GERFHS: Genetic and Environmental Risk Factors for Hemorrhagic Stroke

Sponsor

University of Cincinnati (Other)

Overall Status

Recruiting

CT.gov ID

NCT00682695

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH), University of Maryland, Baltimore (Other), Massachusetts General Hospital (Other), Duke University, Durham, NC (Other), Columbia University (Other), University of Illinois at Chicago (Other), Baptist Health, Louisville (Other)

1,000

Enrollment

Locations

301

Duration (Months)

142.9

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find risk factors for hemorrhagic stroke.

Condition or Disease	Intervention/Treatment	Phase
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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

1000 participants

Observational Model:

Ecologic or Community

Time Perspective:

Prospective

Official Title:

Genetic and Environmental Risk Factors for Hemorrhagic Stroke

Study Start Date :

Sep 1, 1997

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
1 Participants who have had a hemorrhagic stroke at University of Maryland, University of Cincinnati, Massachusetts General Hospital, Duke University, Columbia University and University of Chicago Illinois, age 18 years or greater. Ability of the patient or legal representative to provide informed consent. Racial/ethnic category meets one of the following: African American, Caucasian or Hispanic. Healthy volunteers who are matched to the study cases with hemorrhagic stroke within +/- 5 years of age, same gender and same race.

Arm

Intervention/Treatment

Participants who have had a hemorrhagic stroke at University of Maryland, University of Cincinnati, Massachusetts General Hospital, Duke University, Columbia University and University of Chicago Illinois, age 18 years or greater. Ability of the patient or legal representative to provide informed consent. Racial/ethnic category meets one of the following: African American, Caucasian or Hispanic. Healthy volunteers who are matched to the study cases with hemorrhagic stroke within +/- 5 years of age, same gender and same race.

Outcome Measures

Primary Outcome Measures

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

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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

Exclusion Criteria:

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois Chicago	Chicago	Illinois	United States	60612
2	Baptist Health Louisville	Louisville	Kentucky	United States	40207
3	University of Maryland	Baltimore	Maryland	United States	21201
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Columbia University	New York	New York	United States	10032
6	Duke University	Durham	North Carolina	United States	27710
7	University of Cincinnati	Cincinnati	Ohio	United States	45267