GARNET Pharmacogenomic Studies in the Vitamin Intervention for Stroke Prevention (VISP) trial
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PROVIDER: PRJNA76061 | ENA |
REPOSITORIES: ENA
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Project description:<p>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.</p> <p>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.</p> <p>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.</p> <p>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>.</p>
| phs000343.v1.p1 | EGA
Project description:<p>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.</p> <p>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.</p> <p>The data of the VISP trial have been released to dbGaP users in several segments:</p> <p>Version 1 (phs000343.v1.p1), consisted of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data.</p> <p>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.</p> <p><b>Version 3</b> (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.</p> <p>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>.</p>
| phs000343 | dbGaP
Project description:GARNET Pharmacogenomic Studies in the Vitamin Intervention for Stroke Prevention (VISP) trial
| PRJNA76063 | ENA
Project description:Optimizing Primary Stroke Prevention in Children with Sickle Cell Anemia (STOP II)
| PRJNA715787 | ENA
Project description:Optimizing Primary Stroke Prevention in Children with Sickle Cell Anemia (STOP II)
| PRJNA715788 | ENA
Project description:DNA methylation, a well-characterized epigenetic modification that is influenced by both environment and genetic variation, has previously been implicated in a number of complex diseases, including cardiovascular disease and stroke. The goal of this study was to evaluate epigenome-wide associations with recurrent stroke and the folate one-carbon metabolism-related trait, plasma homocysteine (hcy). Differential methylation analyses were performed on 473,864 autosomal CpG loci, using Illumina HumanMethylation 450K array data in 180 ischemic stroke cases from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial. Linear regression was used to assess associations between number of strokes prior to VISP enrollment and measures of hcy with degree of methylation (?-values), while logistic regression was used to evaluate recurrent stroke status and incident recurrent stroke associations. All regression analyses were stratified by race. Two differentially methylated CpG sites exceeded epigenome-wide significance (p ? 1.055 × 10-7) for prior number of strokes (PNS) in European Americans. The top locus, cg22812874, was located in the ankyrin repeat and SOCS box containing 10 gene (ASB10; p = 3.4 × 10-9; ? = -0.0308; 95% CI = -0.040, -0.002). Methylation locus cg00340919, located in an intron of the tetratricopeptide repeat domain 37 gene, was also statistically significant (TTC37; p = 8.74 × 10-8; ? = -0.0517; 95% CI = -0.069, -0.034). An additional 138 CpG sites met our threshold for suggestive significance (p ? 5 × 10-5). We evaluated DNA methylation associated with recurrent stroke and hcy phenotypes across the epigenome. Hypermethylation at two CpG sites located in ASB10 and TTC37 was associated with fewer strokes prior to VISP enrollment. Our findings present a foundation for additional epigenome-wide studies, as well as mechanistic studies into epigenetic marks that influence recurrent stroke risk.
| S-EPMC6135883 | biostudies-literature
Project description:African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2-3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.
| S-EPMC7932724 | biostudies-literature
Project description:INTRODUCTION: Accurate ischemic stroke (IS) etiologic diagnosis provides an appropriate secondary prevention strategy and better outcome. Currently, 45% of IS are cryptogenic urging to find novel approaches to enhance diagnostic precision and secondary stroke prevention. OBJETIVE: To study the transcriptomic content of circulating extracellular vesicles (EVs) to delineate the molecular profile and potential biomarkers of IS etiologies. RESULTS:21 consecutive patients with moderate or severe ischemic stroke (IS) and different IS etiologies were included to perform the transcriptomic analysis of plasma EVs comprising: atherothrombotic (AT, n=6), Cardioembolic (CE, n=10), and embolic stroke of undetermined source (ESUS, n=5). The RNASeq analysis of EVs detected clusters of differentially expressed genes (DEGs) related to IS etiologies.
2024-05-01 | GSE255087 | GEO
Project description:One explanation for the 'obesity paradox', where obese patients seem to have better cardiovascular outcomes than lean patients, is that obese patients display an identifiable high cardiovascular risk phenotype that may lead to receiving or seeking earlier/more aggressive treatment.We analyzed a clinical trial dataset comprising 3643 recent (<120 days) ischemic stroke patients followed up for 2 years. Subjects were categorized as lean (body mass index [BMI], <25 kg/m2, n=1,006), overweight (25-29.9 kg/m2, n=1,493), or obese (?30 kg/m2, n=1,144). Subjects were classified as level 0 to III depending on the number of secondary prevention prescriptions divided by the number of potentially indicated drugs (0=none of the indicated medications and III=all indicated medications as optimal combination drug treatment [OCT]). Independent associations between each BMI category and stroke/myocardial infarction/vascular death (major vascular events [MVEs]) and all-cause death were assessed.MVEs occurred in 17.4% of lean, 16.1% of overweight, and 17.1% of obese patients; death occurred in 7.3%, 5.5%, and 5.1%, respectively. Individuals with a higher BMI status received more OCT (45.8%, 51.7%, and 55.3%, respectively; P<0.001). In the lean patient group, multivariable adjusted Cox analyses, showed that compared with levels 0-I, level II and level III were linked to lower risk of MVEs (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.32-0.95 and HR 0.48; 95% CI: 0.28-0.83, respectively) and death (0.44; 0.21-0.96 and 0.23; 0.10-0.54, respectively).OCT for secondary prevention after an ischemic stroke is less frequent in lean (vs. obese) subjects, but when implemented is related to significantly better clinical outcomes.
| S-EPMC5466287 | biostudies-other
Project description:BackgroundB vitamins play an important role in homocysteine metabolism, with vitamin deficiencies resulting in increased levels of homocysteine and increased risk for stroke. We performed a genome-wide association study (GWAS) in 2,100 stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) trial, a clinical trial designed to determine whether the daily intake of high-dose folic acid, vitamins B6, and B12 reduce recurrent cerebral infarction.MethodsExtensive quality control (QC) measures resulted in a total of 737,081 SNPs for analysis. Genome-wide association analyses for baseline quantitative measures of folate, Vitamins B12, and B6 were completed using linear regression approaches, implemented in PLINK.ResultsSix associations met or exceeded genome-wide significance (P ≤ 5 × 10(-08)). For baseline Vitamin B12, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the CUBN gene (P = 1.76 × 10(-13)). Two additional CUBN intronic SNPs demonstrated strong associations with B12 (P = 2.92 × 10(-10) and 4.11 × 10(-10)), while a second nsSNP, located in the TCN1 gene, also reached genome-wide significance (P = 5.14 × 10(-11)). For baseline measures of Vitamin B6, we identified genome-wide significant associations for SNPs at the ALPL locus (rs1697421; P = 7.06 × 10(-10) and rs1780316; P = 2.25 × 10(-08)). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B6, six for Vitamin B12, and one for folate measures) provided suggestive evidence for association (P ≤ 10(-07)).ConclusionOur GWAS study has identified six genome-wide significant associations, nine suggestive associations, and successfully replicated 5 of 16 SNPs previously reported to be associated with measures of B vitamins. The six genome-wide significant associations are located in gene regions that have shown previous associations with measures of B vitamins; however, four of the nine suggestive associations represent novel finding and warrant further investigation in additional populations.
| S-EPMC4123605 | biostudies-literature