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


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 trans-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 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.

SUBMITTER: de Vries PS 

PROVIDER: S-EPMC6396174 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

de Vries Paul S PS   Sabater-Lleal Maria M   Huffman Jennifer E JE   Marten Jonathan J   Song Ci C   Pankratz Nathan N   Bartz Traci M TM   de Haan Hugoline G HG   Delgado Graciela E GE   Eicher John D JD   Martinez-Perez Angel A   Ward-Caviness Cavin K CK   Brody Jennifer A JA   Chen Ming-Huei MH   de Maat Moniek P M MPM   Frånberg Mattias M   Gill Dipender D   Kleber Marcus E ME   Rivadeneira Fernando F   Soria José Manuel JM   Tang Weihong W   Tofler Geoffrey H GH   Uitterlinden André G AG   van Hylckama Vlieg Astrid A   Seshadri Sudha S   Boerwinkle Eric E   Davies Neil M NM   Giese Anne-Katrin AK   Ikram M Kamran MK   Kittner Steven J SJ   McKnight Barbara B   Psaty Bruce M BM   Reiner Alex P AP   Sargurupremraj Muralidharan M   Taylor Kent D KD   Fornage Myriam M   Hamsten Anders A   März Winfried W   Rosendaal Frits R FR   Souto Juan Carlos JC   Dehghan Abbas A   Johnson Andrew D AD   Morrison Alanna C AC   O'Donnell Christopher J CJ   Smith Nicholas L NL  

Blood 20190114 9


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 combin  ...[more]

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