Cooperative effect of GNB3 825C>T and GPIIIa PI(A) polymorphisms in enhanced platelet aggregation

Abstract

Introduction: Platelet aggregation contributes to various thrombembolic disorders. Environmental factors affect platelet aggregability but only partially explain the interindividual variability in aggregation. While the platelet glycoprotein IIb/IIIa is involved in the pathogenesis of acute coronary syndromes whereas most platelet activating stimuli act via G Protein coupled receptors we investigated whether the 825C>T polymorphism of the gene GNB3 encoding the G protein beta3 subunit together with the platelet glycoprotein (GP) IIIa Pl(A) polymorphism are predictive of platelet aggregability on stimulation with various agonists acting via GPCRs.

Materials and methods: Platelet aggregation was measured by turbidometry in 150 non-smoking individuals aged 18-40 years at a density of 2 x 10(5) platelets/microl with various agonists according to the method of Born. Genotypes of the GNB3 825C>T and glycoprotein IIb/IIIa PI(A) polymorphisms were determined using Pyrosequencing technology and restriction analysis. All functional studies were completed within 3 h. The data were analysed by Student's t-test for paired data.

Results: Low concentrations of agonists resulted in enhanced platelet aggregation in subjects with the GNB3 CC-genotype compared to carriers of a 825T-allele. This effect was further enhanced in carriers of the GPIIIa Pl(A2) allele (2 microM ADP: 42% vs. 19%, p=0.017; 1 microM U-46619: 51% vs. 30%, p=0.03; 5 microM epinephrine: 69% vs. 53%, p=0.025). No significant pattern of aggregation was observed on stratification by GPIIIa genotypes alone.

Conclusions: Our findings indicate that two genetic markers contribute synergistically to increased platelet aggregation. This will help to identify patients at increased risk for thrombosis.