The Secondary Prevention of Small Subcortical Strokes (SPS3) clinical trial aims to define efficacious approaches for therapeutic prevention of stroke recurrence and cognitive decline in patients with symptomatic small subcortical stroke (S3). The 2x2 factorial design trial randomly allocates S3 patients to aspirin plus clopidogrel versus aspirin alone;and to usual (SBP 130-149 mmHg) vs. aggressive (SBP <130 mmHg) blood pressure control. The primary outcome is recurrent stroke and the trial is projected to close in spring 2012. This is a time-sensitive substudy proposal to SPS3 for genetic sample collection, to be used for testing pharmacogenomic and genomic hypotheses. Recent studies of clopidogrel-treated patients with heart disease have shown poorer outcomes in those with the loss of function CYP2C19*2 allele, a finding explained by the inability of these individuals to convert clopidogrel to its active metabolite. We hypothesize that similar decrements in clopidogrel efficacy will be observed in S3 patients.
Specific Aim 1. Build an SPS3 genetics database and determine if CYP2C19*2 carriers treated with clopidogrel have higher rates of recurrent stroke than clopidogrel-treated individuals with the CYP2C19*1*1 genotype. Ongoing research also points to additional genetic variants that may influence efficacy of clopidogrel, aspirin, and antihypertensive drugs and SPS3 represents an excellent dataset for more broadly advancing our understanding of these genetic determinants.
Specific Aim 2. Determine if genetic loci previously associated with pharmacologic response to antiplatelet or antihypertensive medications are associated with recurrent stroke in a treatment specific manner in SPS3 participants. A genetic cohort in SPS3 also represents an excellent opportunity for advancing stroke genomics, since SPS3 is among the largest collections of S3 cases in the world.
Specific Aim 3. Conduct a genome wide association study (GWAS) in SPS3 along with a GWAS meta-analysis to detect novel SNPs associated with small subcortical stroke. Additionally we will determine if subcortical stroke- associated SNPs are associated with recurrent stroke in S3 patients. We will partner with the NINDS-supported Ischemic Stroke Genetics Consortium to conduct Aim 3 studies and to insure that SPS3 genomics data advance the stroke genomics field to the full extent possible. In summary, we propose to build an SPS3 DNA bank to test hypotheses on the influence of CYP2C19 genotype on the SPS3 primary outcome;to advance understanding of the genetic variants important to antiplatelet and antihypertensive drug efficacy;and to discover novel genetic determinants of primary and secondary subcortical stroke.

Public Health Relevance

Small subcortical strokes (S3) are a common stroke subtype and contribute importantly to vascular dementia. The SPS3 trial seeks to define optimal treatment approaches with antiplatelet and antihypertensive medications to prevent recurrent stroke in S3 patients. We will collect genetic samples from SPS3 participants and conduct studies to help define if there are genetic factors that influence responses to antiplatelet and antihypertensive medications. We will also conduct a study to identify genetic variants that increase the risk for subcortical stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073346-02
Application #
8239529
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Moy, Claudia S
Project Start
2011-03-15
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$671,934
Indirect Cost
$82,998
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Johnson, Julie A; Cavallari, Larisa H (2013) Pharmacogenetics and cardiovascular disease--implications for personalized medicine. Pharmacol Rev 65:987-1009
Meschia, James F; Arnett, Donna K; Ay, Hakan et al. (2013) Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes. Stroke 44:2694-702
Johnson, Julie A (2013) Pharmacogenetics in clinical practice: how far have we come and where are we going? Pharmacogenomics 14:835-43
Shahin, Mohamed H A; Johnson, Julie A (2013) Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice? Curr Opin Cardiol 28:305-14
Johnson, J A; Klein, T E; Relling, M V (2013) Clinical implementation of pharmacogenetics: more than one gene at a time. Clin Pharmacol Ther 93:384-5
Johnson, Julie A (2012) Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 125:1964-6
Johnson, J A; Roden, D M; Lesko, L J et al. (2012) Clopidogrel: a case for indication-specific pharmacogenetics. Clin Pharmacol Ther 91:774-6