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Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.

Marine Germain 1 Daniel I Chasman 2 Hugoline de Haan 3 Weihong Tang 4 Sara Lindström 5 Lu-Chen Weng 4 Mariza de Andrade 6 Marieke C H de Visser 7 Kerri L Wiggins 8 Pierre Suchon 9, 10 Noémie Saut 9, 10 David M Smadja 11, 12, 13 Grégoire Le Gal 14, 15, 16 Astrid van Hylckama Vlieg 3 Antonio Di Narzo 17 Ke Hao 17 Christopher P Nelson 18, 19 Ares Rocanin-Arjo 1 Lasse Folkersen 20 Ramin Monajemi 21 Lynda M Rose 22 Jennifer A Brody 23 Eline Slagboom 24 Dylan Aïssi 1 France Gagnon 25 Jean-François Deleuze 26 Panos Deloukas 27, 28 Christophe Tzourio 29 Jean-Francois Dartigues 29 Claudine Berr 30 Kent D Taylor 31 Mete Civelek 32 Per Eriksson 33 Bruce M Psaty 34, 23 Jeanine Houwing-Duitermaat 21 Alison H Goodall 19, 18 François Cambien 1 Peter Kraft 5 Philippe Amouyel 35, 36 Nilesh J Samani 19, 37 Saonli Basu 38 Paul M Ridker 2 Frits R Rosendaal 3 Christopher Kabrhel 39 Aaron R Folsom 4 John Heit 40 Pieter H Reitsma 7 David-Alexandre Trégouët 1 Nicholas L Smith 41, 34, 8 Pierre-Emmanuel Morange 42, 10 
Abstract : Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.
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Submitted on : Thursday, January 21, 2016 - 12:04:40 PM
Last modification on : Tuesday, November 22, 2022 - 2:26:16 PM

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Marine Germain, Daniel I Chasman, Hugoline de Haan, Weihong Tang, Sara Lindström, et al.. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.. American Journal of Human Genetics, 2015, 96 (4), pp.532-42. ⟨10.1016/j.ajhg.2015.01.019⟩. ⟨hal-01259946⟩



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