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

Blood. 2019 Feb 28;133(9):967-977. doi: 10.1182/blood-2018-05-849240. Epub 2019 Jan 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Ischemia / etiology*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Cohort Studies
  • Coronary Artery Disease / etiology
  • Coronary Artery Disease / metabolism
  • Coronary Artery Disease / pathology
  • Factor VII / genetics*
  • Factor VII / metabolism
  • Female
  • Follow-Up Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Mendelian Randomization Analysis
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Stroke / etiology*
  • Stroke / metabolism
  • Stroke / pathology
  • Venous Thromboembolism / etiology
  • Venous Thromboembolism / metabolism
  • Venous Thromboembolism / pathology

Substances

  • JAZF1 protein, human
  • Membrane Transport Proteins
  • Neoplasm Proteins
  • REEP3 protein, human
  • Factor VII

Grant support