title: Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.
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.
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, 75013 Paris, France; Institute for Cardiometabolism and Nutrition (ICAN), 75013 Paris, France.
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authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
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authors.affiliation: Department of Thrombosis and Hemostasis, Department of Clinical Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
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authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.
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authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
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authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.
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authors.affiliation: Laboratory of Haematology, La Timone Hospital, 13385 Marseille, France; INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, 13385 Marseille, France; Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, UMR_S 1062, 13385 Marseille, France.
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authors.affiliation: Laboratory of Haematology, La Timone Hospital, 13385 Marseille, France; INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, 13385 Marseille, France; Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, UMR_S 1062, 13385 Marseille, France.
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authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; AP-HP, Hopital Européen Georges Pompidou, Service d'Hématologie Biologique, 75015 Paris, France; Faculté de Pharmacie, INSERM, UMR_S 1140, 75006 Paris, France.
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authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
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authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, 75013 Paris, France; Institute for Cardiometabolism and Nutrition (ICAN), 75013 Paris, France.
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authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, 75013 Paris, France; Institute for Cardiometabolism and Nutrition (ICAN), 75013 Paris, France.
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authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Panos
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authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, 75013 Paris, France; Institute for Cardiometabolism and Nutrition (ICAN), 75013 Paris, France.
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authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, 75013 Paris, France; Institute for Cardiometabolism and Nutrition (ICAN), 75013 Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
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authors.forename: Nicholas L
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authors.affiliation: Laboratory of Haematology, La Timone Hospital, 13385 Marseille, France; INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, 13385 Marseille, France; Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, UMR_S 1062, 13385 Marseille, France. Electronic address: pierre.morange@ap-hm.fr.
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mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D016017:Odds Ratio; D059470:Tetraspanins / Q000235:genetics*; D054556:Venous Thromboembolism / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C484524:SLC44A2 protein, human; C556850:TSPAN15 protein, human; D059470:Tetraspanins