TY - JOUR
T1 - Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism
AU - Germain, Marine
AU - Chasman, Daniel I.
AU - De Haan, Hugoline
AU - Tang, Weihong
AU - Lindström, Sara
AU - Weng, Lu Chen
AU - De Andrade, Mariza
AU - De Visser, Marieke C H
AU - Wiggins, Kerri L.
AU - Suchon, Pierre
AU - Saut, Noémie
AU - Smadja, David M.
AU - Le Gal, Grégoire
AU - Van Hylckama Vlieg, Astrid
AU - Di Narzo, Antonio
AU - Hao, Ke
AU - Nelson, Christopher P.
AU - Rocanin-Arjo, Ares
AU - Folkersen, Lasse
AU - Monajemi, Ramin
AU - Rose, Lynda M.
AU - Brody, Jennifer A.
AU - Slagboom, Eline
AU - Aïssi, Dylan
AU - Gagnon, France
AU - Deleuze, Jean Francois
AU - Deloukas, Panos
AU - Tzourio, Christophe
AU - Dartigues, Jean Francois
AU - Berr, Claudine
AU - Taylor, Kent D.
AU - Civelek, Mete
AU - Eriksson, Per
AU - Psaty, Bruce M.
AU - Houwing-Duitermaat, Jeanine
AU - Goodall, Alison H.
AU - Cambien, François
AU - Kraft, Peter
AU - Amouyel, Philippe
AU - Samani, Nilesh J.
AU - Basu, Saonli
AU - Ridker, Paul M.
AU - Rosendaal, Frits R.
AU - Kabrhel, Christopher
AU - Folsom, Aaron R.
AU - Heit, John
AU - Reitsma, Pieter H.
AU - Trégouët, David Alexandre
AU - Smith, Nicholas L.
AU - Morange, Pierre Emmanuel
N1 - Publisher Copyright:
© 2015 The American Society of Human Genetics.
PY - 2015/4/2
Y1 - 2015/4/2
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2015.01.019
DO - 10.1016/j.ajhg.2015.01.019
M3 - Article
C2 - 25772935
AN - SCOPUS:84926245873
SN - 0002-9297
VL - 96
SP - 532
EP - 542
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -