Genetic and Environmental Risk Factors for Hemorrhagic Stroke
- Conditions
- Stroke
- Registration Number
- NCT00682695
- Lead Sponsor
- University of Cincinnati
- Brief Summary
The purpose of this study is to find risk factors for hemorrhagic stroke.
- Detailed Description
The proposed research builds on the most robust, statistically significant and replicated association identified to determine the mechanism by which it may relate to intracerebral hemorrhage (ICH) risk. Given that ICH is an extreme phenotype on a spectrum of manifestations of cerebral small vessel disease, the findings that emerge from our proposed studies offer the promise of broad impact for research and treatment in a wide variety of cerebrovascular disorders.
In the genetic epidemiology of hemorrhagic stroke, we propose to perform an in-depth fine-mapping of the entire 1q22 genomic region (\~250kb) to investigate whether genetic variants influence gene expression that correlates with ICH status or changes in expression over time in ICH cases. As existing samples were not processed for gene expression analysis, we will recruit 500 non-lobar ICH cases (\~150 black, \~350 white) and 1000 controls (300 black, 700 white) to correlate sequence variation with gene expression levels in the same samples. Identified associations will be replicated in 6,000 cases of ICH and 9,361 individuals in the CHARGE consortium with MRI white matter hyperintensity volume measurements and 5,000 controls. The current proposal takes the next logical step by pursuing the most promising findings of our Genome-Wide Association Study (GWAS) to complete the following aims:
Specific Aim #1: Perform deep DNA sequencing of Chr 1q22 among non-Hispanic white and black ICH cases and controls to identify all genomic variation within these regions and test the following:
Hypothesis #1a: Variants strongly associated with ICH risk at 1q22 are either directly causal or in linkage disequilibrium to causal variants that influence ICH risk, and sequencing of these regions will reveal both common and rare variants that exert this causal influence.
Hypothesis #1b: Variants strongly associated with ICH risk at 1q22 will be associated with risk of, or severity of, leukoaraiosis.
Specific Aim #2: Prospectively collect DNA, RNA, and serum on ICH cases and geographic region site-specific controls both at the time of ICH and in the convalescent period. We will perform RNA expression profiling between cases and controls and over time in cases. We will compute expression quantitative trait locus (eQTL) analysis with Single Nucleotide Polymorphisms (SNPs) arising from Aim 1. We will also determine whether alternatively spliced transcripts differ between cases and controls.
Hypothesis #2a: Variation in gene expression or alternatively spliced transcripts affects risk of ICH.
Hypothesis #2b: Variations identified by DNA sequencing will affect gene expression and/or alternatively spliced transcripts that affect risk of ICH.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 1000
- Age 18 or older
- Resident (6 months or longer) within the recruitment center
- Fulfillment of the criteria for spontaneous ICH
- No evidence of trauma, brain tumor/metastases or infectious processes as a cause of the hemorrhage
- Ability of the patient or legal representative to provide consent for an interview, blood pressure determinations and DNA sampling
- N/A
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Perform deep DNA sequencing of Chr 1q22 Ongoing to be completed at the end of June 2021 Perform deep DNA sequencing of Chr 1q22 among non-Hispanic white and black ICH cases and controls to identify all genomic variation within these regions.
- Secondary Outcome Measures
Name Time Method Collect and analyze DNA, RNA, and serum on ICH cases and matched control participants. Ongoing to be completed at the end of June 2021 Collect and analyze DNA, RNA, and serum on ICH cases and matched controls both at the time of ICH and in the convalescent period. We will perform RNA expression profiling between cases and controls and over time in cases.
Trial Locations
- Locations (7)
Baptist Health Louisville
🇺🇸Louisville, Kentucky, United States
University of Illinois Chicago
🇺🇸Chicago, Illinois, United States
Columbia University
🇺🇸New York, New York, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Duke University
🇺🇸Durham, North Carolina, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States