Meta-Analysis

. 2015 Apr 2;96(4):532-42.

doi: 10.1016/j.ajhg.2015.01.019. Epub 2015 Mar 12.

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

Marine Germain¹, Daniel I Chasman², Hugoline de Haan³, Weihong Tang⁴, Sara Lindström⁵, Lu-Chen Weng⁴, Mariza de Andrade⁶, Marieke C H de Visser⁷, Kerri L Wiggins⁸, Pierre Suchon⁹, Noémie Saut⁹, David M Smadja¹⁰, Grégoire Le Gal¹¹, Astrid van Hylckama Vlieg³, Antonio Di Narzo¹², Ke Hao¹², Christopher P Nelson¹³, Ares Rocanin-Arjo¹, Lasse Folkersen¹⁴, Ramin Monajemi¹⁵, Lynda M Rose¹⁶, Jennifer A Brody¹⁷, Eline Slagboom¹⁸, Dylan Aïssi¹, France Gagnon¹⁹, Jean-Francois Deleuze²⁰, Panos Deloukas²¹, Christophe Tzourio²², Jean-Francois Dartigues²², Claudine Berr²³, Kent D Taylor²⁴, Mete Civelek²⁵, Per Eriksson²⁶; Cardiogenics Consortium; Bruce M Psaty²⁷, Jeanine Houwing-Duitermaat¹⁵, Alison H Goodall¹³, François Cambien¹, Peter Kraft⁵, Philippe Amouyel²⁸, Nilesh J Samani¹³, Saonli Basu²⁹, Paul M Ridker², Frits R Rosendaal³, Christopher Kabrhel³⁰, Aaron R Folsom⁴, John Heit³¹, Pieter H Reitsma⁷, David-Alexandre Trégouët¹, Nicholas L Smith³², Pierre-Emmanuel Morange³³

Affiliations

¹ 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.
² Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
³ Department of Thrombosis and Hemostasis, Department of Clinical Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁴ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.
⁵ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
⁶ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
⁷ Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
⁸ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁹ 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.
¹⁰ 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.
¹¹ Université de Brest, EA3878 and CIC1412, 29238 Brest, France; Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON K1Y 4E9, Canada.
¹² Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
¹³ Department of Cardiovascular Sciences, University of Leicester, LE1 7RH Leicester, UK; National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester LE3 9QP, UK.
¹⁴ Department of PharmacoGenetics, Novo Nordisk Park 9.1.21, 2400 Copenhagen, Denmark.
¹⁵ Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
¹⁶ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98195-5852, USA.
¹⁸ Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
¹⁹ Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
²⁰ Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Génomique, Centre National de Génotypage, 91057 Evry, France.
²¹ 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.
²² Inserm Research Center U897, University of Bordeaux, 33000 Bordeaux, France.
²³ Inserm Research Unit U1061, University of Montpellier I, 34000 Montpellier, France.
²⁴ Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrence, CA 90502, USA.
²⁵ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁶ Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
²⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98195-5852, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
²⁸ Institut Pasteur de Lille, Université de Lille Nord de France, INSERM UMR_S 744, 59000 Lille, France; Centre Hospitalier Régional Universitaire de Lille, 59000 Lille, France.
²⁹ Division of Biostatistics, University of Minnesota, Minneapolis, MN 55455, USA.
³⁰ Department of Emergency Medicine, Massachusetts General Hospital, Channing Network Medicine, Harvard Medical School, Boston, MA 2114, USA.
³¹ Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
³² Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA; Seattle Epidemiologic Research and Information Center, VA Office of Research and Development, Seattle, WA 98108, USA. Electronic address: nlsmith@u.washington.edu.
³³ 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.

PMID: 25772935
PMCID: PMC4385184
DOI: 10.1016/j.ajhg.2015.01.019

Meta-Analysis

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

Marine Germain et al. Am J Hum Genet. 2015.

. 2015 Apr 2;96(4):532-42.

doi: 10.1016/j.ajhg.2015.01.019. Epub 2015 Mar 12.

Authors

Affiliations

¹ 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.
² Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
³ Department of Thrombosis and Hemostasis, Department of Clinical Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁴ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.
⁵ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
⁶ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
⁷ Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
⁸ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁹ 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.
¹⁰ 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.
¹¹ Université de Brest, EA3878 and CIC1412, 29238 Brest, France; Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON K1Y 4E9, Canada.
¹² Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
¹³ Department of Cardiovascular Sciences, University of Leicester, LE1 7RH Leicester, UK; National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester LE3 9QP, UK.
¹⁴ Department of PharmacoGenetics, Novo Nordisk Park 9.1.21, 2400 Copenhagen, Denmark.
¹⁵ Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
¹⁶ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98195-5852, USA.
¹⁸ Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
¹⁹ Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
²⁰ Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Génomique, Centre National de Génotypage, 91057 Evry, France.
²¹ 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.
²² Inserm Research Center U897, University of Bordeaux, 33000 Bordeaux, France.
²³ Inserm Research Unit U1061, University of Montpellier I, 34000 Montpellier, France.
²⁴ Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrence, CA 90502, USA.
²⁵ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁶ Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
²⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98195-5852, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
²⁸ Institut Pasteur de Lille, Université de Lille Nord de France, INSERM UMR_S 744, 59000 Lille, France; Centre Hospitalier Régional Universitaire de Lille, 59000 Lille, France.
²⁹ Division of Biostatistics, University of Minnesota, Minneapolis, MN 55455, USA.
³⁰ Department of Emergency Medicine, Massachusetts General Hospital, Channing Network Medicine, Harvard Medical School, Boston, MA 2114, USA.
³¹ Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
³² Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA; Seattle Epidemiologic Research and Information Center, VA Office of Research and Development, Seattle, WA 98108, USA. Electronic address: nlsmith@u.washington.edu.
³³ 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.

PMID: 25772935
PMCID: PMC4385184
DOI: 10.1016/j.ajhg.2015.01.019

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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Figures

**Figure 1**
Regional Association Plot at the *TSPAN15* Locus Association results were derived from the meta-analysis of 12 GWASs (top) that were further conditioned on the effect of *TSPAN15* rs7870713 (bottom). SNPs are colored according to their pairwise LD r² with the lead rs7870713. r² was estimated from 1000 Genomes (Mar 2012 Eur) database.

**Figure 2**
Regional Association Plot at the *SLC44A2* Locus Association results were derived from the meta-analysis of 12 GWASs (top) that were further conditioned on the effect of *SLC44A2* rs2288904 (bottom). SNPs are colored according to their pairwise LD r² with the lead rs2288904. r² was estimated from 1000 Genomes (Mar 2012 Eur) database.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous