Abstract 2380: A Genome Wide Scan Supports Linkage of Collagen-Induced Platelet Aggregation Following Aspirin Therapy to the D15S1005 Locus
Resistance to the platelet inhibitory effect of low dose aspirin (ASA) has been proposed as a mechanism for recurrent coronary artery disease (CAD) events onserved in patients taking ASA. The response of platelets to ASA varies among individuals, and genetic variation has been proposed as a possible mechanism in aspirin responsiveness. To determine whether a genetic locus might be linked to platelet measures of possible aspirin resistance, we measured ex vivo aggregation of platelets to collagen, 5 μg/ml, in platelet rich plasma, at baseline and following ASA, 81 mg/day for 14 days, in 1584 apparently healthy relatives from 418 families with premature CAD. This particular platelet phenotype has been shown to be highly heritable in the Framingham Heart Study. A 550 short tandem repeat (STR) marker genome-wide scan was performed on all subjects. We looked for linkage using the classical Haseman-Elston regression in 602 full sibling and 129 half sibling pairs from this population, using the program SIB-PAIR. This analysis revealed a significant linkage peak on chromosome 15 marker D15S1005 (LOD=3.2 at 86.487922 cM; genome-wide p=0.0001) for the post-ASA platelet phenotype. No significant linkage peaks were observed for collagen-induced aggregation at baseline. The gene BCL2A1 known to be up-regulated by CD40, an aggregation-induced signal is in close proximity to this marker. This suggests that this linkage peak occurs in a region that is of putative importance in aspirin resistance. Fine mapping of this locus will be needed to identify the specific gene(s) responsible for variations in collagen-induced platelet aggregation following ASA.