A genome-wide association study identifies KNG1 as a genetic determinant of plasma factor XI level and activated partial thromboplastin time

Maria Sabater-Lleal, Angel Martinez-Perez, Alfonso Buil, Lasse Folkersen, Juan Carlos Souto, Maria Bruzelius, Montserrat Borrell, Jacob Odeberg, Angela Silveira, Per Eriksson, Laura Almasy, Anders Hamsten, José Manuel Soria

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Objective-Elevated plasma levels of coagulation factor XI (FXI) are implicated in the pathogenesis of venous thromboembolism and ischemic stroke, and polymorphisms in the F11 gene are associated both with risk of venous thromboembolism and an elevated plasma FXI level. Methods and Results-Here, we report the first hypothesis-free genome-wide genetic analysis of plasma FXI levels. Two genome-wide significant loci were detected in the family-based Genetic Analysis of Idiopathic Thrombophilia 1 cohort: one located in the kininogen 1 gene (KNG1) (rs710446; P=7.98×10) and one located in the structural F11 gene (rs4241824; P=1.16×10). Both associations were replicated in a second population-based Swedish cohort. A significant effect on KNG1 mRNA expression was also seen for the 2 most robustly FXI-associated single nucleotide polymorphisms located in KNG1. Furthermore, both KNG1 single nucleotide polymorphisms were associated with activated partial thromboplastin time, suggesting that FXI may be the main mechanistic pathway by which KNG1 and F11 influence activated partial thromboplastin time and risk of thrombosis. Conclusion-These findings contribute to the emerging molecular basis of venous thromboembolism and, more importantly, help in understanding the biological regulation of a phenotype that has proved to have promising therapeutic properties in relation to thrombosis.

Original languageEnglish (US)
Pages (from-to)2008-2016
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • activated partial thromboplastin time
  • factor XI
  • genome-wide associations
  • kininogen
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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