Project description:The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with Hcy levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization [Toole, 2002]. The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200mcg pyridoxine, 6mcg cobalamin and 20mcg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled. Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of the Genomics and Randomized Trials Network (GARNET, <a href="http://www.garnetstudy.org" target="_blank">http://www.garnetstudy.org</a>) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington. The data of the VISP trial have been released to dbGaP users in several segments: Version 1 (phs000343.v1.p1), consisted of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data. Version 2 (phs000343.v2.p1) included n=14 additional phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=970 phenotype variables. Version 3 (phs000343.v3.p1), the current release, includes all n=36 phenotype datasets (plus pedigree, consent, and sample-mapping data), and increases the available data to a total of n=1918 phenotype variables. Toole, J. F. (2002). Vitamin intervention for stroke prevention. J Neurol Sci, 203-204, 121-4. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12417369" target="_blank">12417369</a>.

Project description:The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with Hcy levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization [Toole, 2002]. The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200µg pyridoxine, 6 µg cobalamin and 20µg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled. Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of the Genomics and Randomized Trials Network (GARNET, <a href="http://www.garnetstudy.org" target="_blank">http://www.garnetstudy.org</a>) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington. The data of the VISP trial will be released to dbGaP users in several segments; the current segment, version 1 (phs000343.v1.p1), consists of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data. Toole, J. F. (2002). Vitamin intervention for stroke prevention. J Neurol Sci, 203-204, 121-4. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12417369" target="_blank">12417369</a>.

Project description:Purpose: Signaling pathways mediated by microRNAs (miRNAs) represent one of the mechanisms that regulate stroke progression and recovery. The goal of this study is to investigate miRNA expression signatures in freshly removed human stroke brain tissue. Methods: Human brain samples (5 stroke and 3 non-stroke samples) obtained at 48-72 hours after stroke onset during craniectomy and stroke-ectomy, were subjected to histopathological and immunofluorescence microscopy analyses. NGS sequencing was performed by Qiagen company and analyses were carried out using QIAseq miRNA Quantification workflow and RNA-seq Analysis tools within CLC Genomics Workbench (version 20.0.2). Reads were normalized for expression analysis using trimmed mean of M-values method (TMM). miRNA profiling was performed using the EdgeR in Bioconductor package. Whole transcriptome RNA-sequencing Analysis: The unmapped reads from the NGS miRNA analysis were extracted, deduplicated and mapped to the genome. Gene expressions were calculated by counting number of reads mapping to the annotated gene loci. Human miR-155 Targets RT2 Profiler PCR Array (Qiagen) was performed using 3 RNA samples per stroke and control groups. The PCR Array Data analysis was performed using an automated PCR Analysis Web Portal and GeneGlobe Data Analysis (Qiagen). Results: Human stroke brain tissue was characterized by classic ischemic changes, including significant neuronal and vascular damage, and prominent edema. The absence of monocytes and notable neutrophil infiltration indicated the early stage of leukocyte response to ischemia. miRNA NGS analysis detected 36 miRNAs with significantly aberrant expression in stroke tissue, as compared to non-stroke samples. Of these miRNAs, 19 were previously identified in stroke patient blood and CSF, while dysregulation of 16 miRNAs was newly detected in this study. Bioinformatics pathway enrichment analysis demonstrated a strong association of the identified miRNAs with stroke-related biological processes and signaling pathways Conclusions: Dysregulated miRNAs detected in our study could be regarded as potential candidates for biomarkers and/or targets for therapeutic intervention. The obtained data will serve for better understanding of the molecular basis of stroke and provide valuable information for the future functional studies in the experimental models of stroke.

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GARNET Pharmacogenomic Studies in the Vitamin Intervention for Stroke Prevention (VISP) trial

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