A Meta-Analysis of Genome-Wide Association Studies Identifies a Novel Locus Associated with Thrombin Generation Potential. A. Rocañín-Arjó1, L. Carcaillon2, W. Cohen3, N. Saut3, M. Germain1, L. Letenneur4, M. Alhenc-Gelas5, A. M. Dupuy6, M. Bertrand7, P. Amouyel8, P. Y. Scarabin2, D. A. Trégouët1, P. E. Morange3 1) INSERM UMR_S 937; ICAN Institute, Université Pierre et Marie Curie, Paris, Paris, France; 2) Inserm, U1018, Universit e Paris Sud 11, Villejuif, France Villejuif, France; 3) INSERM, UMR_S 626, Marseille, France; Université de la Méditerranée, Marseille, France; 4) INSERM, U897, Bordeaux, France; Université Victor Segalen, Bordeaux, France; 5) Assistance Publique des Hopitaux de Paris, Laboratoire d'hématologie, Hôpital Européen Georges Pompidou, Paris, France; 6) INSERM U888, Hôpital La Colombière, Montpellier, France; 7) INSERM UMR_S 708, Université Pierre et Marie Curie (UPMC, Paris 6), Paris, France; 8) INSERM U744, Lille, France; Institut Pasteur de Lille, Lille, France Université de Lille Nord de France, CHRU de Lille, Lille, France.

   High thrombin generation levels have been associated with the risk of venous thrombosis and ischemic stroke. In order to investigate the genetic architecture underlying the inter-individual variability of thrombin generation, we measured three quantitative biomarkers for thrombin generation, the Endogeneous Thrombin Potential (ETP), the Peak height and the Lag-time in two independent samples, the Three City Study and MARTHA, with genome-wide genotype data. By applying an imputation strategy based on the 1000 Genomes project to these two samples totalling 2,100 individuals inferred for ~6,6M markers, genome-wide significant associations were observed for ETP and Peak at the F2 gene (p = 4.62 10-22 and p = 1.05 10-8, respectively), a well-established susceptibility locus for thrombin generation. Further conditional analysis on the F2 signal revealed suggestive evidence (p 10-6) at 6 additional independent single nucleotide polymorphisms (SNPs) for at least one of the three phenotypes. These 6 SNPs were tested for replication in a third independent sample of 796 individuals part of the MARTHA12 study. For one SNP located on chromosome 9, the association with Lag-time was highly significant (p = 3.26 10-7). We further replicated this association (p = 4.8 10-3) in another independent sample of 530 healthy patients from the FITE-NAT study. When the results of the four data sets were combined, the overall evidence for association at the chr. 9 locus with Lag-time reached p = 1.71 10-14. This locus has never been reported associated to thrombin generation, paving the way for novel mechanistic pathways in the aetiology of thrombotic disorders.

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