Increased platelet aggregability associated with platelet GPIII alpha Pl(A2) polymorphism - The Framingham Offspring Study

The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in pl atelet aggregation. Recent data suggest that the Pl(A2) polymorphism of GPI IIa may be associated with an increased risk for cardiovascular disease. Ho wever, it is unknown if there is any association between this polymorphism and platelet reactivity. We determined GP IIIa genotype and platelet reacti vity phenotype data in 1422 subjects from the Framingham Offspring Study. G enotyping was performed using PCR-based restriction fragment length polymor phism analysis. Platelet aggregability was evaluated by the Born method. Th e threshold concentrations of epinephrine and ADP were determined. Allele f requencies of Pl(A1) and Pl(A2) were 0.84 and 0.16, respectively. The prese nce of 1 or 2 Pl(A2) alleles was associated with increased platelet aggrega bility as indicated by incrementally lower threshold concentrations for epi nephrine and ADP. For epinephrine, the mean concentrations were 0.9 mu mol/ L (0.9 to 1.0) for homozygous Pl(A1), 0.7 mmol/L (0.7 to 0.9) for the heter ozygous Pl(A1)/Pl(A2), and 0.6 mu mol/L (0.4 to 1.0) for homozygous Pl(A2) individuals, P=0.009. The increase in aggregability induced by epinephrine remained highly significant (P=0.007) after adjustment for covariates. For ADP-induced aggregation, the respective mean concentrations were 3.1 mu mol /L (3.0 to 3.2), 3.0 mu mol/L (2.9 to 3.2), and 2.8 mu mol/L (2.4 to 3.3); P=0.19 after adjustment for covariates. Our findings indicate that molecula r variants of the gene encoding GP IIIa play a role in platelet reactivity in vitro. Our observations are compatible with and provide an explanation f or the reported association of the Pl(A2) allotype with increased risk for cardiovascular disease.