Gene Environment Association Studies (GENEVA): Genetics of Early Onset Stroke (GEOS) Study

The Genetics of Early Onset Stroke (GEOS) Study is a population-based case-control study designed to identify genes associated with early-onset ischemic stroke and to characterize interactions of identified stroke genes and/or SNPs with environmental risk factors such as smoking and oral contraceptive use. The GEOS study consists of 921 ischemic stroke cases with age of first stroke 16-50 years and a similar number of controls, identified from the Baltimore-Washington area. Cases and controls were recruited in 3 different time periods: Stroke Prevention in Young Women-1 (SPYW-1) conducted from 1992-1996, Stroke Prevention in Young Women-2 (SPYW-2) conducted from 2001-2003, and Stroke Prevention in Young Men (SPYM) conducted from 2003-2007. The overall GEOS sample includes 477 cases who self-reported their race as "white" and 396 cases who self-reported their race as "African American."

Traditional stroke risk factors and other study variables, including age, ethnicity, and history of hypertension, diabetes, myocardial infarction (MI), current smoking status, and current oral contraceptive use (both defined as use within one month prior to event for cases and at a comparable reference time for controls), were also collected during standardized interview and were included as covariates in our analyses.

This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to early-onset ischemic stroke through large-scale genome-wide association studies of cases and controls of European and African descent from the Baltimore-Washington area. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1862
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH

Cases:
Inclusion: age at stroke 16-50
Exclusions: stroke occurring as an immediate consequence of trauma; stroke within 48 hours after a hospital procedure, stroke within 60 days after the onset of a non-traumatic subarachnoid hemorrhage, and cerebral venous thrombosis. Additional exclusions for these genetic analyses were known single-gene or mitochondrial disorder recognized by a distinctive phenotype (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), homocystinuria, Fabry disease, or sickle cell anemia); mechanical aortic or mitral valve at the time of index stroke; untreated or actively treated bacterial endocarditis at the time of the index stroke; neurosyphilis or other CNS infections; neurosarcoidosis; severe sepsis with hypotension at the time of the index stroke; cerebral vasculitis by angiogram and clinical criteria; post-radiation arteriopathy; left atrial myxoma; major congenital heart disease; and cocaine use in the 48 hours prior to their stroke.

Controls:
Exclusions: history of stroke

Name of grants: Stroke Prevention in Young Women
Agency number: National Institute of Neurologic and Communicative Disorders and Stroke, NS16332-09A2; Stroke Center, Project 1
PI: Steven J. Kittner, MD
Dates: 09/30/91-09/29/97
Specific aims: To determine 1) the relative and attributable risk of ischemic stroke in users of oral contraceptives containing 50ug or less of estrogen; 2) the effect of progestin potency and dose on stroke risk, 3) the effect of smoking, migraine headache, HDL cholesterol, anticardiolipin antibodies, and homocysteine onstroke risk and, in particular, on the stroke risk associated with oral contraceptive use; 4) the relative risk of the factors mentioned for 3 subtypes of ischemic stroke; strokes with a cardiac source of embolism, and lacunar or nonlacunar strokes without a cardiac source of embolism.

Name of grants: The Stroke Prevention in Young Women Study
Agency number: Centers for Disease Control and Prevention, Cooperative Agreements Administered through the Association of Teachers of Preventive Medicine TS203 13/14
PI: Steven J. Kittner, MD
Dates: 9/30/97-9/30/00
Specific aims: To determine how genetic factors influence the risk of stroke in young women.

Name of grants: Behavior, Infection, and Genetics in Early-Onset Stroke
Agency number: Centers for Disease Control and Prevention, Cooperative Agreement Administered through the Association of Teachers of Preventive Medicine, protocol 33029
PI: Steven J. Kittner, MD
Dates: 09/30/00-09/29/04
Specific aims: To examine the environmental and genetic determinants of inflammatory markers; genotype 200 inflammatory genes; relate inflammatory markers and genes to CVD and incident hypertension.

Name of grants: Genetics of Early-Onset Stroke
Agency number: NIH, 5 RO1 NS045012-05
PI: Steven J. Kittner, MD
Dates: 07/01/08-06/30/11
Specific aims: The major goal of this project is to: 1) perform a case-control study of stroke in young men 2) to identify novel sequence variants in the thrombomodulin, endothelial protein receptor, and plasminogen activator inhibitor-1 genes and 3) to examine the relationships of these variants, both singly and jointly, with stroke susceptibility to early onset stroke and related phenotypes in Caucasian and African American men.

Name of grants: Genetic Risk to Stroke in Smokers and Non-smokers
Agency number: NIH, 5 U01 HG004436
PI: Braxton D. Mitchell, PhD
Dates: 07/01/03-06/30/10
Specific aims: The goal of this project is to identify genes associated with young onset stroke and to determine how the effects of these genes are modified by smoking.

• Primary Phenotype: Stroke

• Principal Investigator
  • Braxton D. Mitchell, PhD. University of Maryland, Baltimore, MD, USA.
• Co-Investigator
  • Steven J. Kittner, MD. University of Maryland, Baltimore, MD, USA.
• Funding Source
  • U01HG004436. National Institutes of Health, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for Genotyping
  • U01HG004438-01. NIH GEI grant "JH/CIDR Genotyping for Genome-Wide Association Studies". National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.