TY - JOUR
T1 - A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology
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.
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019
Y1 - 2019
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067244341&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067244341&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-05-849240
DO - 10.1182/blood-2018-05-849240
M3 - Article
C2 - 30642921
AN - SCOPUS:85067244341
SN - 0006-4971
VL - 133
SP - 967
EP - 977
JO - Blood
JF - Blood
IS - 9
ER -