Fine-mapping a novel locus on Chromosome 1 for associations with recurrent stroke
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Date
2019-07-18
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Authors
Safa, Dunya Moneer
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Publisher
East Carolina University
Abstract
INTRODUCTION: Stroke is a complex, multifactorial cerebrovascular disease that afflicts millions of individuals both nationally and globally. Of the annual 795,000 stroke incidents, approximately 185,000 are recurrent attacks. These recurrent events are more deadly and more likely to result in a debilitating disability than an initial stroke. Despite the higher mortality and disability rates for recurrent events, few studies have evaluated the underlying genetic associations for recurrent stroke.
PRELIMINARY DATA: The Vitamin Intervention for Stroke Prevention (VISP) clinical trial was a double-blind, randomized, and controlled clinical trial that conducted to determine whether daily supplementation of vitamins B6, B12, and folic acid reduces the risk of recurrent stroke, myocardial infarction, or death. 2,100 VISP participants consented to genetic studies, of which 182 had recurrent attacks. Cox Proportional Hazards survival analyses identified two single nucleotide polymorphisms (SNPs), in a gene-sparse region of Chromosome 1 (rs6664786 and rs2184006), associated with recurrent stroke. To determine the most significant variant(s) contributing to this association, fine-mapping was performed across a 750 kb region encompassing the significantly associated SNPs.
MATERIALS AND METHODS: Next-generation sequencing (NGS) for 183 VISP recurrent stroke individuals was performed using Illumina Nextera Custom Capture targeted sequencing. Raw data underwent FASTQ processing and 7,398 variants were identified within this region. Following SNP prioritization, 18 high priority SNPs were selected and genotyped using TaqMan SNP genotyping assays. A total of 133 SNPs (18 genotyped and 115 GWAS SNPs) were analyzed for associations with recurrent stroke and stroke-related biomarkers using Cox Proportional Hazards survival analyses, as well as multiple linear and logistic regression models.
RESULTS: Survival analyses validated statistical significance (p≤ 3.76 x 10-4) for two previously reported genome-wide significant genetic variant associations (rs6664786, p= 2.23 x 10-7; rs2184006, p= 3.34 x 10-7) for days to recurrent stroke. Survival analyses for composite endpoints revealed significant associations for the same two variants (rs6664786, p= 5.06 x 10-5; rs2184006, p= 6.34 x 10-5). In addition, six other genetic associations were identified for recurrent stroke via survival analysis. Logistic regression analyses revealed no statistically significant associations, while three statistically significant associations were identified in the linear regression analyses for stroke-related traits. These associations were found between diastolic blood pressure (DBP) and rs17131801 (p= 1.52 x 10-4), C-reactive protein (CRP) and rs12137283 (p= 3.07 x 10-4), and Rankin Stroke Scale (RSS) and rs17530979 (p= 3.02 x 10-4).
CONCLUSION: This study validated previously identified variants associated with recurrent stroke and identified additional significant variants with recurrent stroke and composite endpoint through survival analyses. Furthermore, association with stroke-related traits such as DBP, CRP, and RSS, highlight the need for functional assays to isolate the exact role of these associated variants and their implications in disease susceptibility. In addition, functional studies can attest clinical relevance and help in drug development for stroke and recurrent stroke cases.