A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology

Paul S de Vries, Maria Sabater-Lleal, Jennifer E Huffman, Jonathan Marten, Ci Song, Nathan Pankratz, Traci M Bartz, Hugoline G de Haan, Graciela E Delgado, John D Eicher, Angel Martinez-Perez, Cavin K Ward-Caviness, Jennifer A Brody, Ming-Huei Chen, Moniek P M de Maat, Mattias Frånberg, Dipender Gill, Marcus E Kleber, Fernando Rivadeneira, José Manuel SoriaWeihong Tang, Geoffrey H Tofler, André G Uitterlinden, Astrid van Hylckama Vlieg, Sudha Seshadri, Eric Boerwinkle, Neil M Davies, Anne-Katrin Giese, M Kamran Ikram, Steven J Kittner, Barbara McKnight, Bruce M Psaty, Alex P Reiner, Muralidharan Sargurupremraj, Kent D Taylor, Myriam Fornage, Anders Hamsten, Winfried März, Frits R Rosendaal, Juan Carlos Souto, Abbas Dehghan, Andrew D Johnson, Alanna C Morrison, Christopher J O'Donnell, Nicholas L Smith

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Abstract

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of nine genome-wide association studies of plasma FVII levels (seven FVII activity and two FVII antigen) among 27,495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the seven studies that measured FVII activity, and a secondary analysis included all nine studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using siRNA and then measuring F7 mRNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke, and venous thromboembolism. We identified two novel (REEP3 and JAZF1-AS1) and six known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, while silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of ischemic stroke. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of ischemic stroke in the general population.

Original languageEnglish
Pages (from-to)967-977
Number of pages10
JournalBlood
Volume133
Issue number9
Early online date28 Feb 2019
DOIs
Publication statusE-pub ahead of print - 28 Feb 2019

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    de Vries, P. S., Sabater-Lleal, M., Huffman, J. E., Marten, J., Song, C., Pankratz, N., Bartz, T. M., de Haan, H. G., Delgado, G. E., Eicher, J. D., Martinez-Perez, A., Ward-Caviness, C. K., Brody, J. A., Chen, M-H., de Maat, M. P. M., Frånberg, M., Gill, D., Kleber, M. E., Rivadeneira, F., ... Smith, N. L. (2019). A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. Blood, 133(9), 967-977. https://doi.org/10.1182/blood-2018-05-849240