Abstract 1440: Platelet Response to Aspirin is Under Polygenic Control of Variants in the VAV3 and Phospholipase C Gamma 2 (PLCG2) Genes
Background: VAV3 (a guanine nucleotide exchange factor) and PLCG2 (phospholipase Cγ2) participate in platelet activation via outside-in signaling mediated by integrin receptor αIIbβ3. VAV3 plays a crucial role in regulating PLCG2 activity. However, the effect of genetic variants in these genes on platelet function and response to aspirin (ASA) has not been reported.
Methods: We measured platelet aggregation in platelet rich plasma to adenosine diphosphate (ADP, 2μM), both at baseline and after 2 weeks of ASA, 81 mg/day in 1848 apparently healthy family members of people with premature coronary artery disease (CAD); mean age was 44±13; 59% were women, and 42% were African American. Single nucleotide polymorphisms (SNPs) were selected to optimize coverage of the gene at a 4 kb density and were genotyped using the Illumina platform (122 SNPs for VAV3 and 56 for PLCG2). The ASA response phenotype was expressed as post-ASA aggregation adjusted for baseline aggregation. Phenotype-genotype associations were examined by race, using the Likelihood Ratio test in SAGE, which accounts for family structure.
Results: Variants in VAV3 and PLCG2 were associated with the magnitude of inhibition of platelet aggregation after aspirin treatment in both races (Table⇓). In addition, the effects of rs6697852 (VAV3) and rs4889443 (PLCG2) on response to aspirin were additive in Whites. For a total of 2– 4 minor alleles between the 2 genes, aggregation averaged 2.29±14.6 % (n=57), while for 0–1 alleles aggregation was significantly higher (11.58±13.19 %, n=1006, p= 3.356E-7, linear regression).
Conclusion: Novel variants in VAV3 and PLCG2 are associated with the inhibitory effect of ASA on platelet aggregation and the effect of these variants appear to be additive in Whites.