Variations in apolipoprotein D and sigma non-opioid intracellular receptor 1 genes with relation to risk, severity and outcome of ischemic stroke

Background: In experimental studies, the apolipoprotein D (APOD) and the sigma receptor type 1 (SIGMAR1) have been related to processes of brain damage, repair and plasticity. Methods: We examined blood samples from 3081 ischemic stroke (IS) patients and 1595 control subjects regarding 10 single nucleotide polymorphisms (SNPs) in the APOD (chromosomal location 3q29) and SIGMAR1 (chromosomal location 9p13) genes to find possible associations with IS risk, IS severity (NIHSS-score) and recovery after IS (modified Rankin Scale, mRS, at 90 days). Simple/multiple logistic regression and Spearman's rho were utilized for the analyses. Results: Among the SNPs analyzed, rs7659 within the APOD gene showed a possible association with stroke risk (OR = 1.12; 95% CI: 1.01-1.25; P = 0.029) and stroke severity (NIHSS >= 16) (OR = 0.70; 95% CI: 0.54-0.92; P = 0.009) when controlling for age, sex and vascular risk factors for stroke. No SNP showed an association with stroke recovery (mRS). Conclusions: We conclude that the SNP rs7659 within the APOD gene might be related to risk and severity of ischemic stroke in patients

Investigation of 91 proteins implicated in neurobiological processes identifies multiple candidate plasma biomarkers of stroke outcome

The inter-individual variation in stroke outcomes is large and protein studies could point to potential underlying biological mechanisms. We measured plasma levels of 91 neurobiological proteins in 209 cases included in the Sahlgrenska Academy Study on Ischemic Stroke using a Proximity Extension Assay, and blood was sampled in the acute phase and at 3-month and 7-year follow-ups. Levels were also determined once in 209 controls. Acute stroke severity and neurological outcome were evaluated by the National Institutes of Health Stroke Scale. In linear regression models corrected for age, sex, and sampling day, acute phase levels of 37 proteins were associated with acute stroke severity, and 47 with 3-month and/or 7-year outcome at false discovery rate < 0.05. Three-month levels of 8 proteins were associated with 7-year outcome, of which the associations for BCAN and Nr-CAM were independent also of acute stroke severity. Most proteins followed a trajectory with lower levels in the acute phase compared to the 3-month follow-up and the control sampling point. Conclusively, we identified multiple candidate plasma biomarkers of stroke severity and neurological outcome meriting further investigation. This study adds novel information, as most of the reported proteins have not been previously investigated in a stroke cohort

A Comprehensive Sequencing-Based Analysis of Allelic Methylation Patterns in Hemostatic Genes in Human Liver

Characterizing the relationship between genetic, epigenetic (e.g., deoxyribonucleic acid [DNA] methylation), and transcript variation could provide insights into mechanisms regulating hemostasis and potentially identify new drug targets. Several hemostatic factors are synthesized in the liver, yet high-resolution DNA methylation data from human liver tissue is currently lacking for these genes. Single-nucleotide polymorphisms (SNPs) can influence DNA methylation in cis which can affect gene expression. This can be analyzed through allele-specific methylation (ASM) experiments. We performed targeted genomic DNA- and bisulfite-sequencing of 35 hemostatic genes in human liver samples for SNP and DNA methylation analysis, respectively, and integrated the data for ASM determination. ASM-associated SNPs (ASM-SNPs) were tested for association to gene expression in liver using in-house generated ribonucleic acid-sequencing data. We then assessed whether ASM-SNPs associated with gene expression, plasma proteins, or other traits relevant for hemostasis using publicly available data. We identified 112 candidate ASM-SNPs. Of these, 68% were associated with expression of their respective genes in human liver or in other human tissues and 54% were associated with the respective plasma protein levels, activity, or other relevant hemostatic genome-wide association study traits such as venous thromboembolism, coronary artery disease, stroke, and warfarin dose maintenance. Our study provides the first detailed map of the DNA methylation landscape and ASM analysis of hemostatic genes in human liver tissue, and suggests that methylation regulated by genetic variants in cis may provide a mechanistic link between noncoding SNPs and variation observed in circulating hemostatic proteins, prothrombotic diseases, and drug response

Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

DNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood-liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 <= r <0.75) were detected for 6% and strong correlations ( r 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood-liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results

Serum IGFBP-1 Concentration as a Predictor of Outcome after Ischemic Stroke—A Prospective Observational Study

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates insulin-like growth factor-I (IGF-I) bioactivity, and is a central player in normal growth, metabolism, and stroke recovery. However, the role of serum IGFBP-1 (s-IGFBP-1) after ischemic stroke is unclear. We determined whether s-IGFBP-1 is predictive of poststroke outcome. The study population comprised patients (n = 470) and controls (n = 471) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months, 2, and 7 years using the modified Rankin Scale (mRS). Survival was followed for a minimum of 7 years or until death. S-IGFBP-1 was increased after 3 months (p 2) after 7 years [fully adjusted odds ratio (OR) per log increase 2.9, 95% confidence interval (CI): 1.4-5.9]. Moreover, higher s-IGFBP-1 after 3 months was associated with a risk of poor functional outcome after 2 and 7 years (fully adjusted: OR 3.4, 95% CI: 1.4-8.5 and OR 5.7, 95% CI: 2.5-12.8, respectively) and with increased mortality risk (fully adjusted: HR 2.0, 95% CI: 1.1-3.7). Thus, high acute s-IGFBP-1 was only associated with poor functional outcome after 7 years, whereas s-IGFBP-1 after 3 months was an independent predictor of poor long-term functional outcome and poststroke mortality

Serum magnesium and calcium levels in relation to ischemic stroke

Objective: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69–0.89; p = 1.3 × 10−4) for all ischemic stroke, 0.63 (95% CI 0.50–0.80; p = 1.6 × 10−4) for cardioembolic stroke, and 0.60 (95% CI 0.44–0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67–1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88–1.21) or with any subtype. Conclusions: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Visión general de las percepciones regionales sobre el rol de la educación superior para el desarrollo humano y social

Nuestro informe ha estudiado en su Parte I temas globales seleccionados acerca del rol de la educación superior para el desarrollo humano y social. Este trabajo es una síntesis de las perspectivas regionales -África Subsahariana, Estados Árabes, Asia y el Pacífico, Europa, América del Norte y América Latina y el Caribe- acerca del rol de la educación superior para el desarrollo humano y social basado en la contribución de los autores en cinco áreas claves: una de ellas es el estado de la educacion superior en cada región desde la celebración de la Conferencia Mundial sobre Educación Superior (CMES, 1998); y otra de las cuatro áreas clave se refiere a los posibles roles futuros, estrategias y acciones de la educación superior para promover el desarrollo humano y social.Peer Reviewe

Diversity in genetic risk of recurrent stroke: a genome-wide association study meta-analysis

IntroductionStroke is a leading cause of death and disability worldwide. Recurrent strokes are seven times more lethal than initial ones, with 54% leading to long-term disability. Substantial recurrent stroke risk disparities exist among ancestral groups. Notably, Africans face double the risk and higher fatality rates compared to Europeans. Although genetic studies, particularly GWAS, hold promise for uncovering biological insights into recurrent stroke, they remain underexplored. Our study addresses this gap through meta-analyses of recurrent stroke GWAS, considering specific ancestral groups and a combined approach.MethodsWe utilized four independent study cohorts for African, European, and Combined ancestry recurrent stroke GWAS with genotyping, imputation, and strict quality control. We harmonized recurrent stroke phenotype and effect allele estimates across cohorts. The logistic regression GWAS model was adjusted for age, sex, and principal components. We assessed how well genetic risk of stroke informs recurrent stroke risk using Receiver Operating Characteristic (ROC) curve analysis with the GIGASTROKE Consortium's polygenic risk scores (PRS).ResultsHarmonization included 4,420 participants (818 African ancestry and 3,602 European ancestry) with a recurrent stroke rate of 16.8% [median age 66.9 (59.1, 73.6) years; 56.2% male]. We failed to find genome-wide significant variants (p < 5e−8). However, we found 18 distinct suggestive (p < 5e−6) genetic loci with high biological relevance consistent across African and European ancestries, including PPARGC1B, CCDC3, OPRL1, and MYH11 genes. These genes affect vascular stenosis through constriction and dilation. We also observed an association with SDK1 gene, which has been previous linked with hypertension in Nigerian and Japanese populations). ROC analysis showed poor performance of the ischemic stroke PRS in discriminating recurrent stroke status (area under the curve = 0.48).DiscussionOur study revealed genetic associations with recurrent stroke not previously associated with incident ischemic stroke. We found suggestive associations in genes previously linked with hypertension. We also determined that knowing the genetic risk of incident stroke does currently not inform recurrent stroke risk. We urgently need more studies to understand better the overlap or lack thereof between incident and recurrent stroke biology

Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study.

OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

GISCOME – Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study

© 2017, © European Stroke Organisation 2017. Introduction: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. Methods: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. Results: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60–190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Conclusion: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses