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

TitleA genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.
Publication TypeJournal Article
Year of Publication2019
Authorsde Vries, PS, Sabater-Lleal, M, Huffman, JE, Marten, J, Song, C, Pankratz, N, Bartz, TM, de Haan, HG, Delgado, GE, Eicher, JD, Martinez-Perez, A, Ward-Caviness, CK, Brody, JA, Chen, M-H, de Maat, MPM, Frånberg, M, Gill, D, Kleber, ME, Rivadeneira, F, Soria, JManuel, Tang, W, Tofler, GH, Uitterlinden, AG, Vlieg, Avan Hylcka, Seshadri, S, Boerwinkle, E, Davies, NM, Giese, A-K, M Ikram, K, Kittner, SJ, McKnight, B, Psaty, BM, Reiner, AP, Sargurupremraj, M, Taylor, KD, Fornage, M, Hamsten, A, Marz, W, Rosendaal, FR, Souto, JCarlos, Dehghan, A, Johnson, AD, Morrison, AC, O'Donnell, CJ, Smith, NL
Corporate AuthorsINVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium
JournalBlood
Volume133
Issue9
Pagination967-977
Date Published2019 02 28
ISSN1528-0020
KeywordsBrain Ischemia, Cohort Studies, Coronary Artery Disease, Factor VII, Female, Follow-Up Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Membrane Transport Proteins, Mendelian Randomization Analysis, Middle Aged, Neoplasm Proteins, Phenotype, Polymorphism, Single Nucleotide, Prognosis, Stroke, Venous Thromboembolism
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 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 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 -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA 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 (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 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 in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

DOI10.1182/blood-2018-05-849240
Alternate JournalBlood
PubMed ID30642921
PubMed Central IDPMC6396174
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MC_UU_12013/1 / MRC_ / Medical Research Council / United Kingdom
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MC_UU_12013/9 / MRC_ / Medical Research Council / United Kingdom
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