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

INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium

Research output: Contribution to journalArticle

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 metaanalysis 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 trans-ancestry metaanalysis. 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 F7 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 (REEP3 and JAZF1-AS1) 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 REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Original languageEnglish (US)
Pages (from-to)967-977
Number of pages11
JournalBlood
Volume133
Issue number9
DOIs
StatePublished - Jan 1 2019

Fingerprint

Factor VII
Genome-Wide Association Study
Genes
Stroke
Mendelian Randomization Analysis
Meta-Analysis
Antigens
Genetic Loci
Venous Thromboembolism
Gene Silencing
Coagulation
Liver
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium (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

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. / INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium.

In: Blood, Vol. 133, No. 9, 01.01.2019, p. 967-977.

Research output: Contribution to journalArticle

INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium 2019, 'A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology', Blood, vol. 133, no. 9, pp. 967-977. https://doi.org/10.1182/blood-2018-05-849240
INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium. A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. Blood. 2019 Jan 1;133(9):967-977. https://doi.org/10.1182/blood-2018-05-849240
INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium. / A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. In: Blood. 2019 ; Vol. 133, No. 9. pp. 967-977.
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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 metaanalysis 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 trans-ancestry metaanalysis. 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 F7 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 (REEP3 and JAZF1-AS1) 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 REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.",
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AU - INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium

AU - De Vries, Paul S.

AU - Sabater-Lleal, Maria

AU - Huffman, Jennifer E.

AU - Marten, Jonathan

AU - Song, Ci

AU - Pankratz, Nathan

AU - Bartz, Traci M.

AU - De Haan, Hugoline G.

AU - Delgado, Graciela E.

AU - Eicher, John D.

AU - Martinez-Perez, Angel

AU - Ward-Caviness, Cavin K.

AU - Brody, Jennifer A.

AU - Chen, Ming Huei

AU - De Maat, Moniek P.M.

AU - Frånberg, Mattias

AU - Gill, DIpender

AU - Kleber, Marcus E.

AU - Rivadeneira, Fernando

AU - Soria, José Manuel

AU - Tang, Weihong

AU - Tofler, Geoffrey H.

AU - Uitterlinden, André G.

AU - Van Hylckama Vlieg, Astrid

AU - Seshadri, Sudha

AU - Boerwinkle, Eric

AU - Davies, Neil M.

AU - Giese, Anne Katrin

AU - Ikram, M. Kamran

AU - Kittner, Steven J.

AU - McKnight, Barbara

AU - Psaty, Bruce M.

AU - Reiner, Alex P.

AU - Sargurupremraj, Muralidharan

AU - Taylor, Kent D.

AU - Smith, Nicholas L.

AU - Fornage, Myriam

AU - Hamsten, Anders

AU - März, Winfried

AU - Rosendaal, Frits R.

AU - Souto, Juan Carlos

AU - Dehghan, Abbas

AU - Johnson, Andrew D.

AU - Morrison, Alanna C.

AU - O'Donnell, Christopher J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 metaanalysis 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 trans-ancestry metaanalysis. 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 F7 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 (REEP3 and JAZF1-AS1) 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 REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

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