Low dose aspirin (ASA) is cost effective and efficacious for the prevention and treatment of coronary heart disease (CHD). The benefit of ASA is thought to be related to the irreversible acetylation of platelet cyclo-oxygenase-1 (COX-1), resulting in a reduction in platelet aggregation and platelet-mediated inflammation. Considerable inter-individual variation exists in the effect of ASA on platelet function, and this variability may be related to genetic variations across individuals. This study will characterize the inhibitory effect of ASA on agonist-induced platelet aggregation, thromboxane and ATP release, aggregation under shear conditions, and surface expression of P-selectin and CD40 ligand in 3200 subjects from 400 multi-generational families, half African American and half white. Participants will be high-risk siblings of patients with premature CHD (previously identified in the Johns Hopkins Sibling Study), along with their adult offspring. Platelet function and plasma inflammatory markers (C-reactive protein, interleukin-1 Beta, interleukin-6, monocyte chemotactic protein-1, and matrix metalloproteinase-9) will be measured at baseline and after 14 days of ASA, 81 mg/day, to characterize ASA-response phenotypes. From a list of candidate genes involved in the known biochemical pathways of platelet aggregation and platelet-mediated inflammation, 20 genes will be initially selected for genotyping of 15-20 single nucleotide polymorphisms (SNPs) per gene, based on biological importnace and the presence of sufficient known SNPs in coding and/or regulatory regions. After the first 1600 participants have been phenotyped, a complementary genome wide scan of short tandem repeat (STR) markers and fine mapping of up to 5 regions of interest will be done using SNP clusters. Based on linkage analysis, the list of candidate genes will be re-prioritized and additional genotyping will be performed. Analyses will be performed to determine whether ASA responsiveness is heritable and whether it is associated with specific variations in candidate genes or defined haplotypes. The results should lead to a better understanding of the variability among individuals in ASA responsiveness, including possible racial differences, and should enable genotype tailoring of preventive therapy for CHD in high-risk individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL072518-02
Application #
6667261
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Hasan, Ahmed AK
Project Start
2002-09-30
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$3,980,607
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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