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Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Sabater-Lleal, M; Huffman, JE; de Vries, PS; Marten, J; Mastrangelo, MA; Song, C; Pankratz, N; Ward-Caviness, CK; Yanek, LR; Trompet, S; et al. Sabater-Lleal, M; Huffman, JE; de Vries, PS; Marten, J; Mastrangelo, MA; Song, C; Pankratz, N; Ward-Caviness, CK; Yanek, LR; Trompet, S; Delgado, G; Guo, X; Bartz, TM; Martinez-Perez, A; Germain, M; de Haan, HG; Ozel, AB; Polasek, O; Smith, AV; Eicher, JD; Reiner, AP; Tang, W; Davies, NM; Stott, DJ; Rotter, JI; Tofler, GH; Boerwinkle, E; de Maat, MPM; Kleber, ME; Welsh, P; Brody, JA; Chen, M-H; Vaidya, D; Soria, JM; Suchon, P; van Hylckama Vlieg, A; Desch, KC; Kolcic, I; Joshi, PK; Launer, LJ; Harris, TB; Campbell, H; Rudan, I; Becker, DM; Li, JZ; Rivadeneira, F; Uitterlinden, AG; Hofman, A; Franco, OH; Cushman, M; Psaty, BM; Morange, P-E; McKnight, B; Chong, MR; Fernandez-Cadenas, I; Rosand, J; Lindgren, A; Gudnason, V; Wilson, JW; Hayward, C; Ginsburg, D; Fornage, M; Rosendaal, FR; Souto, JC; Becker, LC; Jenny, NS; März, W; Jukema, JW; Dehghan, A; Trégounët, D-A; Morrison, AC; Johnson, AD; O'Donnell, CJ; Strachan, DP; Lowenstein, CJ; Smith, NL; INVENT Consortium, ; MEGASTROKE consortium of the International Stroke Genetics Corpo, (2019) Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. Circulation, 139 (5). pp. 620-635. ISSN 0009-7322 https://doi.org/10.1161/CIRCULATIONAHA.118.034532
SGUL Authors: Strachan, David Peter

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Abstract

Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. Methods: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. Results: We identified 13 novel genome-wide significant (p≤2.5x10-8) associations; 7 with FVIII levels (FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels (PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA, beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Item Type: Article
Additional Information: This is a non-final version of an article published in final form in Sabater-Lleal, M; Huffman, JE; de Vries, PS; Marten, J; Mastrangelo, MA; Song, C; Pankratz, N; Ward-Caviness, C; Yanek, LR; Trompet, S; et al. (2018) Genome-wide association trans-ethnic meta-analyses identifies novel associations regulating coagulation Factor VIII and von Willebrand Factor plasma levels. Circulation. 2018;139:620–635
SGUL Research Institute / Research Centre: Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: Circulation
ISSN: 0009-7322
Dates:
DateEvent
January 2019Published
20 November 2018Published Online
21 September 2018Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
G0000934Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
068545/Z/02Wellcome Trusthttp://dx.doi.org/10.13039/100004440
076113/B/04/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
079895Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MC_UU_12013/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_12013/9Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
URI: http://openaccess.sgul.ac.uk/id/eprint/110163
Publisher's version: https://doi.org/10.1161/CIRCULATIONAHA.118.034532

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