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Genome-Wide Association Study Identifies a Novel Genetic Risk Factor for Recurrent Venous Thrombosis

Abstract : BACKGROUND Genetic risk factors for a first venous thrombosis (VT) seem to have little effect on recurrence risk. Therefore, we aimed specifically to identify novel genetic determinants of recurrent VT. To date, genome-wide association studies are lacking. METHODS AND RESULTS We performed a genome-wide association scan in 1279 patients from the MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) follow-up study; 832 patients who remained recurrence free during a median follow-up time of 6.1 years and 447 recurrent VT patients with a median time-to-recurrence of 2.6 years. We analyzed genotype probabilities of approximate to 8.6 million variants, imputed to the Genome of the Netherlands project reference panel, with a minor allele frequency >= 1% for an association with recurrent VT. One region exceeded genome-wide significance (P <= 5 x 10(-8)), mapping to the well-known factor V Leiden locus. Conditional association analyses on factor V Leiden did not yield any secondary association signals. We also identified 52 suggestive association signals (P < 1 x 10(-5)) at 17 additional loci. None of these loci were previously implicated in VT risk. Replication analyses for 17 lead variants were performed in 350 patients with recurrent VT and 1866 patients with a single VT event from the MEGA follow-up study, THE-VTE (Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism) study, and LETS (Leiden Thrombophilia Study). We observed an association with recurrence for an intergenic variant at 18q22.1 with an odds ratio of 1.7 (95% confidence interval, 1.2-2.6) per copy of the minor allele. CONCLUSIONS We confirmed the association of factor V Leiden and identified a novel risk locus at 18q22.1 in the first large genetic study on recurrent VT.
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https://hal-cea.archives-ouvertes.fr/cea-02291349
Contributor : Marianne Leriche <>
Submitted on : Wednesday, September 18, 2019 - 4:21:05 PM
Last modification on : Tuesday, September 1, 2020 - 3:21:38 AM

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Hugoline G. de Haan, Astrid van Hylckama Vlieg, Marine Germain, Trevor P. Baglin, Jean-François Deleuze, et al.. Genome-Wide Association Study Identifies a Novel Genetic Risk Factor for Recurrent Venous Thrombosis. Circulation-Genomic and Precision Medicine, 2018, 11 (2), pp.e001827. ⟨10.1161/CIRCGEN.117.001827⟩. ⟨cea-02291349⟩

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