Abstract Number: PB1013
Meeting: ISTH 2021 Congress
Background: Summary statistics from large genome-wide association studies (GWAS) are used to derive polygenic risk scores (PRS) which combine multiple associated DNA variants’ (SNPs) effects to assess individuals’ genetic predisposition to diseases. Platelets are contributors to CVD pathogenesis and are effective drug targets. Thus, an individual’s genetic propensity to developing CVD may be mediated through effects on platelets.
Aims: We analyzed the association of PRS for multiple CVDs and platelet reactivity traits via five distinct assays.
Methods: PRS for coronary artery disease (CAD), stroke, atrial fibrillation (AF), and venous thromboembolism (VTE) were derived from the largest GWAS. Platelet reactivity traits were measured across multiple agonists in the Framingham Heart Study (N=3,065) using light transmission aggregometry (LTA), Multiplate whole blood impedence aggregometry (MP), Total-Thrombus Formation Assay System (T-TAS), Optimul 96-well plate assay, and flow cytometry (FC). We used linear mixed effects models to test association between each PRS and platelet traits, after adjustment for age, sex and aspirin use.
Results: The strongest positive associations were found between VTE PRS and T-TAS:AUC (P=8.2E-05), MP:collagen AUC (P=1.8E-03), MP:ristocetin AUC (P=1.8E-03), and LTA:ristocetin slope (P=4.5E-07), respectively. A majority of VTE PRS SNPs had congruent effects for these traits with alleles increasing platelet reactivity also increasing VTE risk. Multiple loci were implicated including ABO, GP6, F5, F11 and 4 others. CAD, AF, and stroke PRS had positive associations with ADP-induced platelet activation in whole blood and PRP FC assays (PAC-1, CD63, CD62P).
Conclusions: ADP activation associating with arterial disease PRS is consistent with ADP inhibition being efficacious in CVD prevention. Strong associations with different platelet assays and VTE PRS suggests distinct platelet-contributing genes in this disorder. Given an expanding set of anti-platelet drugs (e.g., GP6, GP1b, PAR4 inhibitors) in development, targeting to specific CVD indications might be improved based on the platelet pathways implicated by our results.
To cite this abstract in AMA style:Grech J, Chan M, Lachapelle A, Thibord F, Schneider Z, Armstrong P, Wallace de Melendez C, Warner T, Chen M-, Johnson A. Common Cardiovascular Disease Polygenic Risk Scores for Arterial and Venous Disease Influence Different Platelet Reactivity Tests [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/common-cardiovascular-disease-polygenic-risk-scores-for-arterial-and-venous-disease-influence-different-platelet-reactivity-tests/. Accessed December 6, 2023.
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