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Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.
Friday,2015-04-17 13:49 America/Los_Angeles — zdrager
| Title | Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Germain, M, Chasman, DI, de Haan, H, Tang, W, Lindström, S, Weng, L-C, de Andrade, M, de Visser, MCH, Wiggins, KL, Suchon, P, Saut, N, Smadja, DM, Le Gal, G, Vlieg, Avan Hylcka, Di Narzo, A, Hao, K, Nelson, CP, Rocanin-Arjo, A, Folkersen, L, Monajemi, R, Rose, LM, Brody, JA, Slagboom, E, Aïssi, D, Gagnon, F, Deleuze, J-F, Deloukas, P, Tzourio, C, Dartigues, J-F, Berr, C, Taylor, KD, Civelek, M, Eriksson, P, Psaty, BM, Houwing-Duitermaat, J, Goodall, AH, Cambien, F, Kraft, P, Amouyel, P, Samani, NJ, Basu, S, Ridker, PM, Rosendaal, FR, Kabrhel, C, Folsom, AR, Heit, J, Reitsma, PH, Trégouët, D-A, Smith, NL, Morange, P-E |
| Corporate/Institutional Authors | Cardiogenics consortium, |
| Journal | Am J Hum Genet |
| Volume | 96 |
| Issue | 4 |
| Pagination | 532-42 |
| Date Published | 2015 Apr 2 |
| ISSN | 1537-6605 |
| Keywords | Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Membrane Glycoproteins, Membrane Transport Proteins, Odds Ratio, Tetraspanins, Venous Thromboembolism |
| Abstract | <p>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.</p> |
| DOI | 10.1016/j.ajhg.2015.01.019 |
| Alternate Journal | Am. J. Hum. Genet. |
| PubMed ID | 25772935 |
| PubMed Central ID | PMC4385184 |
| Grant List | P30 DK063491 / DK / NIDDK NIH HHS / United States R01 HL043201 / HL / NHLBI NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States R01 HL060739 / HB / NHLBI NIH HHS / United States R01 HL068639 / HL / NHLBI NIH HHS / United States R01 HL068986 / HL / NHLBI NIH HHS / United States R01 HL073410 / HL / NHLBI NIH HHS / United States R01 HL074745 / HL / NHLBI NIH HHS / United States R01 HL085251 / HL / NHLBI NIH HHS / United States R01 HL095080 / HL / NHLBI NIH HHS / United States R01 HL116854 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States UM1 CA182913 / CA / NCI NIH HHS / United States / / Canadian Institutes of Health Research / Canada |