PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

RATIONALE: Ischemic stroke 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 GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month 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

A ética do silêncio racial no contexto urbano: políticas públicas e desigualdade social no Recife, 1900-1940

Mais de meio século após o preconceito racial ter se tornado o principal alvo dos movimentos urbanos pelos direitos civis nos Estados Unidos e na África do Sul, e décadas depois do surgimento dos movimentos negros contemporâneos no Brasil, o conjunto de ferramentas legislativas criado no Brasil para promover o direito à cidade ainda adere à longa tradição brasileira de silêncio acerca da questão racial. Este artigo propõe iniciar uma exploração das raízes históricas desse fenômeno, remontando ao surgimento do silêncio sobre a questão racial na política urbana do Recife, Brasil, durante a primeira metade do século XX. O Recife foi eé um exemplo paradigmático do processo pelo qual uma cidade amplamente marcada por traços negros e africanos chegou a ser definida política e legalmente como um espaço pobre, subdesenvolvido e racialmente neutro, onde as desigualdades sociais originaram na exclusão capitalista, e não na escravidão e nas ideologias do racismo científico. Neste sentido, Recife lança luzes sobre a política urbana que se gerou sob a sombra do silêncio racial.More than half a century after racial prejudice became central to urban civil rights movements in the United States and South Africa, and decades after the emergence of Brazil’s contemporary Black movements, Brazil's internationally recognized body of rights-to-the-city legislation still adheres to the country's long historical tradition of racial silence. This article explores the historical roots of this phenomenon by focusing on the emergence of racial silence in Recife, Brazil during the first half of the 20th Century. Recife was and remains a paradigmatic example of the process through which a city marked by its Black and African roots came to be legally and politically defined as a poor, underdeveloped and racially neutral space, where social inequalities derived from capitalist exclusion rather than from slavery and scientific racism. As such, Recife'sexperience sheds light on the urban policies that were generated in the shadow of racial silence

PATJ low frequency variants are associated with worse ischemic stroke functional outcome: a genome-wide meta-analysis

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 PATJ gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, beta=0·40, p=1·70x10-9). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month 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

Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study

BACKGROUND: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. METHODS: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. FINDINGS: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. INTERPRETATION: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present