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

Sabater-Lleal, Maria; Huffman, Jennifer E; de Vries, Paul S; Marten, Jonathan; Mastrangelo, Michael A; Song, Ci; Pankratz, Nathan; Ward-Caviness, Cavin K; Yanek, Lisa R; Trompet, Stella; Delgado, Graciela E; Guo, Xiuqing; Bartz, Traci M; Martinez-Perez, Angel; Germain, Marine; de Haan, Hugoline G; Ozel, Ayse B; Polasek, Ozren; Smith, Albert V; Eicher, John D; ... (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. Lippincott Williams & Wilkins 10.1161/CIRCULATIONAHA.118.034532

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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 ≈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 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≤2.5×10) 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. Mendelian randomization 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:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)

UniBE Contributor:

Franco Duran, Oscar Horacio

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services

ISSN:

0009-7322

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Beatrice Minder Wyssmann

Date Deposited:

04 Mar 2019 14:00

Last Modified:

21 Nov 2019 02:30

Publisher DOI:

10.1161/CIRCULATIONAHA.118.034532

PubMed ID:

30586737

Uncontrolled Keywords:

cardiovascular diseases factor VIII genetics genome-wide association studies risk factors von Willebrand factor

BORIS DOI:

10.7892/boris.127374

URI:

https://boris.unibe.ch/id/eprint/127374

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