Abstract 9543: Targeted Deep Resequencing Identifies Coding Variants in The PEAR1 Gene That Play a Role in Platelet Aggregation in Individuals at High Risk for Coronary Artery Disease

Abstract

Background: The Genetic Study of Aspirin Responsiveness (GeneSTAR) is a family-based study, designed to examine genetic determinants of platelet aggregation in African American (AA) and European American (EA) healthy subjects with a family history of CAD. Platelet aggregation is heritable, and a previous genomewide association study (GWAS) detected strong association with a common genetic variant in intron 1 of the platelet endothelial aggregation receptor1 (PEAR1) gene in AA and EA GeneSTAR subjects. To build upon these results, we exploited a sequencing approach to identify additional functional genetic variants in PEAR1 that may also play a role in platelet aggregation. Methods: 104 subjects (45% male, age = 52.34±13.27) were selected based on the hyper and hypo aggregation across three different platelet agonists (Collagen, Epinephrine, and ADP). A 0.3Mb target including PEAR1 was Sanger sequenced at deCODE Genetics. Variants were annotated for function and novelty. Single-variant tests for association (variant presence/absence vs. hyper/hypo aggregation) were performed using Fisher's Exact Test. Collapsed multi-variant tests for association were performed using the Combined Multivariate Collapsing and the Weighted Sum methods. For these tests, variants were collapsed based on: 1) minor allele frequency (MAF) and 2) predicted function. Results: 235 variants were identified, and 104 were novel. Sixteen missense variants were observed, ten of which were novel. More rare variants (MAF < 5%) were noted in AAs compared to EAs (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in the AA sample (p=7.9E-5); no association was seen for additional exonic variants. However, collapsed multi-variant tests suggest that exonic variants play a more significant role in the EA sample (p = 0.01 for the collapsed coding variants compared to p = 0.05 for rs12041331). Conclusions: Genetic variants in the PEAR1 are determinants of an individual's platelet aggregation response. We confirm that a common intronic variant has the strongest association in African Americans, and show that additional exonic variants play a role in platelet aggregation, particularly in European Americans.