Fine-mapping a novel locus on Chromosome 1 for associations with recurrent stroke

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Dunya Moneer Safa (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

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.

Additional Information

Publication

Thesis

Language: English

Date: 2019

Keywords

GWAS, fine-mapping, VISP, recurrent stroke, B vitamin, statistical analyses, SNP, next-generation sequencing, multiple regressions

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