusAnàlisi de múltiples trets; Puntuació de risc poligènic; IctusBackground: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.J. Cárcel-Márquez has received funding through an AGAUR Contract (Agència de Gestió d'Ajuts Universitaris i de Recerca; FI_DGR 2019, grant number 2020FI_B1 00157) co-financed with Fons Social Europeu (FSE) (https://agaur.gencat.cat). From Instituto de Salud Carlos III: E. Muiño is funded by a Río Hortega Contract (CM18/00198), M. Lledós is funded by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud, FI19/00309), C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER), T. Sobrino (CPII17/00027), and F. Campos (CPII19/00020) are recipients of research contracts from the Miguel Servet Program (https://www.isciii.es). This study has been funded by Instituto de Salud Carlos III PI15/01978, PI17/02089, PI18-01338, and RICORS-ICTUS RD21/0006/0006 (Instituto de Salud Carlos III), by Marató TV3 support of the Epigenesis study (https://www.ccma.cat/tv3/marato/), by the Fundació Docència i Recerca FMT grant for the Epigenesis project (https://www.mutuaterrassa.com), by Eranet-Neuron of the Ibiostroke project (AC19/00106) (https://www.neuron-eranet.eu), by Boehringer Ingelheim of the SEDMAN Study (https://www.boehringer-ingelheim.it), and GCAT Cession Research Project PI-2018-01 (http://www.gcatbiobank.org). GCAT was funded by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); and have additional suport by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529)

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke

Clopidogrel is one of the most used antiplatelet drugs in patients with cardiovascular disease. However, 16% to 50% of patients have a high on-clopidogrel platelet reactivity and an increased risk of ischemic events. The pathogenesis of high on-treatment platelet reactivity in patients with stroke is only partially explained by genetic variations. This study aims to find differentially methylated sites across the genome associated with vascular recurrence in ischemic stroke patients treated with clopidogrel