Abstract P392: Exome Sequencing From Extreme Responders to Aspirin Identifies a Novel Variant Associated With Platelet Aggregation
Platelet dysregulation is integral in the formation of thrombi, and abnormal thrombus formation may ultimately lead to myocardial infarctions or stroke. Thus platelets, and more specifically platelet activation and aggregation pathways, are prime targets for intervention. Aspirin or Dual Anti-Platelet Therapy with Aspirin and Clopidogrel (DAPT) is often prescribed for primary and secondary prevention of cardiovascular events, however, these treatments often fail to significantly reduce thrombi formation in a large percentage of patients. Recent studies indicate that platelet aggregation response is highly heritable. To identify novel variants that may have a significant impact on platelet aggregation, we conducted whole exome sequencing and follow-up DNA genotyping on a cohort of Old Order Amish subjects with well tracked family histories and platelet response phenotypes. 30 individuals from the extremes of collagen-mediated platelet aggregation response to aspirin were analyzed to identify variants enriched in the high or low responders. One of the top hits in this analysis was rs17834991, a synonymous variant in the SVIL gene enriched in the high aspirin response group that has not previously been associated with platelet aggregation. The SVIL gene encodes two proteins: a muscle-specific isoform, Archvillin, as well as a ubiquitous form, Supervillin, that is expressed in platelets. In a previous study, mutations in SVIL were found to be associated with inhibition of platelet aggregation under shear stress conditions.
To follow up our initial findings, we genotyped rs17834991 in 851 healthy Amish individuals with platelet aggregation measured before and after a two-week 81mg/day Aspirin intervention from our HAPI dataset. An additional 661 Amish subjects with platelet aggregation measured before and after 1 week of Clopidogrel treatment, and following one 81mg dose of Aspirin plus Clopidogrel from our PAPI cohort were genotyped. We then conducted a multivariable linear regression controlling for age, sex, BMI, and two known effectors of platelet aggregation: CYP2C19*2 and rs12041331. Our findings indicate that rs17834991 is significantly associated with change in collagen-mediated aggregation with aspirin in whole blood (p=4.8x10-4), as well as lag time until maximum aggregation with collagen post aspirin (1.6x10-3) in whole blood. Additional associations were identified with collagen mediated aggregation in PRP, the strongest being change in lag time in post DAPT vs post Clopidogrel-alone samples (6.59x10-5). These findings suggest that SVIL variant rs17834991 significantly alters platelet response following Aspirin and DAPT treatment. Taken with previous findings, SVIL may not only play a role in platelet function but may also impact anti-platelet intervention. Further studies are warranted to elucidate its potential impact on cardiovascular disease.
Author Disclosures: J. Backman: None. B. Ning: None. W. Lou: None. J. Perry: None. L. Shi: None. A. Shuldiner: A. Employment; Significant; Regeneron Pharmaceuticals, Inc. L. Yerges-Armstrong: B. Research Grant; Significant; NIH K01 HL116770.
- © 2015 by American Heart Association, Inc.