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Thromb Haemost 2015; 114(02): 245-257
DOI: 10.1160/TH14-12-1043
Coagulation and Fibrinolysis
Schattauer GmbH

Genetic determinants of tissue factor pathway inhibitor plasma levels

Jessica Dennis
1   Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
,
Irfahan Kassam
1   Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
,
Pierre-Emmanuel Morange
2   Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1062, Marseille, France
3   Inra, UMR_INRA 1260, Marseille, France
4   Aix Marseille Université, Marseille, France
,
David-Alexandre Trégouët
5   Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, Paris, France
6   Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular DiseasesParis, France
7   Institute for Cardiometabolism and Nutrition (ICAN), Paris, France
,
France Gagnon
1   Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
› Author Affiliations Financial support: This work was supported by the Canadian Institutes of Health Research (Grant MOP 86466) and by the Heart and Stroke Foundation of Canada (Grant T6484). JD is a Vanier Canada Graduate Scholar and Fellow in the Canadian Institutes of Health Research Strategic Training for Advanced Genetic Epidemiology (CIHR STAGE) program. FG holds a Canada Research Chair.
Further Information

Publication History

Received: 15 December 2014

Accepted after minor revision: 24 February 2015

Publication Date:
21 November 2017 (online)

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Summary

Tissue factor pathway inhibitor (TFPI) impedes early stages of the blood coagulation response, and low TFPI plasma levels increase the risk of thrombosis. TFPI plasma levels are heritable, but specific genetic determinants are unclear. We conducted a comprehensive review of genetic risk factors for TFPI plasma levels and identified 26 studies. We included 16 studies, as well as results from two unpublished genome-wide studies, in random effects meta-analyses of four commonly reported genetic variants in TFPI and its promoter (rs5940, rs7586970/rs8176592, rs10931292, and rs10153820) and 10 studies were summarised narratively. rs5940 was associated with all measures of TFPI (free, total, and activity), and rs7586970 was associated with total TFPI. Neither rs10931292 nor rs10153820 showed evidence of association. The narrative summary included 6 genes and genetic variants (P151L mutation in TFPI, PROS1, F5, APOE, GLA, and V617F mutation in JAK2) as well as a genome-wide linkage study, and suggested future research directions. A limitation of the systematic review was the heterogeneous measurement of TFPI. Nonetheless, our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are candidate risk factors for thrombosis, and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene.

Keywords

Coagulation - genetic - systematic review - meta-analysis - tissue factor pathway inhibitor

 

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